s-1-(combination) and Colorectal-Neoplasms

This study aimed to compare the efficacy and safety of S-1 and capecitabine in patients with metastatic colorectal carcinoma (mCRC).. Eligible prospective clinical trials were searched and available data were extracted. Odds ratio and hazard ratio of available outcomes including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were pooled for analysis.. A total of 6 studies including 828 patients were included. The results of pooled analysis showed no statistical difference in short-term efficacy including ORR (95% confidence interval [CI]: 0.68-1.19; P = .48) or DCR (95% CI: 0.65-1.29; P = .61), or long-term efficacy including PFS (95% CI: 0.75-1.08; P = .26) or OS (95% CI: 0.78-1.13; P = .50). Symptoms of diarrhea at any grade were more prevalent (95% CI: 1.21-2.29; P = .002) in patients treated with S-1, while hand-foot syndrome (HFS) at any grade (95% CI: 0.24-0.48; P < .0001) or high grade (95% CI: 0.09-0.48; P < .0001) was more frequent in capecitabine group. AEs including leucopenia, neutropenia, anemia, thrombocytopenia, vomiting, oral mucositis, stomatitis, elevated alanine transaminase, or peripheral neuropathy showed no statistical difference between S-1 and capecitabine group (all P > .05).. This meta-analysis reveals that S-1 has comparable efficacy, lower risk of HFS and higher incidence of diarrhea compared to capecitabine for treatment in patients with mCRC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Humans; Neoplasm Metastasis; Oxonic Acid; Proportional Hazards Models; Randomized Controlled Trials as Topic; Survival Analysis; Tegafur

S-1 is an oral fluoropyrimidine that consists of tegafur, 5-chloro-2, 4-dihydroxypyridine and potassium oxonate. It has been developed as a prodrug of 5-fluorouracil with the goal of improving therapeutic efficacy and tolerability.. This review aims to provide an evidence-based update of clinical trials that have investigated the clinical efficacy, adverse-event profile, dosage and administration of S-1, given alone or in combination with conventional chemotherapeutics and new target-oriented drugs, in the management of colorectal cancer (CRC). Additionally, differences in the tolerability and pharmacokinetics of S-1 between Caucasians and Asians have been described. Finally, the therapeutic efficacy of S-1 regarding metastatic CRC or postoperative CRC has been discussed. Available data have stimulated further research, including Phase III trials for the treatment of advanced CRC.. Treatment using S-1 combined with oxaliplatin (± bevacizumab) and irinotecan has achieved promising results in terms of feasibility, safety and effectiveness. Furthermore, S-1 is an acceptable treatment as adjuvant chemotherapy for colon cancer.

Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Chemotherapy, Adjuvant; Colon; Colorectal Neoplasms; Drug Combinations; Humans; Irinotecan; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Rectum; Tegafur

A combination of irinotecan (CPT-11) with continuous intravenous infusions of (infusional) 5-fluorouracil (5-FU) and Leucovorin (LV) is one of the standard treatments for advanced colorectal cancer patients. However, recent concerns about safety and convenience have prompted the development of new oral fluoropyrimidine derivatives and improved regimens. TS-1, the oral fluoropyrimidine widely used in the treatment for gastric cancer, was approved for advanced colorectal cancer. Recently, several phase I/II studies assessed the efficacy and safety of combined treatment with TS-1 plus CPT-11 in patients with advanced colorectal cancer. These results showed that TS-1 plus CPT-11 was very effective. Toxicity was generally mild and manageable on an outpatient basis. Current evidence showed that a combination of CPT-11 plus TS-1 was more convenient and easier to administer than a combination of CPT-11 plus infusional 5-FU and LV. It is essential to prove that the combination of TS-1 plus CPT-11 can replace the combination of infusional 5-FU and LV plus CPT-11 without negatively affecting efficacy and toxicity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Evidence-Based Medicine; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Recurrence, Local; Oxonic Acid; Survival Rate; Tegafur

Chemotherapy for colorectal cancer is now improving rapidly due to new drugs like oxaliplatin and molecular targeting drugs. The key drug, however, is still 5-fluorouracil (5-FU). S-1 is an oral 5-FU anti-tumor drug that combines three pharmacological agents: tegafur, 5-chloro-2,4-dihydroxypyridine, which inhibits dihydropyrimidine dehydrogenase activity, and potassium oxonate, which reduces gastrointestinal toxicity. The results of the phase II study suggested that S-1 as a single agent was active against metastatic colorectal cancer: CR rate was 36-40% and MST was about one-year. Toxicity was all tolerable. Clinical trials of S-1 with oxaliplatin or CPT-11 combination chemotherapy are ongoing in Japan. S-1 with molecular targeting drugs will also be studied. Therefore, S-1 is expected to play an important part in chemotherapy for colorectal cancer.

Topics: Administration, Oral; Anorexia; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Fluorouracil; Humans; Irinotecan; Leukopenia; Neutropenia; Oxonic Acid; Survival Rate; Tegafur

A combination therapy of irinotecan hydrochloride (CPT-11) with continuous intravenous infusions of (infusional) 5-fluorouracil (5-FU) and Leucovorin (LV) is often used to treat advanced colorectal cancer. However, recent concerns on safety and convenience have prompted the development of new oral fluoropyrimidine derivatives which improved regimens. Yamada et al conducted a phase I study to assess the maximum tolerated dose and recommended dose of S-1 combined with CPT-11. The study recommended that 150 mg/m2 of CPT-11 be given on day 1 and 80 mg/m2 of S-1 daily on days 1 to 14 every 3 weeks. Recently, several phase I/II studies assessed the efficacy and safety of the combined therapy with S-1 and CPT-11 in patients with advanced colorectal cancer. Some of the studies which were ongoing assessed a tri-weekly schedule regimen. Our results showed that S-1 plus CPT-11 was very effective, with a response rate of 63% and PFS of 8 months. Toxicity was generally mild and manageable on an outpatient basis. The current evidence showed that a combination of S-1 and CPT-11 was more convenient and easier to administer than a combination of CPT-11 plus infusional 5-FU and LV. It will be essential to prove that the combination of S-1 plus CPT-11 can replace the combination of infusional 5-FU and LV plus CPT-11 without negatively affecting efficacy and toxicity.

Topics: Adult; Aged; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Female; Humans; Irinotecan; Leukopenia; Male; Middle Aged; Neutropenia; Oxonic Acid; Remission Induction; Survival Rate; Tegafur

Hepatic arterial infusion chemotherapy (HAIC) for liver metastases from digestive cancer has passed through a long history. In spite of its significant high tumor reduction rate, this therapeutic modality has been rejected as the first-line therapy for liver metastases from colorectal cancer because of the negative results of RCTs compared to systemic chemotherapy. However, recently some excellent results have been reported by the combination with systemic chemotherapy,and a positive result of RCT using a satisfactory study design has been reported. Thus, the combination with systemic chemotherapy and RCT in comparison with modern standard systemic chemotherapy as the first-line therapy remains an important problem to be solved. On the other hand, the highly-developed technology for HAIC using techniques of interventional radiology has been standardized in Japan. Thus, we now have become the closest in the world to performing good-quality clinical trials of HAIC supported by high-quality technology. We should therefore consider our very important role in resolving such problems and deciding the future of HAIC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cisplatin; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Hepatic Artery; Humans; Infusions, Intra-Arterial; Irinotecan; Liver Neoplasms; Oxonic Acid; Tegafur

We performed surgical resections in 6 cases of advanced gastric cancer and 4 cases of colorectal cancer after preoperatively treating them with TS-1 at a daily dose of 80-100 mg/body for 2 weeks, and evaluated whether one can estimate their sensitivity to TS-1 by a pathological examination. Case 1 of type 3 advanced gastric cancer underwent surgery after one week interval following oral administration of TS-1 at a daily dose of 80 mg/body for 2 weeks. Surprisingly, the pathological examination revealed complete disappearance of cancer cells in the resected stomach and no cancer cells in the regional lymphnodes, judged grade 3 in pathological effectiveness. Case 2 of type 2 advanced gastric cancer was treated with TS-1 at a daily dose of 100 mg/body for 2 weeks and underwent surgery after a three-week interval due to the complication of pneumonia. The pathological effectiveness was judged grade 2 in the resected stomach, and no cancer cells were detected in the regional lymphnodes. In both cases, the postoperative course was uneventful, and no adverse effects were detected. In these cases, their high sensitivity to TS-1 was clearly confirmed, and now they have been treated with TS-1 for the postoperative adjuvant chemotherapy, and have undergone regular check-ups at our outpatient clinic in good condition. Recently, we performed the same protocol in 6 cases of advanced gastric cancer including these 2 cases and also in 4 cases of advanced colorectal cancer. This protocol was found useful for evaluating the pathological effect by TS-1. We consider the protocol quite useful and helpful in determining a suitable regimen for postoperative adjuvant chemotherapy.

Topics: Adenocarcinoma; Aged; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Female; Gastrectomy; Humans; Infant; Middle Aged; Oxonic Acid; Pilot Projects; Pyridines; Stomach Neoplasms; Tegafur

Since its synthesis over 40 years ago, several studies including patients with colorectal cancer have shown that prolonged exposure to 5-fluorouracil (5-FU) is associated with better antitumor activity and decreased toxicity. However, the use of continuous-infusion 5-FU is costly and is associated with the need for a catheter and infusion pump. The use of an oral formulation of 5-FU allows protracted exposure without the inconvenience and cost of intravenous continuous-infusion regimens. Capecitabine is a rationally designed fluoropyrimidine that can be given orally and uses the high concentration of thymidine phosphorylase within cancer cells to concentrate heavily within the tumor. Two large randomized studies that included patients with metastatic colorectal cancer have shown superior response rates for capecitabine compared with bolus regimens of 5-FU with equal times to progression, overall survival, and duration of response. Because of its favorable toxicity profile and the efficacy shown in early trials, capecitabine is currently being investigated in the adjuvant setting and in combination with radiotherapy and with other chemotherapy agents.

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Capecitabine; Clinical Trials as Topic; Colorectal Neoplasms; Deoxycytidine; Drug Combinations; Fluorouracil; Humans; Oxonic Acid; Prodrugs; Pyridines; Tegafur; Uracil

Until recently, few chemotherapy options were available to treat metastatic colorectalcancer. For years, the standard chemotherapy has been a Fluorouracil (5-FU) alone of 5-FU with leucovorin (LV) modulation. The newer cytotoxic drugs irinotecan (CPT-11) and oxaliplatin (L-OHP) has generated further improvement in survival. Additionally, improvement in convenience of drug administration has been achieved with the development of oral fluoropynmidines. In randomized trials, oral fluoropyrimidines were equally effective to bolus 5-FU and LV. Recently completed or ongoing clinical trials to study novel targeting agents have initiated a new generation of drug development such as angiogenesis inhibitors and epidermal growth factor inhibitors. Randomized trials will determine the impact of these newer agents on survival and quality of life.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Pyridines; Tegafur

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Clinical Trials as Topic; Colorectal Neoplasms; Deoxycytidine; Drug Combinations; Fluorouracil; Humans; Infusions, Intravenous; Oxonic Acid; Prognosis; Pyridines; Tegafur; Thymidylate Synthase; Uracil

Topics: Administration, Oral; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Cetuximab; Clinical Trials as Topic; Colorectal Neoplasms; Deoxycytidine; Drug Combinations; Evidence-Based Medicine; Fluorouracil; Humans; Irinotecan; Japan; Leucovorin; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Prognosis; Pyridines; Tegafur; United States; Uracil

5-Fluorouracil (5-FU) has been utilized as part of standard chemotherapy for treatment of early-stage and metastatic colorectal cancer for more than 4 decades. The oral fluoropyrimidines have been studied extensively as an alternative to intravenous 5-FU. The goal of such an approach is to simplify drug administration and to improve the toxicity profile while maintaining efficacy that is at least equivalent to intravenous therapy. The goal of this article is to review the features of the main oral 5-FU prodrugs, which include capecitabine, uracil and tegafur (UFT)/leucovorin, S-1, and BOF-A2 and to describe their potential efficacy in treating colorectal cancer.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Clinical Trials as Topic; Colorectal Neoplasms; Cost-Benefit Analysis; Deoxycytidine; Drug Combinations; Fluorouracil; Humans; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Patient Compliance; Prodrugs; Pyridines; Tegafur; Treatment Outcome

We describe in this paper a therapeutic modality which is based on a self-rescuing concept (SRC) featuring dual activity, i.e., effect-enhancing activity and adverse reaction-reducing activity. We present the theory and practice of S-1, a novel oral fluoropyrimidine anticancer agent designed to enhance anticancer activity and reduce gastrointestinal toxicity through the deliberate combination of the following components: an oral fluoropyrimidine agent, tegafur (FT); a DPD inhibitor (CDHP: 5-chloro-2, 4-dihydroxypyridine) which is about 200-fold more potent than uracil used in UFT; and an ORTC inhibitor (Oxo: potassium oxonate) which is localized in the gastrointestinal tract. We devised a novel oral anticancer agent, S-1, as a combination drug with a molar ratio of 1:0.4:1 for FT, CDHP, and Oxo, respectively. To compare S-1, FT, and UFT in terms of their anticancer activity and adverse reactions, a colon cancer implantation model in rats was used for 4-week consecutive oral administration from the time when the postimplantation tumor weight become about 2 g. The tumor disappeared on day 16 at a given dose of S-1 (as 22.5 mg/kg FT), and the tumor did not reappear for at least three months. Antitumor activity was more marked with S-1 than FT and UFT. Adverse reaction, i.e., stomatitis, depilation, and weight loss, were less frequent in the S-1 group than in the other groups. A clinical pharmacology study examined blood concentrations of 5-FU after twice-a-day administration after meals of S-1 at a dose of 40 mg/m2. Blood concentrations of 5-FU were 60 to 200 ng/ml in all twelve patients examined. Late phase II clinical trials of S-1 were conducted in patients with advanced and recurrent stomach cancers, in the same regimen as for the clinical pharmacology study. It basically consisted in four cycles, each of which comprised 4-week, twice-a-day, consecutive oral administration with a 2-week withdrawal. The overall response rate was 44.6% (45/101). Median survival time (MST) was 224 days. S-1 was given manufacturing approval by the Ministry of Health and Welfare of Japan after a priority review, with indications for advanced and recurrent stomach cancers. A late phase II clinical study of S-1 in patients with advanced/recurrent head and neck cancer was conducted in 59 eligible patients. Objective responses were 4 complete response (CR) and 13 partial response (PR), for a response rate of 28.8% (17/59). MST was 344 days. Grade 4 hemoglobin decrease was observe

Topics: Administration, Oral; Animals; Antimetabolites, Antineoplastic; Clinical Trials as Topic; Colorectal Neoplasms; Drug Combinations; Drug Synergism; Head and Neck Neoplasms; Humans; Oxonic Acid; Pyridines; Rats; Stomach Neoplasms; Tegafur

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Drug Combinations; Fluorouracil; Humans; Leucovorin; Oxonic Acid; Pyridines; Tegafur; Uracil

Among colorectal cancer patients with recurrent or metastatic sites, survival was significantly prolonged for a group undergoing LV/5-FU therapy based on biochemical modulation compared with a group receiving no chemotherapy (best supportive care). LV/5-FU combination therapy is recognized as the standard therapy for colorectal cancer, but recently LV/5-FU plus oxaliplatin and LV/5-FU plus CPT-11 have appeared to be more effective than LV/5-FU in some randomized studies. Capecitabine, UFT/LV and S-1 are new oral drugs that are at least comparable to LV/5-FU in antitumor activity, but superior in tolerability, which benefits the patients' quality of life, especially elderly patients with colorectal cancer. Clinical combination studies using CDDP or CPT-11 with these oral drugs are now being performed. Much is expected of these drugs.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Cisplatin; Clinical Trials as Topic; Colorectal Neoplasms; Deoxycytidine; Drug Administration Schedule; Drug Combinations; Fluorouracil; Humans; Irinotecan; Leucovorin; Oxonic Acid; Pyridines; Tegafur

After nearly four decades of clinical experience with the fluoropyrimidines, 5-fluorouracil (5-FU) remains an integral part of chemotherapy for colorectal cancer. A range of 5-FU treatment regimens with or without biochemical modulation are currently used and toxicity appears to be schedule dependent. The use of oral 5-FU was abandoned because of erratic absorption caused by varying levels of dihydropyrimidine dehydrogenase (DPD) found in the gastrointestinal tract. This effect may be overcome by administering agents that are converted to 5-FU or by inhibiting or inactivating DPD. Xeloda((R)) (capecitabine) was designed as an orally administered, selectively tumoractivated(TM) cytotoxic agent which achieves higher levels of 5-FU in the primary tumor than in plasma or other tissues. The United States Food and Drug Administration (FDA) has approved Xeloda for use in patients with metastatic breast cancer resistant to paclitaxel and in whom further anthracycline therapy is contraindicated. Xeloda is also registered in Canada, Switzerland, Thailand and Argentina. In phase II clinical trials in colorectal cancer, Xeloda produced response rates of 21-24% and median time to disease progression of 127-230 days. Other oral agents in development for the treatment of colorectal cancer include tegafur/uracil plus oral leucovorin, S-1 and eniluracil plus oral 5-FU.

Topics: Administration, Oral; Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents; Breast Neoplasms; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Drug Combinations; Fluorouracil; Humans; Leucovorin; Oxonic Acid; Pyridines; Tegafur; Uracil

Protracted intravenous infusions of fluorouracil (5-FU) in the treatment of colorectal cancer have been associated with a reduction in toxicity and enhanced clinical activity compared with bolus 5-FU schedules. However, these protracted infusions require portable infusion pumps and central venous lines, which are associated with complications of venous thrombosis, infection, and line slippage. An effective oral 5-FU formulation could provide a more convenient protracted treatment method with fewer complications. Because of its inconsistent and erratic absorption, the use of oral 5-FU was abandoned decades ago. The inconsistent absorption of oral 5-FU may be attributed to varying levels of dihydropyrimidine dehydrogenase (DPD) in the gastrointestinal tract. Two methods have been used to circumvent 5-FU's metabolism by DPD in the gastrointestinal tract. First, DPD may be inactivated, allowing for reliable, consistent absorption of 5-FU. Second, 5-FU prodrugs can be administered, being absorbed as intact molecules via the gastrointestinal tract and subsequently converted to 5-FU. The oral fluoropyrimidines discussed here are capable of providing prolonged 5-FU exposure with a reduced incidence of toxicity.

Topics: Animals; Antimetabolites, Antineoplastic; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Enzyme Inhibitors; Fluorouracil; Folic Acid Antagonists; Humans; Leucovorin; Oxidoreductases; Oxonic Acid; Prodrugs; Pyridines; Tegafur; Uracil

The TRICOLORE trial previously demonstrated that S-1 and irinotecan plus bevacizumab was non-inferior, based on progression-free survival (PFS), to 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6)/capecitabine and oxaliplatin (CapeOX) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer (mCRC). Overall survival (OS) data were immature at the time of the primary analysis.. In total, 487 patients from 53 institutions with previously untreated mCRC were randomly assigned (1:1) to receive either mFOLFOX6/CapeOX plus bevacizumab (control group) or S-1 and irinotecan plus bevacizumab (experimental group; 3- or 4-week regimen). The final OS data were analysed from follow-up data collected until 30th September 2017.. With a median follow-up period of 48.7 months, median survival times were 32.6 and 34.3 months (hazard ratio [HR]: 0.89, 95% confidence interval [CI]: 0.72-1.10, P = 0.293) and median PFS durations were 10.8 and 14.0 months in the control and experimental groups, respectively (HR: 0.86, 95% CI: 0.71-1.04, P < 0.0001 for non-inferiority). In patients with left-sided RAS wild-type tumours, median PFS durations were 11.4 and 16.9 months in the control and experimental groups, respectively (HR: 0.68, 95% CI: 0.48-0.96, P = 0.028).. S-1 and irinotecan plus bevacizumab resulted in comparable OS and non-inferior PFS with that of mFOLFOX6/CapeOX plus bevacizumab treatment as first-line chemotherapy for patients with mCRC. We recommend the use of S-1 and irinotecan plus bevacizumab as a standard first-line regimen independent of tumour sidedness or RAS status in mCRC.. UMIN-CTR: 000007834.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Drug Combinations; Female; Fluorouracil; Genes, ras; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Oxonic Acid; Proto-Oncogene Proteins B-raf; Quality of Life; Tegafur

Although chemotherapy for metastatic colorectal cancer (mCRC) has improved, the standard chemotherapy regimens for patients with RAS wild-type mCRC remain debated. This study aimed to compare S-1 and oxaliplatin (SOX) + bevacizumab (B-mab) with SOX + cetuximab (C-mab) in patients with previously untreated recurrent advanced CRC with wild-type KRAS.. This randomized phase II, open-label, multicenter study compared the efficacy and safety of SOX+B-mab with SOX+C-mab in patients with previously untreated advanced CRC with wild-type KRAS. Between February 2012 and October 2016, 45 patients were enrolled.. Overall response rates were 59.1 and 43.5% (p = 0.29) and disease control rates were 90.9 and 91.3% (p = 0.96) in the SOX+B-mab and SOX+C-mab groups, respectively. Median overall survival (OS) was 25.3 and 15.5 months (HR = 0.607, p = 0.167) and median progression-free survival (PFS) were 11.7 and 5.5 months (HR = 0.558, p = 0.077) in the SOX+B-mab and SOX+C-mab groups, respectively. The OS and PFS of patients with early tumor shrinkage (ETS) were not significantly different in the SOX+B-mab group. However, they were significantly better when ETS was ≥20 in the SOX+C-mab group (p = 0.032 and p = 0.003, respectively).. The efficacy and safety of SOX+B-mab and SOX+C-mab for wild-type KRAS recurrent advanced CRC as first-line chemotherapy were almost the same. Consideration of the treatment strategy based on ETS may improve patient prognosis, especially in patients receiving the SOX+C-mab regimen.. UMIN Clinical Trials Registry ( UMIN000006706 ). Date of registration: NOV/11/2011. URL of trial registry record: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000007920.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cetuximab; Colorectal Neoplasms; Drug Combinations; Female; Follow-Up Studies; Humans; Male; Middle Aged; Mutation; Neoplasm Recurrence, Local; Oxaliplatin; Oxonic Acid; Prognosis; Proto-Oncogene Proteins p21(ras); Survival Rate; Tegafur

Fluorouracil and leucovorin combined with oxaliplatin or irinotecan plus bevacizumab (Bmab) or cetuximab (Cmab) are now widely accepted treatment options as first-line or second-line chemotherapy for metastatic colorectal cancer (mCRC). Sequential chemotherapy with oral 5-FU backbone for mCRC without using central venous ports is beneficial for both patients and physicians. We designed the SOBIC trial to validate the effectiveness of the first- and second-line oral combination chemotherapy for mCRC.. From May 2010 through March 2013, 52 patients were enrolled from 47 institutions in the Hyogo Colorectal Cancer Surgery Group. First-line chemotherapy was S-1 + oxaliplatin (SOX) plus Bmab, and second-line chemotherapy after first-line failure was irinotecan + S-1 (IRIS) + Cmab, IRIS + Bmab, or IRIS based on the KRAS status.. The 50 finally included patients received first-line chemotherapy. Second-line therapy was administered to 20 patients (40%): 12 patients received IRIS + Cmab and 8 patients received IRIS + Bmab. The median follow-up period was 48.6 months (range 35-67 months). The median second progression-free survival was 24.2 months (95% confidence interval [CI] 17.7-35.2). The response rate after first- and second-line chemotherapy was 46.7% and 15%, respectively. The median overall survival was 35.2 months (95% CI: 27.8 to not reached). The main grade 3-4 adverse events were sensory neuropathy (18%) and fatigue (10%). There were no treatment-related deaths.. Sequential S-1-based combination regimens including oxaliplatin, irinotecan, Bmab, and Cmab were beneficial for patients with mCRC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cetuximab; Colorectal Neoplasms; Drug Combinations; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Oxonic Acid; Progression-Free Survival; Tegafur; Treatment Outcome

S-1, a new oral fluorouracil chemotherapeutical drug, has been increasingly used in clinical maintenance after first-line chemotherapy for stage III or IV gastric carcinoma (GC) and colorectal carcinoma (CRC) for its own advantages. XiangshaLiujunzi Decoction (XSLJZD), a classic traditional Chinese medicine (TCM) formula with effects of alleviating the adverse reactions of chemotherapy and improving the quality of life of cancer patients has been gradually confirmed, with no more reports about the maintenance therapy mode of combination of chemotherapeutic drugs and TCM. We designed the study of XSLJZD combined with S-1 in the maintenance therapy of Stage III or IV GC and CRC, and hoped that this research program will go further and comprehensively evaluate its efficacy and safety.. The aim of this study was to determine the efficacy and safety of XSLJZD combined with S-1 in the maintenance therapy of stage III or IV GC and CRC.. This study is an open, single-center, randomized study. Patients with stage III or stage IV GC and CRC will be randomized (1:1) into S-1group, S-1 combined with XSLJZD group for 5 years of maintenance therapy. The primary endpoint was progression-free survival, and secondary end point was overall survival and Quality of Life Assessment (QOLA), which include an improvement in symptoms before and after treatment, Karnofsky Performance Status, and adverse events assessment.. This study will provide meaningful clinical information about the combination of chemotherapeutic drugs S-1 with TCM in the maintenance therapy of stage III or IV GC and CRC.. Chinese Clinical Trial Registry: ChiCTR-INR-16008575.

Topics: Colorectal Neoplasms; Drug Combinations; Drugs, Chinese Herbal; Humans; Maintenance Chemotherapy; Neoplasm Staging; Oxonic Acid; Phytotherapy; Randomized Controlled Trials as Topic; Stomach Neoplasms; Tegafur; Treatment Outcome

FOLFIRI plus bevacizumab have been widely used as first-line treatment for metastatic colorectal cancer (mCRC). Pharmacokinetics and pharmacodynamics suggested a low dose of irinotecan given as a long-term infusion is expected to enhance antitumor activity. We conducted a randomized phase II study to compare oral S-1 with a 24-h infusion of irinotecan plus bevacizumab versus FOLFIRI plus bevacizumab.. The subjects comprised 120 chemotherapy-naïve patients with mCRC. The study group received a 24-h infusion of irinotecan at a dose of 125 mg/m2 on days 1 and 15, combined with oral S-1 80 mg/m2 on days 1-14 (24h-SIRI/B). The FOLFIRI/B group received irinotecan at a dose of 150 mg/m2, 5-fluorouracil given at a dose of 400 mg/m2 as a bolus injection and at a dose of 2,400 mg/m2 as a 46-h infusion, and 200 mg/m2 leucovorin on days 1 and 15. Bevacizumab was given at a dose of 5.0 mg/kg on days 1 and 15 in both groups. Treatment was repeated every 4 weeks. The primary endpoint was 1-year progression-free survival (PFS). Secondary endpoints were PFS, response rates (RR), overall survival (OS), and adverse events (AEs).. From December 2013 through January 2018, 120 patients were randomly assigned, 61 patients to the 24h-SIRI/B and 59 patients to the FOLFIRI/B. The median follow-up period was 22.8 months. The 1-year PFS rate was 43.14% in the 24h-SIRI/B arm and 19.15% in the FOLFIRI/B arm (HR = 0.312 [95%CI 0.13-0.78], p = 0.01). The median PFS was 10.2 months (95%CI 8.8-14.3) and 10.0 months (95%CI 7.4-11.0), and the median OS was 29.7 months (95%CI 22.9-43.9) and 28.8 months (95%CI 18.4-ND), respectively (p = 0.3758, p = 0.8234). The overall RR was 86.3 and 61.7%, respectively (p = 0.0053). AEs were similar.. Our results show that the 24h-SIRI/B regimen is an effective and reasonably well-tolerated regimen for the first-line treatment of mCRC.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Oxonic Acid; Progression-Free Survival; Survival Rate; Tegafur; Young Adult

The recommended S-1 dose was 40 mg/m. Daily S-1 plus oral leucovorin administration in a 1-week-on/1-week-off schedule has promising efficacy in gastrointestinal cancer but is associated with high risk of mucositis and diarrhea.. We enrolled 21 patients (3 and 18 patients in levels 1 and 2, respectively). Briefly, 12 and 9 patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0 and 1, respectively, and 8 and 13 patients had 1-3 and ≥4 prior treatment lines, respectively. Dose-limiting toxicity (DLT) was not observed, and level 2 was confirmed as the recommended dose. Common grade 3-4 adverse events at level 2 were anemia (22%), anorexia (6%), and diarrhea (6%). In the entire cohort, response rate, disease control rate, and median progression-free survival were 10%, 71%, and 4.2 months, respectively.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Drug Combinations; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Oxonic Acid; Tegafur; Treatment Outcome

This phase 2 study evaluated the safety and efficacy of perioperative chemotherapy with S-1 plus oxaliplatin (SOX) for stage III colorectal cancer (CRC). Patients with stage III CRC received surgery after neoadjuvant chemotherapy (NAC; SOX 4 cycles) and adjuvant chemotherapy (AC; SOX 4 cycles). The primary endpoints were response rate and safety. We enrolled 30 patients. Their median age was 62 years (range: 43-87 years); 53% were women. They received a median of 4 cycles (range: 1-4) of NAC and a median 4 cycles (range: 0-4) of AC. Five patients interrupted NAC treatment because of toxicity (grade 3 diarrhoea [n = 1], grade 3 ileus [n = 1], and grade 3-4 thrombocytopenia [n = 3]). Patients' responses were complete responses: n = 2 (6.6%), partial responses: n = 21 (70%), stable disease: n = 6 (20.0%), and progressive disease: n = 1 (3.3%; response rate: 73.3%). Curative resection was performed in 29 patients. No patients showed anastomotic leakage. Five-year overall survival and disease-free survival were 83.3% and 76.7%, respectively (median follow-up time: 48 months). NAC using SOX regimen is safe and effective, and may lead to reduced local recurrence and distant metastasis. Long-term outcomes are awaited to evaluate further the efficacy of this strategy (UMIN000006790).

Topics: Adult; Aged; Aged, 80 and over; Chemotherapy, Adjuvant; Colorectal Neoplasms; Drug Combinations; Female; Humans; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Oxaliplatin; Oxonic Acid; Patient Compliance; Perioperative Care; Survival Analysis; Tegafur; Treatment Outcome

The upregulation of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) are important mechanisms of resistance to 5-fluorouracil (5-FU) in metastatic colorectal cancer (mCRC) after long exposure to 5-FU.S-1 (containing a DPD inhibitor) combined with raltitrexed (a TS inhibitor) showed a moderate effect, which needs further study as a third- or later-line therapy in mCRC.. 5-fluorouracil (5-FU) is a fundamental drug in the treatment of metastatic colorectal cancer (mCRC). Patients with mCRC are often exposed to 5-FU and/or its analogues for a long time because of its central role in treatment regimens. The upregulation of dihydropyrimidine dehydrogenase (DPD) and/or thymidylate synthase (TS) are important mechanisms of resistance of 5-FU. To evaluate the efficacy and safety of S-1 (containing a DPD inhibitor) and raltitrexed (a TS inhibitor) for refractory mCRC, a one-center, single-arm, prospective phase II trial was conducted.. Patients who had mCRC that had progressed after treatment with fluoropyrimidine, irinotecan, and oxaliplatin and who had at least one measurable lesion were eligible for this trial. Patients received oral S-1 (80-120 mg for 14 days every 3 weeks) plus an intravenous infusion of raltitrexed (3 mg/m. In total, 46 patients were enrolled. Three patients did not complete the first assessment because of adverse events and unwillingness, leaving tumor response evaluation available in 43 patients. Of 43 evaluable patients, the ORR was 13.9% and disease control rate was 58.1%. In the intention-to-treat population (. S-1 combined with raltitrexed for refractory mCRC showed moderate effect, and it is worthy of further study as third- or later-line therapy in mCRC.

Topics: Adult; Aged; Colorectal Neoplasms; Drug Combinations; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Oxonic Acid; Quinazolines; Tegafur; Thiophenes

The reintroduction of oxaliplatin as a third-or-later-line regimen has been a promising option for patients with metastatic colorectal cancer (mCRC) who previously received chemotherapy including oxaliplatin. In this single-arm phase II study, we evaluated the efficacy of biweekly SOX, which is the combination of oxaliplatin reintroduction and S-1, as a third-or-later-line treatment.. A total of 41 patients from 12 institutes were enrolled. The median PFS and OS survival were 3.3 months (95% confidence interval [CI] 2.7-4.2) and 10.1 months (8.3-14.6), and response rate and disease control rate were 10.0% and 65.0%, respectively. Grade 3 AEs included thrombocytopenia (5.0%), anorexia (5.0%), pneumonia (5.0%) and fatigue (5.0%). There were no cases of grade 4 AEs or treatment-related death.. Biweekly SOX regimen with reintroduction of oxaliplatin could be exploitable as the third- and/or later-line treatments for patients with mCRC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Disease-Free Survival; Drug Administration Schedule; Drug Combinations; Female; Humans; Male; Middle Aged; Oxaliplatin; Oxonic Acid; Retreatment; Survival Rate; Tegafur

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Follow-Up Studies; Hand-Foot Syndrome; Humans; Incidence; Kaplan-Meier Estimate; Oxonic Acid; Progression-Free Survival; Tegafur

Alternate-day administration of S-1 is thought to reduce toxicities. This phase II study evaluated S-1 on alternate days combined with bevacizumab as first-line treatment for elderly patients with metastatic colorectal cancer.. Of 54 enrolled patients, 50 patients were evaluated for efficacy and 53 for safety. The median age was 79 years (range 75-88 years). The median progression-free survival was 8.1 months (95% confidence interval (CI) 6.7-9.5 months). The median overall survival was 23.1 months (95% CI 17.4-28.8 months). The response rate was 44% (95% CI 30.2-57.8%), and the disease control rate was 88% (95% CI 79.0-97.0%). Grade 3 or higher hematologic, non-hematologic, and bevacizumab-related adverse events occurred in 9%, 11%, and 25% of patients, respectively. The most common grade 3 and 4 treatment-related adverse events were hypertension (11%), nausea (6%), fatigue (6%), anemia (6%), and proteinuria (6%). Only 6 patients discontinued treatment due to adverse events.. S-1 on alternate days combined with bevacizumab showed better tolerability and comparable survival compared with the results of similar studies.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Female; Humans; Male; Neoplasm Metastasis; Oxonic Acid; Prognosis; Prospective Studies; Survival Rate; Tegafur

This trial was designed to verify the superiority of 6 months of postoperative adjuvant chemotherapy with SOX (S-1 with oxaliplatin) with UFT (tegafur and uracil) with LV (leucovorin) in terms of disease-free survival in patients with high-risk stage III colon cancer. We report the results of a planned safety analysis.. A total of 966 patients were enrolled, and 932 patients were included in safety analyses. The planned 6-month protocol treatment was received by 76.9% of the patients in the UFT/LV group and 65.8% of those in the SOX group. The overall incidence of any Grade adverse events (AEs) were 91.3% in the UFT/LV group and 98.7% in the SOX group, and those of Grade ≥ 3 AEs were 16.1% and 36.1%, respectively. As for Grade ≥ 3 AEs, leukopenia, neutropenia, thrombocytopenia, and sensory neuropathy were more common in the SOX group. The incidence of Grade ≥ 3 sensory peripheral neuropathy was 4.6% in the SOX group.. The completion rate of adjuvant SOX and its incidence of AEs were acceptable in patients with colon cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Oxaliplatin; Oxonic Acid; Tegafur; Uracil

Combination therapy with oral fluoropyrimidine and irinotecan has not yet been established as first-line treatment of metastatic colorectal cancer (mCRC). We carried out a randomized, open-label, phase III trial to determine whether S-1 and irinotecan plus bevacizumab is noninferior to mFOLFOX6 or CapeOX plus bevacizumab in terms of progression-free survival (PFS).. Patients from 53 institutions who had previously untreated mCRC were randomly assigned (1 : 1) to receive either mFOLFOX6 or CapeOX plus bevacizumab (control group) or S-1 and irinotecan plus bevacizumab (experimental group; a 3-week regimen: intravenous infusions of irinotecan 150 mg/m2 and bevacizumab 7.5 mg/kg on day 1, oral S-1 80 mg/m2 twice daily for 2 weeks, followed by a 1-week rest; or a 4-week regimen: irinotecan 100 mg/m2 and bevacizumab 5 mg/kg on days 1 and 15, S-1 80 mg/m2 twice daily for 2 weeks, followed by a 2-week rest). The primary end point was PFS. The noninferiority margin was 1.25; noninferiority would be established if the upper limit of the 95% confidence interval (CI) for the hazard ratio (HR) of the control group versus the experimental group was less than this margin.. Between June 2012 and September 2014, 487 patients underwent randomization. Two hundred and forty-three patients assigned to the control group and 241 assigned to the experimental group were included in the primary analysis. Median PFS was 10.8 months (95% CI 9.6-11.6) in the control group and 14.0 months (95% CI 12.4-15.5) in the experimental group (HR 0.84, 95% CI 0.70-1.02; P < 0.0001 for noninferiority, P = 0.0815 for superiority). One hundred and fifty-seven patients (64.9%) in the control group and 140 (58.6%) in the experimental group had adverse events of grade 3 or higher.. S-1 and irinotecan plus bevacizumab is noninferior to mFOLFOX6 or CapeOX plus bevacizumab with respect to PFS as first-line treatment of mCRC and could be a new standard treatment.. UMIN000007834.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Progression-Free Survival; Tegafur; Young Adult

The aim of this single-arm phase II clinical trial was to evaluate whether the alternate-day administration of S-1 plus irinotecan would reduce the incidence of severe diarrhea in comparison to consecutive-day S-1 administration (standard IRIS regimen) in second-line treatment for patients with metastatic colorectal cancer.. A total of 51 patients were enrolled. The incidence of grade ≥ 3 diarrhea was 15.7% (8/51). Other common grade ≥ 3 adverse events were neutropenia, anemia, thrombocytopenia and fatigue were 13.7% (7/51), 5.9% (3/51), 2.0% (1/51) and 5.9% (3/51), respectively. The relative dose intensities of irinotecan, bevacizumab, and S-1 were 80.0, 86.8, and 77.7%, respectively. The median progression-free survival and overall survival were 8.4 months (5.8-9.8) and 17.1 months (11.8-22.3).. The alternate-day S-1 administration does not have significant effectiveness to reduce diarrhea in patients who received second-line treatment for metastatic colorectal cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Diarrhea; Disease-Free Survival; Drug Administration Schedule; Drug Combinations; Female; Follow-Up Studies; Humans; Incidence; Irinotecan; Male; Neoplasm Metastasis; Oxonic Acid; Survival Rate; Tegafur

Hand-foot syndrome (HFS) is a common side-effect of capecitabine. S-1 is an oral fluoropyrimidine with comparable efficacy to capecitabine in gastrointestinal cancers but associated with a lower incidence of HFS in Asian patients. This study compares the incidence of HFS between S-1 and capecitabine as first-line treatment in Western metastatic colorectal cancer (mCRC) patients.. Patients with previously untreated mCRC and planned treatment with fluoropyrimidine monochemotherapy were randomized 1 : 1 to receive either capecitabine (1250 mg/m2 orally for patients <70 years; 1000 mg/m2 for patients ≥70 years, twice daily on days 1-14) or S-1 (30 mg/m2 orally twice daily on days 1-14) in 3-weekly cycles, with bevacizumab optional in both groups. The primary endpoint was the incidence of any grade HFS, as assessed by both physicians and patients (diaries). Secondary endpoints included grade 3 HFS, other toxicities, relative dose intensity, progression-free survival, response rate and overall survival.. A total of 161 patients were randomized in 27 centres. The incidence of any grade HFS as assessed by physicians was 73% in the capecitabine group (n = 80) and 45% in the S-1 group (n = 80) [odds ratio (95% confidence interval) 0.31 (0.16-0.60), P = 0.0005]. The incidence of grade 3 HFS was 21% and 4% (P = 0.003), respectively. Patient-assessed any grade HFS was 84% and 58%, respectively (P = 0.004). Grade 3 anorexia was more common in the S-1 group (3% versus 13%, P = 0.03). Median relative dose intensity was 88% in the capecitabine group and 95% in the S-1 group (P = 0.026). There were no statistically significant differences in median progression-free survival, response rate and overall survival rates.. Treatment with S-1 in Western mCRC patients is associated with a significantly lower incidence of HFS compared with capecitabine, with comparable efficacy.. NCT01918852.

Topics: Aged; Capecitabine; Colorectal Neoplasms; Drug Combinations; Female; Humans; Male; Oxonic Acid; Tegafur

This Phase II trial evaluated the safety and efficacy of neoadjuvant chemotherapy (NAC) with S-1 and oxaliplatin (SOX) plus bevacizumab (Bev) in patients with colorectal liver metastasis (CRLM).. Patients with initially resectable CRLM received four cycles of SOX plus Bev as NAC. We adopted the R0 resection rate as the primary endpoint, and the threshold R0 resection rate was set at 80%.. Between December 2010 and August 2014, 61 patients were enrolled in this study and all started NAC. The completion rate of NAC was 82.0%. Three patients (4.9%) developed severe liver dysfunction caused by NAC and one patient finally decided against resection. Three patients (4.9%) were judged as having progressive disease during or after NAC and did not undergo liver resection. Among 57 patients who underwent liver resection after NAC, three patients were diagnosed with CRLM by pre-treatment imaging modalities and received NAC although a final pathological diagnosis was another malignant disease or benign condition. Finally, 47 of the 54 patients (87.0%) with resected CRLM achieved R0 resection. The pathological complete response rate of the 54 patients was 13.0%, and 31.5% were judged as pathological responders. However, the R0 resection rate of 77.0% in the entire cohort did not meet the endpoint.. NAC with SOX plus Bev has an acceptable toxicity profile and achieved a satisfactory pathological response. However, accuracy of pre-operative diagnoses and liver dysfunction caused by NAC were serious problems. Easy introduction of NAC for initially resectable CRLM should not be performed.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Drug Combinations; Female; Humans; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur

A phase II study of S-1 plus leucovorin (LV) given in a 4-week schedule (2 weeks' administration followed by 2 weeks' rest) for patients with untreated metastatic colorectal cancer (mCRC) showed that the combination was effective, but grade 3 toxicities (diarrhea, stomatitis and anorexia) occurred at a relatively high rate. In this phase II study, we evaluated the efficacy and safety of a 2-week schedule of S-1 plus LV. Patients with mCRC received oral S-1 (40-60 mg) and LV (25 mg) twice daily for 1 week, followed by 1 week's rest. Treatment was repeated until disease progression or unacceptable toxicity. The primary endpoint was response rate. The pharmacokinetics of S-1 and LV in Chinese patients were evaluated on day 1 of the first cycle. Seventy-three patients were enrolled in Japan and China. Of 71 eligible patients, the response rate was 53.5%, and the disease control rate was 83.1%. Median progression-free survival and median overall survival were 6.5 and 24.3 months, respectively. The incidences of grade 3 toxicities were diarrhea 8.3%, stomatitis 8.3%, anorexia 2.8% and neutropenia 9.7%. There were no treatment-related deaths. The pharmacokinetics profiles of S-1 plus LV in Chinese patients were similar to those in Japanese patients. This 2-week schedule of S-1 plus LV showed good efficacy and better tolerability than the 4-week schedule. This therapy will be the base regimen for mCRC to be added by other cytotoxic or molecular-targeted drugs. The optimized treatment schedule for S-1 plus LV was 1 week on and 1 week off.

Topics: Adult; Aged; Aged, 80 and over; Anorexia; Antineoplastic Combined Chemotherapy Protocols; China; Colorectal Neoplasms; Diarrhea; Drug Administration Schedule; Drug Combinations; Female; Humans; Japan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Oxonic Acid; Stomatitis; Survival Analysis; Tegafur; Treatment Outcome

S-1 has shown a response rate of 35% in chemonaïve patients with metastatic colorectal cancer (mCRC). Leucovorin enhances the antitumor activity of 5-fluorouracil, and concurrent oral administration of S-1 and leucovorin may represent a more active treatment option for mCRC.. Fifteen patients were enrolled. All three patients had DLTs at level 2, and this level was considered the maximum tolerated schedule. Level 0 was designated as the recommended schedule based on the incidences of DLTs and treatment continuity. The main toxic effects were gastrointestinal, such as diarrhea and stomatitis. There was no grade 4 adverse event or treatment-related death. The overall response rate was 67% (95% confidence interval, 38-88%). The PK profiles of S-1 plus leucovorin were similar to those in previous studies.. The recommended schedule was 2 weeks of S-1 plus leucovorin followed by a 2-week rest. The increased response and gastrointestinal toxicities of S-1 plus leucovorin as compared with S-1 monotherapy suggest that co-administration of leucovorin enhanced the activity of S-1.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Combinations; Female; Humans; Leucovorin; Male; Middle Aged; Oxonic Acid; Tegafur

Fluoropyrimidine and oxaliplatin are widely used for patients with colorectal cancer. This phase II study was conducted to evaluate the efficacy and safety of the combination of S-1, oxaliplatin, and leucovorin (SOL) in the treatment of Chinese patients with metastatic colorectal cancer (mCRC).. Eligible patients with untreated mCRC from four hospitals in China received intravenous oxaliplatin (85 mg/m(2)) on day 1, oral S-1 twice daily (80-120 mg per day) on day 1-7, and leucovorin twice daily (50 mg per day) simultaneously with S-1, every 2 weeks.. Forty patients were enrolled in our study. In total, 296 cycles of SOL were administered. The overall response rate was 50.0%. At a median follow-up of 27 months, progression-free survival and overall survival were 7.0 months (95% confidence interval [CI] 6.0-10.6 months) and 22.2 months (95% CI 15.1-29.3 months), respectively. The most common grade 3/4 non-hematological adverse events were diarrhea (n = 8, 20.0%), nausea (n = 3, 7.5%), and vomiting (n = 3, 7.5%). The most common grade 3/4 hematological toxicities were thrombocytopenia (n = 3, 7.5%), neutropenia (n = 1, 2.5%), and abnormal alanine transaminase/aspartate transaminase levels (n = 1, 2.5%). There was one treatment-related death.. The data indicate that the SOL regimen is effective and moderately tolerated in Chinese patients with mCRC.. ChiCTR-TNRC-100000838.

Topics: Administration, Intravenous; Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; China; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Survival Analysis; Tegafur; Treatment Outcome; Young Adult

Combination chemotherapy with S-1 and irinotecan is one of the standard treatments for metastatic colorectal cancer (mCRC) in Japan. However, there are few alternative practical second-line therapies. We conducted a phase II trial to evaluate the efficacy and safety of the combination of S-1 and irinotecan plus bevacizumab as a second-line treatment for oxaliplatin-refractory mCRC.. Patients with mCRC who were previously treated with oxaliplatin-containing regimens were enrolled. Oral S-1 at a dose of 40 mg/m(2) was administered twice daily for 2 weeks, followed by a 1-week drug-free interval. Irinotecan at a dose of 150 mg/m(2) and bevacizumab at a dose of 7.5 mg/kg were administered on day 1. The primary endpoint was progression-free survival (PFS).. Thirty-seven patients were enrolled, and 34 and 36 patients were assessed for response and safety, respectively. The overall response rate was 20.6 % (95 % confidence interval [CI] 8.7-37.9), and the disease control rate was 76.5 % (95 % CI 58.8-89.3). The median PFS was 5.6 months (95 % CI 3.8-7.0). The median overall survival was 16.4 months (95 % CI 8.1-20.0). The most common grade 3/4 adverse events included neutropenia (25.0 %), anorexia (22.2 %), anemia (16.7 %), and fatigue/malaise (16.7 %). The most common grade 3/4 adverse event of special interest for bevacizumab was hypertension (30.6 %). One treatment-related death caused by gastrointestinal bleeding occurred.. The findings suggest that the combination of S-1 and irinotecan plus bevacizumab is effective and tolerable as second-line chemotherapy for patients with oxaliplatin-refractory mCRC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Drug Administration Schedule; Drug Combinations; Drug Resistance, Neoplasm; Female; Humans; Irinotecan; Japan; Kaplan-Meier Estimate; Male; Middle Aged; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur; Treatment Outcome

The adjuvant chemotherapy trial of TS-1 for colon cancer phase III trial was designed to validate the non-inferiority of the oral fluoropyrimidine S-1 to uracil and tegafur/leucovorin as adjuvant chemotherapy for stage III colonic cancer. As a prospective biomarker study of this trial, DNA copy number was studied using formalin-fixed, paraffin-embedded specimens.. FFPE blocks were obtained from 795 patients of the 1,535 patients enrolled in the study. The quality of extracted DNA was assessed using arbitrarily primed polymerase chain reaction and microfluidic analysis. Genomic copy-number alterations in cancer were analyzed by high-density single-nucleotide polymorphism arrays. Copy-number changes in Japanese patients with colonic cancer were compared with those in Western countries using data from a previously reported meta-analysis. We then compared genome-wide segment copy number and clinicopathological features of colorectal cancer.. Genome-wide copy number was analyzed in 161 samples and DNA copy-number alteration profiles showed frequent DNA copy-number gains at chromosome 7, 8q and 13, and losses at 4, 5q, 8p, 17p and 18q. The weighted kappa statistic from comparing copy-number alteration status with data from Western countries was 0.828 (95% confidence interval=0.786 -0.871). DNA copy-number alterations of 8,684 segments were compared with clinicopathological features in 161 patients. Location of the tumor correlated with genomic segments of chromosome 4, 5, 7, 8, 13, 14, 18 and 20. Differentiation of the tumor correlated with segments in chromosome 4, 6, 8, 11, 13, 14,15, 16, 17 and 20.. Somatic copy-number alteration profiles of stage III colonic cancer in the Japanese ACTS-CC trial closely agreed with the results of previous Western studies. Location and differentiation of the tumor correlated with DNA copy-number alterations. Our findings will facilitate understanding the characteristics of colonic cancer. Further investigation may contribute to the exploration of valid biomarkers.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Asian People; Chemotherapy, Adjuvant; Colorectal Neoplasms; DNA Copy Number Variations; Drug Combinations; Female; Genome-Wide Association Study; Humans; Japan; Leucovorin; Male; Middle Aged; Oxonic Acid; Tegafur; White People; Young Adult

This prospective study was designed to evaluate the tolerability and the efficacy of bi-weekly SOX (S-1 and oxaliplatin)+cetuximab as first-line chemotherapy for wild-type K-RAS metastatic colorectal cancer.. We studied patients with previously untreated, unresectable, advanced or recurrent colorectal cancer who were treated in our hospital between October 2010 and March 2013. Their performance status (PS) was 0 to 1. Cetuximab was combined with S-1 and oxaliplatin (SOX+cetuximab). S-1 was given orally at a dose of 40 mg/m(2) (40-60 mg, calculated according to body surface area) twice daily after meals for 2 weeks, followed by a 2-week rest (course 1). Oxaliplatin (85 mg/m(2)) was given on days 1 and 15 of each course. Cetuximab was administered on days 1 (400 mg/m(2)), 8 (250 mg/m(2)) and 15 (500 mg/m(2)) of course 1, followed by every 2 weeks (500 mg/m(2)) thereafter.. The study group comprised of 18 patients. The mean age was 61 (range=32-72) years, the male:female ratio was 10:8 and the PS was 0 in 12 patients and 1 in 6 patients. The median number of administered courses was 6 (range=2-12). The treatment response was complete response (CR) in 2 and partial response (PR) in 10 (response rate=67% (12/18 patients)). The minimum number of treatment courses until a PR was 2, indicating an early response. Liver resection was performed in 4 patients (22.2%). The incidence of any adverse events (Grade 3/4) was 28% (5/18), including skin disorder (16.7%) as dry skin, cutaneous pruritus, contusion and paronychia, as well as peripheral sensory neuropathy (11.1%). The any-grade events of skin disorders and peripheral sensory neuropathy were mostly observed in all patients. These events were controllable by preventive skin care and by withdrawal and dose reduction, respectively. Death due to adverse events was not observed. Adverse events did not require the withdrawal of this regimen.. Based on the 18 patients studied, combined therapy with SOX+cetuximab was free of serious adverse events and could be safely administered by reducing the dose or temporarily suspending treatment, as required. These regimens seem to be promising for conversion therapy (4 out of 18 patients) because of good outcomes and an early response.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Drug Combinations; Female; Genes, ras; Humans; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Prospective Studies; Recurrence; Tegafur

of Background Data The effectiveness of adjuvant chemotherapy in patients with stage II/III colorectal cancer has been confirmed in various studies. However, no adjuvant chemotherapy for colorectal liver metastasis (CLM) classified to stage IV has been established. Objectives We conducted a phase 1 study of S-1 and oxaliplatin to determine the recommended dose (RD) in patients with CLM as adjuvant therapy in two institutes. Methods S-1 and oxaliplatin were administered from day 1 to day 14 of a 3-week cycle as a 2-h infusion every 3 weeks, respectively. The initial doses of S-1 and oxaliplatin were fixed to 80 mg/m(2) and 100 mg/m(2), respectively (level 1). We scheduled in the protocol a dose change of S-1 and oxaliplatin to level 2 (S-1: 80 mg/m(2) and oxaliplatin: 130 mg/m(2)) or level 0 (S-1: 65 mg/m(2) and oxaliplatin: 100 mg/m(2)) depending on the incidence of dose-limiting toxicity (DLT) at level 1 in six patients. Results Because DLT occurred in one among the initial six patients at level 1, the doses were increased to level 2 in the next six patients. At level 2, grade 3 leukopenia and neutropenia occurred in one (16.7 %) and two (33.3 %) patients, respectively, in the absence of non-hematological event. Because no DLT occurred at level 2, we suggest that the RD can be set to the level 2 dose. The median number of cycles delivered at RD was 8. The mean relative dose intensity of S-1 and oxaliplatin at RD was 0.90 and 0.63, respectively. Conclusion In a patient undergoing hepatectomy for CLM, 80 mg/m(2) of S-1 and 130 mg/m(2) of oxaliplatin are recommended as adjuvant therapy. A further study is required to confirm the efficacy and safety of this regimen on a larger scale.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Drug Combinations; Female; Hepatectomy; Humans; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur

An aging population will increase the number of older patients with metastatic colorectal cancer (mCRC). However, there is limited knowledge about treatment in older patients as they are under-represented in clinical trials. The oral fluoropyrimidine S-1 is associated with a lower rate of adverse events than capecitabine and may therefore be a suitable drug for elderly. However, data on the use of S-1 in Caucasian mCRC patients are lacking/scarce.. In the present study we evaluated safety and the efficacy of S-1 alone or in combination with oxaliplatin (SOx) or irinotecan (IRIS) in older mCRC patients. Patients who received at least one cycle of S-1 (first-line therapy), SOx (mainly first-line therapy) or IRIS (second-line therapy) were included.. From June 2012 to December 2014, 71 older patients received ≥1 cycle of either S-1 (n = 9), SOx (n = 44) or IRIS (n = 18) for mCRC. Median age was 76 years and most patients had a WHO performance status of 0 (32%) or 1 (56%). All patients were evaluable for response and safety. In the SOx group, 18 (41%) and 20 patients (45%) had partial response (PR) and stable disease (SD), respectively (disease control rate 86%). Median progression-free survival (PFS) was 8.5 months and median overall survival (OS) was 18.5 months. In the S-1 group (median age 82 years), PR was 22%, median PFS 6.4 months and median OS 15.8 months. In the IRIS group, PR was 28%, median PFS 7.8 months and the median OS 16.5 months. In general, therapy was well tolerated; main non-hematological toxicities were fatigue and diarrhea.. S-1 monotherapy, SOx and IRIS were well tolerated for older patients with mCRC and could become alternative regimens in older mCRC patients. These regimens are now further evaluated in the randomized ongoing NORDIC9 trial.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Diarrhea; Drug Combinations; Fatigue; Female; Humans; Irinotecan; Male; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur; Treatment Outcome

No salvage treatment had been established for metastatic colorectal cancer (mCRC) with mutated KRAS before the emergence of the new drugs regorafenib and TAS-102. We performed a phase II study of third-line chemotherapy with combined bevacizumab and S-1 for mCRC.. Subjects were mCRC patients with mutated KRAS who showed disease aggravation even after two regimens with oxaliplatin and irinotecan. Bevacizumab was given intravenously every 2 weeks, and S-1 was administered orally on days 1-28 of a 42-day cycle. The primary endpoint was disease control rate (DCR).. In total, 31 subjects were enrolled between August 2009 and June 2011. Three subjects in whom antitumor effects could not be evaluated were excluded. The median follow-up period was 8.6 months. The DCR was 67.9%, the response rate 0%, median progression-free survival 3.7 months, and overall survival 8.6 months. In 30 subjects evaluated for safety, there was no treatment-related death. The most common adverse events were anorexia (grade ≥3, 20%), diarrhea (grade 3, 10%), and decreased hemoglobin (grade ≥3, 17%).. The results suggest that third-line chemotherapy with combined bevacizumab and S-1 is safe and may delay the progression of mCRC resistant to oxaliplatin and irinotecan with mutated KRAS.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Drug Combinations; Female; Humans; Male; Middle Aged; Mutation; Neoplasm Metastasis; Oxonic Acid; Proto-Oncogene Proteins p21(ras); Salvage Therapy; Tegafur

Irinotecan plus S-1 (IRIS) is the only oral fluoropyrimidine-based regimen reported to be non-inferior to FOLFIRI and widely used in clinical practice for metastatic colorectal cancer (mCRC) patients. However, the combination of IRIS plus an anti-EGFR agent has not been evaluated previously. This study aimed to investigate the feasibility and efficacy of IRIS with panitumumab as second-line therapy for wild-type KRAS mCRC.. Main inclusion criteria were patients with wild-type KRAS mCRC refractory to one prior chemotherapy regimen for mCRC, ECOG PS 0-2, and age ≥20 years. Patients received panitumumab (6 mg/kg) and irinotecan (100 mg/m(2)) on days 1 and 15 and S-1 (40-60 mg according to body surface area) twice daily for 2 weeks, repeated every 4 weeks. The primary endpoint was the feasibility of the therapy. The secondary endpoints were response rate (RR), progression-free survival (PFS), and overall survival (OS).. A total of 36 patients received protocol treatment in eight centers. Of these, 23 patients (63.9 %) completed protocol treatment, demonstrating achievement of the primary endpoint. The most frequent grade 3/4 toxicities were diarrhea (16.7 %), acne-like rash (13.9 %), and neutropenia (11.1 %). The overall RR was 33.3 % (12/36). Of these patients, five underwent conversion surgery. Median PFS and OS were 9.5 months (95 % CI 3.5-15.4 months) and 20.1 months (95 % CI 16.7-23.2 months), respectively.. IRIS plus panitumumab has an acceptable toxicity profile and a promising efficacy in patients with previously treated wild-type KRAS mCRC. Accordingly, this regimen can be an additional treatment option for second-line chemotherapy in wild-type KRAS mCRC.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Feasibility Studies; Female; Follow-Up Studies; Humans; Irinotecan; Male; Middle Aged; Neoplasm Metastasis; Oxonic Acid; Panitumumab; Proto-Oncogene Proteins p21(ras); Survival Rate; Tegafur

Anti-epidermal growth factor receptor antibody therapy alone or in combination with irinotecan is recognized as a standard third-line treatment for KRAS wild-type unresectable metastatic colorectal cancer. However, in some cases, it is difficult to administer irinotecan after third-line treatment. Therefore, we examined the efficacy and safety of the combination of cetuximab and S-1 in patients with KRAS wild-type unresectable metastatic colorectal cancer who were previously treated with irinotecan, oxaliplatin, and fluoropyrimidines.. The study was designed as a phase II, non-randomized, open-label, multicenter trial. Cetuximab was initially administered at 400 mg/m(2), followed by weekly infusion at 250 mg/m(2). S-1 was administered at a fixed dose of 80 mg/m(2) orally twice daily for 28 days followed by a 14-day break, resulting in a 6-week treatment course. The primary endpoint was progression-free survival (PFS). The secondary endpoints were the overall response rate (ORR), overall survival (OS), disease control rate (DCR), time to treatment failure, dose intensity, safety, and BRAF mutation status.. Thirty-seven patients were eligible. The median PFS was 5.5 months, the median OS was 13.5 months, the ORR was 29.7 %, and the DCR was 73.0 %. The relative dose intensity was 86.8 % for cetuximab and 88.1 % for S-1. Grade 3-4 adverse events that occurred in >10 % of the patient population included rash, dry skin, diarrhea, paronychia, anorexia, fatigue, mucositis, and neutropenia.. Combination therapy with cetuximab and S-1 was effective and well tolerated in patients with irinotecan-, oxaliplatin-, and fluoropyrimidine-refractory metastatic colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Oxonic Acid; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Survival Rate; Tegafur; Treatment Failure; Treatment Outcome

It has not been elucidated whether the clinical efficacy of oral fluoropyrimidines for adjuvant chemotherapy of colorectal cancer varies with tumor biological characteristics.. A multicenter randomized trial was performed comparing oral tegafur/gimeracil/oteracil (S-1) and uracil-tegafur/ leucovorin (UFT/LV) as adjuvant therapy for stage III colorectal cancer. Postoperative survival was compared based on the 5-FU-related mRNA levels in cancer tissues.. Among patients with tumor expressing dihydropyrimidine dehydrogenase (DPD) mRNA within the 66.7th percentile (lower 2/3) of all cases, overall survival (OS) was significantly better in the S-1 than in the UFT/LV group. In the S-1 group, patients with low DPD-expressing tumors had significantly better OS than those with highly expressing tumors. Patients with low thymidine synthase (TS)-expressing tumors had significantly better OS than those with highly expressing tumors.. The efficacy of oral fluoropyrimidines as adjuvant chemotherapy for colorectal cancer may be influenced by the level of 5-FU-related mRNA in cancer tissues.

Topics: Administration, Oral; Adult; Aged; Antimetabolites, Antineoplastic; Carcinoma; Chemotherapy, Adjuvant; Colorectal Neoplasms; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Orotate Phosphoribosyltransferase; Oxonic Acid; RNA, Messenger; Tegafur; Tetrahydrofolate Dehydrogenase; Thymidine Phosphorylase; Thymidylate Synthase; Treatment Outcome

The FIRIS study previously demonstrated non-inferiority of IRIS (irinotecan plus S-1) to FOLFIRI (5-fluorouracil/leucovorin with irinotecan) for progression-free survival as the second-line chemotherapy for metastatic colorectal cancer (mCRC) as the primary endpoint. The overall survival (OS) data were immature at the time of the primary analysis.. Between 30 January 2006 and 29 January 2008, 426 patients with mCRC who failed in first-line chemotherapy were randomly assigned to receive either FOLFIRI or IRIS. After the primary analysis, the follow-up survey was cut off on 29 July 2010, and the final OS data were analysed.. With a median follow-up of 39.2 months, the median OS was 17.4 months in the FOLFIRI group and 17.8 months in the IRIS group [hazard ratio (HR) 0.900; 95% confidence interval (CI) 0.728-1.112]. In the pre-planned subgroup of patients who received prior chemotherapy containing oxaliplatin, the median OS was 12.7 months in the FOLFIRI group and 15.3 months in the IRIS group (HR 0.755; 95% CI 0.580-0.983).. IRIS is non-inferior to FOLFIRI for OS as second-line chemotherapy for mCRC. IRIS can be an option for second-line chemotherapy of mCRC. (ClinicalTrials.gov Number: NCT00284258).

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Combinations; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Prognosis; Survival Rate; Tegafur

Biochemical modulation of 5-fluorouracil (5-FU) by leucovorin (LV) enhances antitumor activity. LV is thus often added to 5-FU-based regimens for the treatment of metastatic colorectal cancer (mCRC). A combination of S-1, oxaliplatin, and LV (SOL) was shown to be feasible, effective, and safe in a previous phase I trial. We therefore conducted a randomized phase II trial to evaluate efficacy and safety of SOL compared with mFOLFOX6.. Patients with mCRC and no prior chemotherapy were randomly assigned to receive either SOL or mFOLFOX6. SOL consisted of S-1 (40-60 mg bid) plus oral LV (25 mg bid) for 1 week and oxaliplatin (85 mg/m(2)) on day 1, repeated every 2 weeks.. Among 107 patients enrolled from July 2008 through July 2009, 105 (56 in the SOL group and 49 in the mFOLFOX6 group) were eligible and evaluated. The median progression-free survival was 9.6 months in the SOL group and 6.9 months in the mFOLFOX6 group [hazard ratio (HR) 0.83, 95 % confidence interval (CI) 0.49-1.40]. The median overall survival was 29.9 and 25.9 months, respectively (HR 0.91, 95 % CI 0.55-1.49). The response rate was 55 % in both groups. Grade 3 or 4 adverse drug reactions were neutropenia (20 % with SOL vs 41 % with mFOLFOX6), sensory neuropathy (20 vs 2.0 %), anorexia (13 vs 7.8 %), fatigue (11 vs 5.9 %), and diarrhea (11 vs 3.9 %).. SOL demonstrated promising efficacy and acceptable toxicity as first-line chemotherapy for mCRC. Further studies of SOL combined with molecular target agents are warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Survival Rate; Tegafur; Treatment Outcome

Protracted low-dose infusion of irinotecan has been suggested to enhance antitumor activity. A phase II study was conducted to evaluate the safety and efficacy of oral S-1 combined with 24-hour infusion of irinotecan and intravenous bevacizumab for metastatic colorectal cancer (MCRC).. The subjects were 79 patients with MCRC; 57 were chemotherapy naïve. Irinotecan (125 mg/m(2)) was administered as a 24-hour infusion on days 1 and 15, S-1 (80 mg/m(2)) was administered orally on days 1-14, and bevacizumab (5.0 mg/kg) was given on days 1 and 15. The treatment was repeated every 4 weeks.. Median follow-up was 20.0 months, and the mean number of cycles was 7. The overall response rate was 79.7% (95% CI, 69.2-88.0), 86.0% (95% CI, 74.2-93.7) for first-line and 63.6% (95% CI, 40.7-82.8) for second-line treatment. The median progression-free survival was 16.4 months (95% CI, 13.9-21.0) for first-line and 9.4 months (95% CI, 4.9-16.5) for second-line treatment. The median overall survival was not reached. Grade 3-4 toxicities were neutropenia (43%), leukopenia (20.3%), anorexia (19.0%), and diarrhea (10.1%). Toxicity was tolerable.. Combination chemotherapy with oral S-1 and biweekly 24-hour infusions of irinotecan plus bevacizumab appears to be highly active and well tolerated both as first-line and second-line chemotherapy for MCRC.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Female; Humans; Infusions, Intravenous; Irinotecan; Male; Middle Aged; Neoplasm Metastasis; Oxonic Acid; Survival Analysis; Tegafur; Treatment Outcome

Chemotherapeutic regimens for elderly patients with metastatic colorectal cancer (mCRC), such as bevacizumab combined with 5-fluorouracil (5-FU) and leucovorin, often exclude oxaliplatin and irinotecan owing to the risk of toxicity. However, treatment with infusional 5-fluorouracil and leucovorin requires percutaneous port-catheter placement and other precautions, causing unnecessary stress for patients as well as healthcare workers.. We conducted a phase II study to evaluate the efficacy and safety of bevacizumab plus S-1 in elderly patients with previously untreated mCRC. Bevacizumab was given intravenously every two weeks, and S-1 was administered orally on days 1-28 of a 42-day cycle. The primary end-point was progression-free survival (PFS). The secondary end-points were time to treatment failure, response rate (RR), overall survival (OS), treatment completion status and safety.. From October 2007 through March 2010, 56 patients were enroled. The median PFS was 9.9months, the median OS was 25.0months, and the RR was 57%. The main adverse events of grade 3 or higher were hypertension (11%), diarrhoea (9%) and neutropenia (7%).. Our results suggest that combination chemotherapy with S-1 and bevacizumab can be administered safely and continuously on an outpatient basis and is therapeutically effective in elderly patients with mCRC.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Combinations; Female; Humans; Male; Neoplasm Metastasis; Oxonic Acid; Survival Analysis; Tegafur; Treatment Outcome

We previously showed that S-1 after curative resection of colorectal liver metastasis had acceptable toxicity and a high rate of completion of therapy in a prospective phase II trial. We here reported the primary endpoint of disease-free survival (DFS).. Between October 2008 and August 2010, 60 patients were eligible for this study and received S-1 for 28 days followed by a 2-week rest period. Treatment was started within 8 weeks after surgery and repeated for eight cycles.. Median follow-up was 41 months. Among 60 patients, 45 had solitary metastasis, and the median maximum tumor diameter was 2.6 cm. The 3-year DFS and overall survival were 47.4 and 80.0 %, respectively. Recurrences developed in 31 patients, with the remnant liver the most common site (19 patients). Multivariate analysis showed that positive lymph node metastasis around the primary site (p = 0.013) and early liver metastasis (synchronous disease or metachronous disease within 12 months) (p = 0.041) were independent poor prognostic factors for DFS. Patients having both risk factors had a significantly worse DFS than those without these risk factors (p < 0.001). Early liver metastasis was an independent indicator of early recurrence within 1 year.. S-1 after curative liver resection yielded promising survival in patients with a low tumor burden. Outcome in patients having both positive lymph node metastasis around the primary site and early liver metastasis was much worse than in patients without these conditions; therefore, they might warrant more aggressive therapy.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Female; Humans; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Oxonic Acid; Prognosis; Prospective Studies; Survival Analysis; Tegafur

A combination of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) plus bevacizumab has been widely used for the first-line chemotherapy of metastatic colorectal cancer (mCRC). S-1 is an oral fluoropyrimidine preparation that combines tegafur, a prodrug of 5-fluorouracil, with two modulators. Several studies of combination chemotherapy with oxaliplatin plus S-1 (SOX) conducted in Asia have reported promising efficacy and safety in patients with mCRC, suggesting the potential to replace mFOLFOX6. The SOFT trial (JapicCTI-090699) was a randomized Phase III trial designed to evaluate the noninferiority of SOX plus bevacizumab to mFOLFOX6 plus bevacizumab in patients with mCRC. This review summarizes the drug concept of S-1 and the results of clinical trials of S-1 and SOX in CRC and presents an overview of the SOFT trial.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Drug Combinations; Humans; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur; Treatment Outcome

Adding leucovorin to fluorouracil is known to improve response rate and overall survival in first-line chemotherapy for metastatic colorectal cancer (mCRC). The present multicenter phase II study evaluated the efficacy and safety of S-1, oxaliplatin, oral leucovorin, and bevacizumab combination therapy (SOLA).. Patients with unresectable and untreated mCRC received S-1 (40-60 mg bid) plus leucovorin (25 mg bid) orally for 1 week, and oxaliplatin (85 mg/m(2)) and bevacizumab (5 mg/kg) intravenously on day 1, every 2 weeks. Efficacy endpoints, including the response rate (the primary endpoint) and progression-free survival, were assessed by an independent review committee.. Of the 29 eligible patients, 25 patients (86%) had a partial response [95% confidence interval (CI) 68-96%] and the remaining four patients showed stable disease with a trend toward tumor shrinkage. The median progression-free survival was 15 months (95% CI 10-26 months). The median overall survival was not reached after a median follow-up time of 34 months. The 3-year survival rate was 54%. Curative resections of metastatic lesions were performed in eight patients (28%). Common grade 3 or 4 adverse events were neutropenia (20%), hypertension (23%), anorexia (20%), fatigue (17%), diarrhea (10%), and peripheral sensory neuropathy (53%).. The SOLA therapy showed excellent efficacy and tolerable toxicities except for peripheral sensory neuropathy in patients with mCRC. Since oxaliplatin-induced neuropathy can be alleviated by modifying its administration, SOLA is a promising candidate regimen to be compared with FOLFOX plus bevacizumab in a future phase III trial.. JapicCTI-090881.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur

S-1, a novel oral prodrug of 5-fluorouracil (5-FU), and irinotecan with or without bevacizumab is known to be effective in metastatic colorectal cancer (mCRC). However, it is not clear whether S-1 and irinotecan confers benefits compared to 5-FU and leucovorin plus oxaliplatin (FOLFOX) in patients with mCRC. Our aim was to compare the efficacy and safety of these regimens.. We analyzed 187 patients with previously untreated mCRC who were enrolled in four phase II studies: SIR (S-1 and irinotecan, n = 40), SIRB (S-1 and irinotecan with bevacizumab, n = 51), FOLFOX (5-FU and leucovorin plus oxaliplatin, n = 46), and STOX (stop-and-go strategy of modified FOLFOX-6 with bevacizumab, n = 50). We evaluated efficacy and safety between SIR/SIRB and FOLFOX/STOX.. Baseline characteristics were similar in the two groups composed of SIR/SIRB (n = 91) and FOLFOX/STOX (n = 96). The overall response rates were not significantly different between the two groups (65% in SIR/SIRB vs. 52% in FOLFOX/STOX, p = 0.125). The median progression-free survival was 10.9 months in SIR/SIRB versus 12.1 months in FOLFOX/STOX (p = 0.59). The median overall survival was 27.3 months in SIR/SIRB versus 26.8 months in FOLFOX/STOX (p = 0.97). Gastrointestinal adverse events were the most common toxicities in SIR/SIRB, while neutropenia and sensory neuropathy were the most common toxicities in FOLFOX/STOX.. S-1 and irinotecan with or without bevacizumab was well tolerated and showed similar response rates and survival compared to the FOLFOX regimen. This combination should be considered as an experimental first-line treatment for mCRC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Drug Combinations; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur; Treatment Outcome

The mean 5-6-month survival after failed standard chemotherapy for metastatic colorectal cancer (mCRC) necessitates more effective treatments for refractory mCRC. For untreated mCRC, S-1 + oral leucovorin (SL) therapy offers promising results without severe toxicity. The ML18147 trial demonstrated that bevacizumab (Bev) prolongs overall survival after mCRC progression. We conducted a single-centre phase-II trial to evaluate the safety and efficacy of SL/Bev combination chemotherapy as mCRC salvage therapy.. Major eligibility criteria were confirmed adenocarcinoma diagnosis; age >20 years; Eastern Cooperative Oncology Group performance status, 0-2; and progression after administration/intolerance of/to approved drugs for mCRC. (5-FU, oxaliplatin, irinotecan, Bev, and anti-EGFR antibody, if KRAS wild-type). S-1 (80-120 mg/body) and leucovorin (25 mg) were orally administered in a 1-week-on/1-week-off schedule. Bev (5 mg/kg) was administered on day 1 of every 2-week cycle. The primary endpoint was disease control rate (DCR).. A total of 31 patients were enrolled. DCR was 65% [95% confidence interval (CI), 48-100%] and the response rate was 7% (95% CI, 0.7-22%). One patient showing partial response to SL/Bev had a BRAF-mutant tumor. Median progression-free survival and overall survivals were 5.3 [95% CI, 2.1-9.3] and 9.9 [95% CI, 7.4-NA] months, respectively. The most-frequent grade-3/4 adverse events were mucositis (26%) and diarrhea (11%), which were manageable by dose reduction/interruption.. SL/Bev showed impressive activity in refractory mCRC and was tolerable, suggesting its potential as an alternative chemotherapy for refractory mCRC.. This study has been registered in University Hospital Medical Information Network (UMIN) Clinical Trials Registry ( ID UMIN000009083 ) on 11 October 2012.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Drug Combinations; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxonic Acid; Salvage Therapy; Tegafur; Treatment Outcome

The Kyushu Study Group of Clinical Cancer (KSCC) conducted phase II trials of KSCC1002 (UMIN000001308) concerning liver resectability after first-line treatment of initially unresectable or not optimally resectable colorectal liver metastases in a prospective, multicenter study.. Patients with wild-type KRAS received 4-6 cycles of S-1 and oxaliplatin (SOX) plus cetuximab. Liver resectability was evaluated subsequently with the liver resection rate as the primary endpoint.. Of the 33 patients enrolled between March 2010 and July 2013, the median number of administration cycles was 4 (range 0-10). The overall response rate was 63.6 % (95 % confidence interval [CI] 45.1-79.6 %). Liver resection was possible in 16 of 33 (48.5 %) patients, and there were 13 R0 cases (39.4 %). We conducted a central review of liver resectability evaluated by five liver surgeons, and the resectability increased from 18.2 to 66.7 % after chemotherapy, based on imaging. The median overall survival for all 33 cases was 31.6 months (95 % CI 14.8-not reached). The median progression-free survival was 9.7 months (95 % CI 6.2-11.8).. SOX plus cetuximab is safe and effective for advanced colorectal cancer with limited liver metastasis, and may lead to high liver resectability.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Drug Combinations; Follow-Up Studies; Humans; Liver Neoplasms; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Prognosis; Survival Rate; Tegafur

Metastatic colorectal cancer carries a poor prognosis and cannot be cured by currently available therapy. Chemotherapy designed to prolong survival and improve the quality of life (QOL) of patients is the mainstay of treatment. Standard regimens of FOLFOX/bevacizumab and CapeOX/bevacizumab can cause neurotoxicity, potentially disrupting treatment. The results of 3 phase II studies of combination therapy with S-1, irinotecan, and bevacizumab showed comparable efficacy to mFOLFOX6/bevacizumab and CapeOX/bevacizumab, without severe neurotoxicity. Therefore, the establishment and evaluation of S-1-containing irinotecan-based regimens for first-line treatment are expected to become more important.. The TRICOLORE trial is a multicenter, randomized, open-label, controlled phase III study which aims to evaluate the non-inferiority of combination therapy with S-1/irinotecan/bevacizumab (a 3-week regimen [SIRB] or 4-week regimen [IRIS/bevacizumab]) to oxaliplatin-based standard treatment (mFOLFOX6/bevacizumab or CapeOX/bevacizumab) in patients with metastatic colorectal cancer who had not previously received chemotherapy. Patients will be randomly assigned to either the control group (mFOLFOX6/bevacizumab or CapeOX/bevacizumab) or study group (SIRB or IRIS/bevacizumab). The target sample size is 450 patients. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival (OS), response rate (RR), time to treatment failure (TTF), relative dose intensity (RDI), the incidence and severity of adverse events, quality of life (QOL), quality-adjusted life years (QALY), health care costs, and relations between biomarkers and treatment response (translational research, TR).. The results of this study will provide important information that will help to improve the therapeutic strategy for metastatic colorectal cancer, and we believe that this study is very meaningful from the perspective of comparative effectiveness research.. UMIN000007834.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Cost-Benefit Analysis; Disease-Free Survival; Drug Combinations; Female; Fluorouracil; Health Care Costs; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Quality of Life; Tegafur; Young Adult

Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide. The combination of oxaliplatin-based treatments (oxaliplatin plus infusional 5-fluorouracil and leucovorin [FOLFOX] or oxaliplatin plus capecitabine [CapeOX]) and bevacizumab is a standard chemotherapy regimen for metastatic CRC (mCRC). However, several clinical studies that tested S-1 plus oxaliplatin (SOX) indicate that SOX is also a treatment option for mCRC. TSU-68 is an oral compound that inhibits vascular endothelial growth factor receptor and platelet-derived growth factor receptor. The recommended dose of TSU-68 + SOX was previously determined in a phase I study of mCRC patients. The goal of this trial was to evaluate the efficacy of TSU-68 in combination with SOX.. This open-label multicenter randomized phase II trial was performed in Korea. Treatment-naive mCRC patients with a performance status of 0 or 1 were randomized in a 1:1 ratio to receive either TSU-68 + SOX or SOX alone. The primary endpoint was progression-free survival (PFS).. A total of 105 patients (TSU-68 + SOX, 52 patients; SOX alone, 53 patients) were randomized. The median PFS was 7.0 months in the TSU-68 + SOX group (hazard ratio [HR], 1.057) and 7.2 months in the SOX group (p = 0.8401). The most frequent grade 3 and 4 adverse events were thrombocytopenia (9.6 % [TSU-68 + SOX] vs. 26.4 % [SOX]), neutropenia (13.5 % [TSU-68 + SOX] vs. 15.1 % [SOX]), and anemia (3.8 % [TSU-68 + SOX] vs. 13.2 % [SOX]). We observed a difference between the 2 groups for all grades of anemia (15.4 % [TSU-68 + SOX] vs. 32.1 % [SOX]), diarrhea (30.8 % [TSU-68 + SOX] vs. 47.2 % [SOX]), vomiting (50.0 % [TSU-68 + SOX] vs. 26.4 % [SOX]), and chromaturia (23.1 % [TSU-68 + SOX] vs. 0.0 % [SOX]). Analysis using a Cox proportional hazard model showed that baseline interleukin 6 (IL-6) levels were associated with a survival benefit of TSU-68 (p = 0.012).. TSU-68 + SOX had a favorable safety profile. However, TSU-68 did not have a synergistic effect on the efficacy of SOX. The baseline serum IL-6 level could be a prognostic factor for TSU-68 efficacy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Becaplermin; C-Reactive Protein; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Female; Humans; Indoles; Interleukin-6; Interleukin-8; L-Lactate Dehydrogenase; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Oxindoles; Oxonic Acid; Platelet-Derived Growth Factor; Propionates; Proto-Oncogene Proteins c-sis; Pyrroles; Tegafur; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A

We report updated progression-free survival (PFS) and overall survival (OS) data from a trial that compared capecitabine plus oxaliplatin (CapeOX) versus S-1 plus oxaliplatin (SOX) for the first-line treatment of metastatic colorectal cancer.. This trial was a randomized, two-armed, non-inferiority phase 3 comparison of CapeOX (capecitabine 1000 mg/m2 twice daily on days 1-14 and oxaliplatin 130 mg/m2 on day 1) versus SOX (S-1 40 mg/m2 twice daily on days 1-14 and oxaliplatin 130 mg/m2 on day 1). The primary end point was to show non-inferiority of SOX relative to CapeOX in terms of PFS. Thus, a follow-up exploratory analysis of PFS and OS was performed.. The intention to treat (ITT) population was comprised of 340 patients (SOX arm: 168 and CapeOX arm: 172). The updated median PFS was 7.1 months (95% CI 6.4-8.0) in the SOX group and 6.3 months (95% CI 4.9-6.7) in the CapeOX group (hazard ratio [HR], 0.83 [0.66-1.04], p = .10). The median OS was 19.0 months (95% CI 15.3-23.0) in the SOX group and 18.4 months (95% CI 14.1-20.7) in the CapeOX group (HR, 0.86 [0.68-1.08], p = .19). Subgroup analyses according to principal demographic factors such as sex, age, ECOG (Eastern Cooperative Oncology Group) performance status, primary tumor location, measurability, previous adjuvant therapy, number of metastatic organs, and liver metastases showed no interaction between any of these characteristics and the treatment.. Updated survival analysis shows that SOX is similar to CapeOX, confirming the initial PFS analysis. Therefore, the SOX regimen could be an alternative first-line doublet chemotherapy strategy for patients with metastatic colorectal cancer.. NCT00677443 and May 12 2008.

Topics: Adult; Aged; Antineoplastic Agents; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Female; Fluorouracil; Humans; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Survival Analysis; Tegafur; Treatment Outcome

S-1 combination with oxaliplatin and oral leucovorin (SOL regimen) demonstrated well tolerability and efficacy in Japanese patients with metastatic colorectal cancer. The present study was conducted to confirm the safety and efficacy of SOL regimen in Chinese patients with untreated metastatic colorectal cancer.. We planned to enroll 20 untreated, unresectable or recurrent advanced colorectal adenocarcinoma patients. The treatment schedule comprised S-1 40-60 mg bid and leucovorin (LV) 25 mg bid for one week and 2 hour drip infusion of oxaliplatin (L-OHP) 85 mg/m2 on day 1, 1 week off, repeated every 2 weeks. The primary study endpoints were safety. Secondary endpoints were overall response rate (ORR), progression free survival (PFS) and time to treatment failure (TTF).. A total of 21 patients (median age: 65; range: 30-79) were enrolled between August 2009 and December 2009. There were 15 patients with colon cancer and 6 with rectal cancer. Data cut-off date was April, 2011. In total, 168 cycles were administered (median 7 per patient; range 1-19). The common toxicities were neutropenia, thrombocytopenia, fatigue, diarrhea, nausea/vomiting, peripheral neurotoxicity and anemia. The common grade 3/4 adverse events were diarrhea (19.1%), thrombocytopenia (9.5%) and nausea/vomiting (9.5%). Dose-adjusted was executed in 11 patients owing to AEs, including S-1 in 9 cases and L-OHP in 9 cases. Death due to adverse event was not observed. Responses were evaluated in 20 patients with measurable disease, the overall response rate was 45% (1 CR and 8 PR: 95% CI, 23-68%) and the disease control rate was 70% (95% CI, 46%-88%). Pathologic complete response was observed in 1 patient after 5 cycles of treatment. Median PFS was 9.0 (95% CI, 3.7- 14.4) months. Median TTF was 4.2 (95% Cl, 3.5-5.6) months.. This result indicates that the SOL regimen is well tolerated and effective in Chinese patients with metastatic colorectal cancer.

Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; China; Colorectal Neoplasms; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Drug Combinations; Feasibility Studies; Female; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur; Time Factors; Treatment Outcome

A number of clinical trials, including the FIRIS study, have shown that S-1 plus irinotecan (IRIS) is safe and effective in patients with colorectal cancer. Several different treatment protocols for IRIS are commonly used in Japan, besides the one used in the FIRIS study. This study was designed to evaluate the feasibility of a 5-week cycle of IRIS.. Between January 2005 and February 2008, a total of 55 patients with metastatic colorectal cancer were enrolled at nine centers in Japan. All patients received irinotecan intravenously (80 mg/m(2)) on days 1 and 15 and S-1 orally (40-60 mg twice daily, according to body surface area) on days 1-21 of a 5-week repeated cycle.. The overall response rate was 29.1 %. The response rate was 43.8 % in patients who received IRIS as first-line therapy and 23.1 % in those who received IRIS as second-line or subsequent therapy. The median survival time was 678 days (22.6 months). Adverse events of Grade 3 or higher that occurred at an incidence of ≥10 % were neutropenia (12.7 %) and diarrhea (10.9 %).. Our efficacy and safety data suggest that a 5-week cycle of IRIS is an effective alternative to used currently regimens.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Drug Administration Schedule; Drug Combinations; Feasibility Studies; Female; Humans; Injections, Intravenous; Irinotecan; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Recurrence, Local; Oxonic Acid; Tegafur

S-1 is an oral fluoropyrimidine that mimics infusional 5-fluorouracil. The aim of this phase II trial was to explore the clinical efficacy of the triplet regimen TIROX, which consists of S-1, irinotecan and oxaliplatin.. Forty-two chemo-naive patients with metastatic colorectal cancer (mCRC) were planned to be enrolled and be treated with irinotecan 150 mg m(-2) followed by oxaliplatin 85 mg m(-2) on day 1 and S-1 80 mg m(-2) per day from day 1 to 14 every 3 weeks. Polymorphisms in the UGT1A1, UGT1A6, UGT1A7 and CYP2A6 genes were analysed.. Between July 2007 and February 2008, 43 patients were enrolled. An objective response was noted in 29 patients (67.4%, 95% confidence interval: 53.4-81.4), of which 2 achieved durable complete responses. The median progression-free survival was 10.0 months and the median overall survival was 19.2 months. Significant grade 3 or 4 adverse events were neutropenia (45.2%), febrile neutropenia (9.5%), diarrhoea (7.1%) and vomiting (9.5%). Increased gastrointestinal toxicities were associated with the presence of UGT1A6*2 or UGT1A7*3 and an improved tumour response was noted in those without variant alleles of CYP2A6 or UGT1A1*60.. The combination of S-1, irinotecan and oxaliplatin showed favourable efficacy and tolerability in untreated patients with mCRC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Aryl Hydrocarbon Hydroxylases; Camptothecin; Colorectal Neoplasms; Cytochrome P-450 CYP2A6; Drug Combinations; Female; Glucuronosyltransferase; Humans; Irinotecan; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Pharmacogenetics; Polymorphism, Genetic; Tegafur

We conducted a phase I study of S-1 combined with irinotecan and oxaliplatin (TIROX) to determine the maximum-tolerated dose (MTD) and recommended dose (RD) and to assess its safety, pharmacokinetics, pharmacogenetics, and preliminary efficacy in patients with metastatic colorectal cancer (MCRC) or metastatic gastric cancer (MGC).. Patients received escalating doses of S-1 (30-40 mg/m² b.i.d.) orally on days 1-14, an escalating dose of intravenous irinotecan (120-150 mg/m²) on day 1, and a fixed dose of intravenous oxaliplatin (85 mg/m²) on day 1 every 3 weeks.. Twenty-three patients (10 MCRC, 13 MGC; 13 chemonaive, 10 previously treated for metastatic disease) were treated across six dose levels. Because only one patient experienced a dose-limiting toxicity of grade 3 anorexia at the highest dose level (S-1 40 mg/m² b.i.d., irinotecan 150 mg/m², and oxaliplatin 85 mg/m²) (n = 8), the MTD was not obtained, and this level was established as the RD. With a median of 10 cycles per patient, the most common grade 3 or 4 adverse events included neutropenia (43 %), diarrhea (13 %), and nausea (13 %). In 22 efficacy-evaluable patients, the objective tumor response rate was 59.1 % (75 % for both MCRC and MGC in the first-line setting) and the disease control rate was 100 %. The exploratory pharmacokinetic/pharmacogenetic study showed that CYP2A6 variants (*4, *7, *9) are associated with a lower metabolic ratio of S-1 (exposure ratio of 5-fluorouracil to tegafur).. The new triplet TIROX regimen has shown promising antitumor activity and a favorable toxicity profile in patients with MCRC and MGC.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aryl Hydrocarbon Hydroxylases; Camptothecin; Cohort Studies; Colorectal Neoplasms; Cytochrome P-450 CYP2A6; Dose-Response Relationship, Drug; Drug Combinations; Female; Follow-Up Studies; Half-Life; Humans; Irinotecan; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Polymorphism, Genetic; Stomach Neoplasms; Survival Analysis; Tegafur

Studies done in Asia have shown that a regimen of S-1 plus oxaliplatin (SOX) has promising efficacy and safety in patients with metastatic colorectal cancer. We aimed to establish whether SOX plus bevacizumab is non-inferior to mFOLFOX6 (modified regimen of leucovorin, fluorouracil, and oxaliplatin) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer.. We undertook an open-label, non-inferiority, randomised phase 3 trial in 82 sites in Japan. We enrolled individuals aged 20-80 years who had metastatic colorectal cancer, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had assessable lesions, had received no previous chemotherapy or radiotherapy, could take drugs orally, and had adequate organ function. Eligible patients were randomly assigned (1:1) to receive either mFOLFOX6 plus bevacizumab (on day 1 of each 2-week cycle, 5 mg/kg intravenous infusion of bevacizumab and a simultaneous intravenous infusion of 85 mg/m(2) oxaliplatin, 200 mg/m(2)l-leucovorin, 400 mg/m(2) bolus fluorouracil, and 2400 mg/m(2) infusional fluorouracil) or SOX plus bevacizumab (on day 1 of each 3-week cycle, 7·5 mg/kg intravenous infusion of bevacizumab and 130 mg/m(2) intravenous infusion of oxaliplatin; assigned dose of S-1 twice a day from after dinner on day 1 to after breakfast on day 15, followed by 7-day break). Randomisation was done centrally with the minimisation method, with stratification by institution and whether postoperative adjuvant chemotherapy had been given. Participants, investigators, and data analysts were not masked to treatment assignment. The primary endpoint was progression-free survival (PFS), which was defined as the interval between enrolment and progressive disease (≥20% increase in sum of longest dimensions of target lesions from baseline, or appearance of new lesions) or death, whichever came first. The primary analysis was done by modified intention to treat. This trial is registered with the Japan Pharmaceutical Information Center, number JapicCTI-090699.. Between Feb 1, 2009, and March 31, 2011, 512 patients underwent randomisation. 256 patients assigned to receive SOX plus bevacizumab and 255 assigned to receive mFOLFOX6 plus bevacizumab were included in the primary analysis. Median PFS was 11·5 months (95% CI 10·7-13·2) in the group assigned to mFOLFOX6 plus bevacizumab and 11·7 months (10·7-12·9) in the group assigned to SOX plus bevacizumab (HR 1·04, 95% CI 0·86-1·27; less than non-inferiority margin of 1·33, pnon-inferiority=0·014). The most common haematological adverse events of grade 3 or higher were leucopenia (21 [8%] of 249 patients given mFOLFOX6 plus bevacizumab included in safety analysis vs six [2%] of 250 given SOX plus bevacizumab; p=0·0029) and neutropenia (84 [34%] vs 22 [9%]; p<0·0001). Grade 3 or higher anorexia (13 [5%] vs three [1%]; p=0·019) and diarrhoea (23 [9%] vs seven [3%]; p=0·0040) were significantly more common in patients given SOX plus bevacizumab than in those given mFOLFOX6 plus bevacizumab. We recorded seven treatment-related deaths (three in the group given mFOLFOX6 plus bevacizumab; four in that given SOX plus bevacizumab).. SOX plus bevacizumab is non-inferior to mFOLFOX6 plus bevacizumab with respect to PFS as first-line treatment for metastatic colorectal cancer, and could become standard treatment in Asian populations.. Taiho.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Drug Administration Schedule; Drug Combinations; Female; Fluorouracil; Humans; Infusions, Intravenous; Japan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur; Treatment Outcome

This study attempted to determine the therapeutic dosage of irinotecan and S-1 (IRIS) as a second-line treatment for colorectal cancer (CRC).. S-1 was administered on days 1-14 of a 28-day cycle. Irinotecan was administered on days 1 and 15. The irinotecan dose was then escalated to determine the maximum-tolerated dose and the recommended dose at a fixed dosage of S-1 (80 or 65 mg·m(-2)·day(-1)). The S-1 dose was reduced to 65 mg·m(-2)·day(-1) when dose-limiting toxicities were observed at 80 mg·m(-2)· day(-1) and the irinotecan dose was increased.. The recommended dose was 65 mg/m(2) for S-1 and 75 mg/m(2) for irinotecan. Twenty-one patients were treated at the recommended dose. The overall response rate was 28.6%.. This modified IRIS regimen is considered effective with acceptable toxicities for advanced CRC resistant to treatment with 5-fluorouracil/leucovorin or uracil and tegafur/leucovorin.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Combinations; Drug Resistance, Neoplasm; Female; Humans; Irinotecan; Male; Maximum Tolerated Dose; Middle Aged; Oxonic Acid; Tegafur; Treatment Outcome

We evaluated the safety, efficacy, and compliance of 1-year treatment with S-1 in patients with stage II/III resectable colorectal cancer.. S-1 was administered orally in two divided doses daily. The dose was assigned according to body surface area (BSA) as follows: BSA <1.25 m(2), 80 mg/day; BSA ≥1.25 to <1.5 m(2), 100 mg/day; and BSA ≥1.5 m(2), 120 mg/day. S-1 was given for 28 consecutive days, followed by a 14-day rest. The study objects were the rate of completion of treatment as planned at 1 year, the ratio of the actually administered dose to the planned dose at 1 year, and the total number of days of treatment.. At 1 year, the rate of completion of treatment as planned was 77.7 % (42/54 patients), and the ratio of the actually administered dose to the planned dose was 82.9 %. The mean and median total numbers of days of treatment were 209 and 252, respectively. Grade 3 or higher toxicity (watery eyes) occurred in only 1 patient.. S-1 adjuvant chemotherapy had acceptable compliance, safety, and efficacy in patients with colorectal cancer. S-1 adjuvant chemotherapy is considered a possible standard treatment regimen for colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Drug Administration Schedule; Drug Combinations; Feasibility Studies; Female; Humans; Male; Middle Aged; Oxonic Acid; Tegafur; Treatment Outcome

This phase II trial was designed to evaluate the safety and efficacy of adjuvant chemotherapy with S-1 in patients with curatively resected liver metastasis from colorectal cancer. Results of an interim analysis of safety and short-term outcomes are reported.. Patients who underwent curative resection of liver metastasis from colorectal cancer received S-1 monotherapy (on days 1-28, followed by 14 days' rest, 8 cycles) as adjuvant chemotherapy.. Among 62 patients enrolled between October 2008 and August 2010, a total of 60 patients were eligible for analysis. The most frequent grade 3 or higher hematologic toxicity involved neutropenia in three patients (5.0 %). Nonhematologic toxicities of grade 3 or higher were fatigue in 6.7 % of patients. Grade 4 enteritis occurred in one patient, but resolved promptly after withdrawal of S-1 therapy. The completion rate of the eight scheduled cycles of chemotherapy was 58.3 %. The most common reasons for withdrawal of treatment was the detection of early relapse in 16 patients (64 %). When the 16 patients who had recurrence during adjuvant treatment were excluded from analysis, 79.5 % of the remaining 44 patients completed the scheduled treatment. Early recurrence within 1 year after curative liver resection occurred in 21 patients (35 %). The most common site was the remnant liver in 14 patients.. Orally administered S-1 after curative liver resection has an acceptable toxicity profile and a high rate of completion of the therapy. S-1 can be safely used and might be a viable treatment option in an adjuvant setting.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Colorectal Neoplasms; Drug Combinations; Feasibility Studies; Female; Follow-Up Studies; Humans; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Oxonic Acid; Prognosis; Salvage Therapy; Tegafur; Young Adult

The combination of an oral fluoropyrimidine derivative, S-1, and irinotecan has been reported to be a promising regimen for advanced colorectal cancer. However, the safety and efficacy of bevacizumab (BV) to combine with irinotecan and S-1 has not been determined. The aim of the study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of BV combined with irinotecan plus S-1, and to observe the safety and efficacy of this regimen as second-line chemotherapy in patients with advanced colorectal cancer.. This study initially had been planned as a phase I/II study. Eighty mg/m(2) of irinotecan on days 1 and 8, 80 mg/m(2) of S-1 for 14 consecutive days, and two doses of BV (Level 1; 10 mg/kg, Level -1; 7.5 mg/kg) were administered on day 1 every 3 weeks.. Fourteen patients were enrolled in phase I of the study between January 2008 and September 2010. Dose-limiting toxicities were diarrhea, abdominal pain, and infection. The MTD and RD of BV were determined to be 10 mg/kg and 7.5 mg/kg, respectively. The main adverse events were leukopenia, anorexia, and diarrhea. There were no treatment-related deaths. An independent review committee was scheduled to evaluate safety in phase I, but this trial closed early due to toxicity.. This study identified the risk of gastrointestinal toxicity with the combination of irinotecan, S-1 and BV as second-line chemotherapy in patients with advanced colorectal cancer.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Combinations; Female; Gastrointestinal Diseases; Humans; Irinotecan; Male; Maximum Tolerated Dose; Middle Aged; Oxonic Acid; Tegafur

The aim of this study is to prospectively evaluate the efficacy of combination chemotherapy with every second week cetuximab and irinotecan in patients with pretreated metastatic colorectal cancer harboring wild-type KRAS. Patients with wild-type KRAS metastatic colorectal cancer that had progressed after chemotherapy with irinotecan, oxaliplatin, and fluoropyrimidine were included. Cetuximab was administered at 500 mg/m(2) biweekly with irinotecan. The primary endpoint was response rate. The pharmacokinetics of cetuximab was also evaluated in 5 patients. From May 2009 to February 2010, a total of 31 patients were enrolled from five institutions. One patient was not eligible. Among the 30 patients who were treated with biweekly cetuximab plus irinotecan, partial response was observed in 9 patients. The objective response rate was 30.0% (95% confidence interval [CI], 14.7%-49.4%) and the disease control rate (complete response, partial response, or stable disease) was 76.7% (95% CI, 57.7%-90.0%). The median progression-free survival was 5.3 months and median overall survival was 10.8 months. Grade 3 skin toxicity was observed in 3 patients (10.0%) and one treatment related death due to pneumonia was observed. Combination chemotherapy with biweekly cetuximab and irinotecan was effective for pretreated metastatic colorectal cancer with wild-type KRAS.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Drug Combinations; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Japan; Kaplan-Meier Estimate; Male; Middle Aged; Mutation; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Prospective Studies; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Tegafur; Treatment Failure

TSU-68 is a novel multiple tyrosine kinase inhibitor that inhibits VEGFR-2, FGF and PDGF receptors. We conducted a phase I study to evaluate the safety and pharmacokinetic of TSU-68 when used with S-1 and oxaliplatin (SOX) in metastatic colorectal cancer (mCRC) patients. Patients with mCRC were treated with TSU-68 200 mg (Level 1) or 400 mg (Level 2) b.i.d. daily, S-1 35 mg/m(2) b.i.d. on Days 1-14 and oxaliplatin 130 mg/m(2) i.v. on Day 1 repeatedly every 3 weeks. Of eleven patients enrolled, two patients were excluded from dose limiting toxicity (DLT) assessment. Six patients at Level 1 experienced no DLT. Of three patients at Level 2, two patients experienced DLTs (one patient: grade 3 hiccup and palmar-plantar erythrodysaesthesia syndrome, another one: grade 2 neutropenia which prevented the initiation of next cycle within 14 days). The maximal tolerated dose (MTD) and recommended dose (RD) of TSU-68 was 200 mg b.i.d. C(max) and AUC(0-t) of TSU-68 at Level 2 were higher than those at Level 1, but doubling the dose of TSU-68 increased C(max) and AUC(0-t) less than two-fold. There was no appreciable difference in the PK of S-1 components (FT, CDHP and Oxo), 5-FU and oxaliplatin-derived platinum between Levels 1 and 2. A significant decrease in PDGF after TSU-68 treatment was identified and it might serve as pharmacodynamic marker of TSU-68. Administration of TSU-68 in combination with SOX is generally well tolerated. The MTD and RD of TSU-68 in this study was 200 mg b.i.d. daily.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Combinations; Female; Fibroblast Growth Factors; Humans; Indoles; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxindoles; Oxonic Acid; Platelet-Derived Growth Factor; Propionates; Protein Kinase Inhibitors; Pyrroles; Tegafur; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-2

Fluorouracil (5-FU) plus irinotecan combined with bevacizumab has significant activity in metastatic colorectal cancer (mCRC), but S-1 has become a substitute for continuous infusion of 5-FU and has a very low incidence of hand-foot syndrome. With the S-1 plus irinotecan regimen (SIR), the response rate was 62.5%, and the progression-free survival was 8.0 months. We report here on an update of efficacy and safety of the SIR plus bevacizumab (SIRB) regimen as first line treatment for mCRC patients. Fifty-one eligible patients with histologically confirmed advanced or recurrent colorectal cancer received this treatment. S-1 was administered orally on days 1-14 of a 21-day cycle. Patients were assigned on the basis of body surface area (BSA) to receive one of the following oral doses twice daily: 40 mg, 50 mg, or 60 mg. Irinotecan (150 mg/m(2)) plus bevacizumab (7.5 mg/kg) were administered by intravenous infusion on day 1. Safety analysis identified a grade 3/4 neutropenia rate of 26%. Other grade 3/4 toxicities were diarrhea (8%), nausea (6%), vomiting (2%), and hypertension (8%). The response rate was 67% and the median progression-free survival time was 373 days. The SIRB regimen appears to be highly active and well tolerated as first-line treatment for mCRC.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Female; Humans; Irinotecan; Male; Middle Aged; Neoplasm Metastasis; Oxonic Acid; Tegafur; Treatment Outcome

In Japan, a study comparing the effectiveness and safety of irinotecan plus S-1 (IRIS) with those of a combination of 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) as second-line treatment in patients with advanced or recurrent colorectal cancer demonstrated that IRIS was non-inferior to FOLFIRI. We previously reported that IRIS is also effective as first-line treatment.. Eligibility criteria included inoperable recurrent colorectal cancer with a confirmed diagnosis of adenocarcinoma, age ≥20 years, and no history of prior chemotherapy. S-1 (40-60 mg twice daily) was given orally on Days 1 to 14, and irinotecan (100 mg/m(2)) and bevacizumab (5 mg/kg) were given intravenously on Days 1 and 15 of a 28-day cycle. The primary endpoint was safety. The secondary endpoints included overall response (OR), progression-free survival (PFS), and overall survival (OS).. A total of 52 eligible patients were enrolled from October 2007 through March 2009. In safety analysis, the incidences of grade 3 or 4 adverse reactions were as follows: neutropenia, 27%; hypertension, 21%; and diarrhea, 17%. The overall response rate was 57.7%. Median progression-free survival was 16.7 months.. IRIS plus bevacizumab is a well-tolerated, highly effective chemotherapeutic regimen that is easy to administer.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Diarrhea; Drug Administration Schedule; Drug Combinations; Female; Humans; Hypertension; Irinotecan; Japan; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Staging; Neutropenia; Oxonic Acid; Severity of Illness Index; Tegafur; Treatment Outcome

We investigated the efficacy and safety of the combination of irinotecan (CPT-11) and S-1 (IRIS regimen) as a first-line treatment in patients with metastatic colorectal cancer. We also evaluated the association between UGT1A1 and CYP2A6 polymorphisms and clinical phenotypes.. The patients received CPT-11 (225 mg/m(2)) on day 1 and S-1 (80 mg/m(2)) on days 1-14 every 3 weeks. The association of the UGT1A1 (*6 and *28) and CYP2A6(*4, *7, *9, and *10) polymorphisms with toxicities and efficacy were analyzed.. Thirty patients were treated. The overall response rate was 66.7% (95% CI 48.7-84.6). The median time to progression was 7.6 months (95% CI 5.8-9.5). The most common grade 3/4 hematologic and non-hematologic toxicity were neutropenia (53.4%) and diarrhea (16.7%), respectively. The allele frequencies of UGT1A1*6 and *28 were 15.5 and 10.3%, respectively. The frequencies of CYP2A6*4, *7, *9, and *10 were 15.5, 8.6, 29.3, and 3.5%, respectively. Stratification of patients according to the number of UGT1A1*28 and *6 alleles showed a significant correlation between the number of defective alleles and the incidence of grade 3/4 neutropenia.. Our results indicate that IRIS is a promising first-line regimen in patients with metastatic colorectal cancer. Severe neutropenia may be associated with interindividual variations in UGT1A1 polymorphisms.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Aryl Hydrocarbon Hydroxylases; Camptothecin; Colorectal Neoplasms; Cytochrome P-450 CYP2A6; Drug Combinations; Female; Glucuronosyltransferase; Humans; Irinotecan; Male; Middle Aged; Oxonic Acid; Polymorphism, Genetic; Tegafur; Treatment Outcome

The current study aimed to assess the long-term efficacy of combination therapy with oral S-1, a fluoropyrimidine prodrug, plus irinotecan in previously untreated patients with metastatic colorectal cancer.. Between April 2004 and February 2005, 41 patients with previously untreated advanced or recurrent colorectal cancer were enrolled in the study. Chemotherapy consisted of oral administration in S-1 at 40 mg/m(2) twice daily on days 1 to 14 and intravenous infusion of irinotecan at 150 mg/m(2) on day 1 in a 21-day cycle.. The median patient follow-up was 78.0 months. The median survival time was 23.7 months, and the 2-year survival rate was 50%. The median time to tumor progression was 8.3 months.. The results of this long-term update confirmed that first-line combination therapy with oral S-1 plus irinotecan was effective in patients with metastatic colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Female; Follow-Up Studies; Humans; Irinotecan; Male; Middle Aged; Neoplasm Metastasis; Oxonic Acid; Prospective Studies; Tegafur; Young Adult

Capecitabine plus oxaliplatin (CapeOX) is one of the reference doublet cytotoxic chemotherapy treatments for patients with metastatic colorectal cancer. We aimed to compare the efficacy and safety of CapeOX with that of S-1 plus oxaliplatin (SOX), a promising alternative treatment for patients with metastatic colorectal cancer.. In this open-label, multicentre, randomised phase 3 trial, we randomly assigned patients (1:1) from 11 institutions in South Korea to receive either CapeOX (capecitabine 1000 mg/m(2) twice daily on days 1-14 and oxaliplatin 130 mg/m(2) on day 1) or SOX (S-1 40 mg/m(2) twice daily on days 1-14 and oxaliplatin 130 mg/m(2) on day 1). Treatment was repeated every 3 weeks and continued for as many as nine cycles of oxaliplatin-containing chemotherapy, except in instances of disease progression, unacceptable toxicity, or a patient's refusal. Maintenance chemotherapy with S-1 or capecitabine was allowed after discontinuation of oxaliplatin. Randomisation was done with a computer-generated sequence (stratified by primary sites, previous adjuvant or neoadjuvant treatment, and the presence of measurable lesions). The primary endpoint was to show non-inferiority of SOX relative to CapeOX in terms of progression-free survival (PFS). The primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00677443.. Between May 14, 2008, and Sept 23, 2009, we randomly assigned 168 patients to receive SOX and 172 to receive CapeOX. Median PFS was 8·5 months (95% CI 7·6-9·3) in the SOX group and 6·7 months (6·2-7·1) in the CapeOX group (hazard ratio, 0·79 [95% CI 0·60-1·04]; p(non-inferiority)<0·0001, p(log-rank)=0·09). The upper limit of the CI was below the predefined margin of 1·43, showing the non-inferiority of SOX to CapeOX. We recorded a higher incidence of grade 3-4 neutropenia (49 [29%] vs 24 [15%]), thrombocytopenia (37 [22%] vs 11 [7%]), and diarrhoea (16 [10%] vs seven [4%]) in the SOX group than in the CapeOX group. The frequency of any grade of hand-foot syndrome was greater in the CapeOX group than it was in the SOX group (51 [31%] vs 23 [14%]).. The SOX regimen could be an alternative first-line doublet chemotherapy strategy for patients with metastatic colorectal cancer. Further investigation is needed to explore its potential when used together with other targeted agents or as adjuvant chemotherapy.. Korea Healthcare Technology Research and Development Project, Ministry of Health and Welfare, South Korea.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Disease-Free Survival; Drug Combinations; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Republic of Korea; Tegafur

To determine the efficacy and tolerance of irinotecan in combination with S-1 (IRIS) for patients whose disease progressed after treatment with an oxaliplatin-based therapy for colorectal cancer (CRC). Each patient's disease had progressed after the administration of a regimen containing oxaliplatin and 5-FU. S-1 was administered orally at a fixed dose of 40 mg/m(2) twice daily on days 1-14 and 21-35. Irinotecan (150 mg/m(2)) was administered via intravenous infusion on days 1, 15, and 29. Courses were repeated every 6 weeks. 20 patients were enrolled in this study between April 2006 and March 2008. The median age was 63 years (range: 34-74), and the dominant metastasis sites were the liver, lung, and lymph nodes. The objective response rate was 20%; 1 patient registered complete response and 3 patients registered partial responses; 7 patients were stabilized (35%); and 9 evidenced progression of disease (45%). Median progression-free survival was 3.0 months (95% CI, 2.1-3.9 months) and median overall survival was 9.8 months (95% CI, 6.3-13.3 months). For the 41 cycles analyzed, the most commonly detected hematologic toxicity was grade I-II anemia (63.4%). Leukopenia occurred in 18 cycles (41.5%), including eight cycles (19.5%) of grade 3-4 leukopenia. Frequently observed non-hematologic toxicities included the following: grade I vomiting was reported in 4 patients (20%), grade 2 neuropathy occurred in 3 patients (15%), and grade 2 mucositis was noted in 2 patients (10%). Two patients died from sepsis and hematemesis during treatment. Although the response rate in stage I reached the target (≥ 3/18, p0 = 10%) established for movement to stage II, this study had to be discontinued because two patients died during treatment. Additionally, the follow-up loss rate was higher (16.6%) than we had anticipated (<10%). Even though a regime consisting of irinotecan combined with S-1 (IRIS) has proven effective in oxaliplatin-pretreated patients with advanced CRC, treatment-related mortalities and the high follow-up loss rate suggested that this IRIS protocol should result in early closure and modification.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Decision Making; Disease Progression; Dose-Response Relationship, Drug; Drug Combinations; Drug Resistance, Neoplasm; Female; Humans; Irinotecan; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Research Personnel; Survival Analysis; Tegafur; Time Factors; Treatment Outcome

To evaluate the efficacy and safety of S-1 in combination with oxaliplatin in a biweekly schedule as first-line treatment in metastatic colorectal cancer and the association between genetic polymorphisms and treatment outcomes.. Eligibility included age 18-75 years, at least one measurable lesion, no prior chemotherapy except adjuvant chemotherapy, and Eastern Cooperative Oncology Group Performance Status (PS) 0-2. S-1 40 mg/m(2) b.i.d. on days 1-7 with 85 mg/m(2) of oxaliplatin on day 1 was repeated every 2 weeks. Genomic DNA from whole blood was analyzed for 15 single-nucleotide polymorphisms (SNPs) among 8 genes.. Fifty-two patients (median age 63 years, range 37-74) were enrolled: 37 men and 15 women; 44 with a PS of 0 and 8 with a PS of 1; and 41 with initially metastatic cancer and 11 with relapsed disease. Among 51 evaluable patients, objective response rate was 47.1% [95% confidence interval (CI) 32.9-61.2]. Median follow-up duration was 17.1 months (range 3.9-28.2 months). Median progression-free survival (PFS) was 6.4 months (95% CI 4.8-8.1), and median overall survival had not been reached yet. Reported grade 3 toxicities were neutropenia (7.7%), thrombocytopenia (5.8%), sensory neuropathy (7.7%) and diarrhea (1.9%). There was no grade 4 toxicity or neutropenic fever. Patients with A/G or G/G genotype in GSTP1 Ile105Val SNP had longer PFS than patients with A/A (median 8.3 vs. 6.1 months, P = 0.04).. Biweekly S-1 with oxaliplatin is effective and has improved tolerability and convenience compared to other fluoropyrimidine with oxaliplatin combinations. GSTP1 Ile105Val SNP is associated with treatment outcomes.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Drug Administration Schedule; Drug Combinations; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxonic Acid; Polymorphism, Single Nucleotide; Prospective Studies; Pyridines; Tegafur

To investigate the combination of S-1 and irinotecan (CPT-11) as an alternative to infusional 5-fluorouracil/leucovorin plus CPT-11, we performed a phase I trial to determine the maximum tolerated dose, recommended dose (RD), and dose-limiting toxicities (DLTs) in patients with metastatic or recurrent colorectal cancer.. S-1 and CPT-11 doses were escalated using a standard 3 + 3 design. S-1 was administered orally at 70 mg/m(2) (levels 1-3) or 80 mg/m(2) (levels 4 and 5) for 14 consecutive days followed by 1-week rest. CPT-11 was administered intravenously on day 1, at 175 mg/m(2) (level 1), 200 mg/m(2) (level 2), 225 mg/m(2) (levels 3 and 4), or 250 mg/m(2) (level 5). Treatment was repeated every 3 weeks, unless disease progression or severe toxicities were observed.. Twenty-three patients were treated. One patient at each of levels 2 and 4 developed a DLT, grade 3 ileus, and grade 3 diarrhea, respectively. At both levels, an additional three patients did not experience DLTs. At level 5, two of five patients experienced DLTs, including grade 3 enteritis and grade 4 neutropenia for more than 5 days. The RD was determined at level 4 (80 mg/m(2) S-1 and 225 mg/m(2) CPT-11). An objective response was observed in 7 of 17 patients with measurable disease: 2 of 5 at level 2; 3 of 4 at level 4; and 2 of 4 at level 5.. The RDs of CPT-11 and S-1 were determined as 225 and 80 mg/m(2), respectively, and further phase II trials are warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Combinations; Female; Humans; Irinotecan; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Oxonic Acid; Tegafur; Treatment Outcome

A combination of fluorouracil and leucovorin (5-FU/LV) with oxaliplatin (FOLFOX) is an established first-line therapy for metastatic colorectal cancer (mCRC). However, the cumulative neurotoxicity of oxaliplatin often requires therapy to be discontinued while the patient is still responding. A strategy to stop FOLFOX, deliver 5-FU/LV as a maintenance therapy and reintroduce FOLFOX was found to be equivalent in terms of efficacy while neurotoxicity was substantially reduced. The aim of this study was to evaluate feasibility of a stop-and-go strategy with S-1, an oral fluoropyrimidine derivative, as a maintenance therapy administered between modified FOLFOX6 (mFOLFOX6) as a first-line treatment of mCRC.. Thirty patients with untreated mCRC were treated with six cycles of mFOLFOX6 followed by maintenance therapy with oral S-1. Reintroduction of mFOLFOX6 was scheduled after four cycles of S-1 or upon tumor progression. The primary endpoint was duration of disease control (DDC).. Twenty-one of the 30 patients who achieved responses or stabilizations received S-1 maintenance therapy. mFOLFOX6 was reintroduced in 15 patients. Median DDC and progression-free survival were 9.3 and 7.9 months, respectively. The response rates and disease control rates were 40.0 and 86.6% for the initial mFOLFOX6, 23.8 and 57.1% for S-1 maintenance therapy and 20.0 and 73.3% for mFOLFOX6 reintroduction, respectively. Twenty-eight patients (93.3%) had peripheral neuropathy, but grade 3 neurotoxicity was observed in only 1 patient (3.3%).. The planned oxaliplatin stop-and-go strategy with oral S-1 maintenance therapy was feasible as a first-line treatment for Japanese mCRC patients. Further prospective randomized control study is warranted.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur

This phase II study was designed to evaluate the efficacy and safety of oral fluoropyrimidine S-1 plus irinotecan (IRIS regimen) in patients with previously untreated metastatic colorectal cancer.. The response rate was the primary endpoint. Safety, progression-free survival time, and median survival time were secondary endpoints. The subjects were untreated patients with inoperable advanced colorectal cancer. Irinotecan was administered at a dose of 100 mg/m² (on days 1 and 15). S-1 (40 mg/m²) was administered for 2 weeks (on days 1 to 14) and followed by a 2-week rest.. Forty patients were enrolled. Four patients had grade 4 neutropenia, and six patients had grade 3 diarrhea. No other serious hematologic or nonhematologic adverse reactions occurred, and all patients received IRIS safely on an outpatient basis. The response rate was 52.5% (95% confidence interval [CI], 36.1-68.5%). Median progression-free survival was 8.6 months (95% CI, 5.3-11.9), and median survival time was 23.4 months (95% CI, 15.9-30.8).. IRIS produced a high response rate and could be given safely. IRIS may become a first-line treatment for inoperable or recurrent advanced colorectal cancer.

Topics: Adenocarcinoma; Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Combinations; Female; Humans; Irinotecan; Leukopenia; Male; Middle Aged; Neoplasm Recurrence, Local; Neutropenia; Oxonic Acid; Tegafur; Treatment Outcome

S-1, a novel oral fluoropyrimidine, is well tolerated in patients with metastatic colorectal cancer (mCRC). The response rate of S-1 for colorectal cancer is high, ranging from 35% to 40%. This study aimed to evaluate the safety and efficacy of S-1 combined with oral leucovorin (LV) to enhance antitumor activity in chemotherapy-naive patients with mCRC.. S-1 was given orally twice daily for two consecutive weeks at a daily dose of 80-120 mg, followed by a 2-week rest period, within a 4-week cycle. LV was given orally twice a day at a daily dose of 50 mg, simultaneously with S-1.. Of the 56 patients with previously untreated mCRC, 32 (57%) had partial responses. The median follow-up period was 27.2 months. The median time to progression was 6.7 months (95% confidence interval 5.4-7.9). The median survival time was 24.3 months. There was no treatment-related death or grade 4 toxicity. The most common grade 3 toxic effects were diarrhea (32%), anorexia (21%), stomatitis (20%), and neutropenia (14%).. S-1 combined with LV therapy demonstrated promising efficacy and acceptable safety in chemotherapy-naive patients with mCRC without the concurrent use of irinotecan, oxaliplatin, or molecular-targeted drugs.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Disease Progression; Drug Administration Schedule; Drug Combinations; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxonic Acid; Survival Analysis; Tegafur; Treatment Outcome

We carried out this study to examine the health-related quality of life (HRQOL) of patients with advanced colorectal cancer treated with the oral fluoropyrimidine S-1 plus irinotecan (CPT-11).. HRQOL was assessed at baseline (pretreatment) and at 5-week intervals during treatment, using the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR38 questionnaires. The HRQOL data for 12 preselected scales and 21 courses of treatment were then analyzed longitudinally.. Thirty-seven patients completed the baseline and post-treatment HRQOL assessments. Statistically significant differences between the baseline and post-treatment HRQOL scores were observed for the global QOL, social function, and pain scales (all QLQ-C30), as well as the body image, future perspective, gastrointestinal tract symptoms, weight loss, and chemotherapy side effects scales (all QLQ-CR38); favorable post-treatment results were observed for all the scales except for body image and chemotherapy side effects, for which post-treatment deteriorations were observed. The changes in body image, future perspective, weight loss, and chemotherapy side effects were each greater than ten points and seemed clinically significant.. Combined treatment with S-1 plus CPT-11 resulted in an acceptable deterioration in HRQOL functioning and symptoms, compared with baseline levels.

Topics: Adenocarcinoma; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Combinations; Female; Humans; Irinotecan; Longitudinal Studies; Male; Middle Aged; Oxonic Acid; Quality of Life; Surveys and Questionnaires; Tegafur; Time Factors; Treatment Outcome

A combination of irinotecan with continuous infusional 5-fluorouracil (5-FU) is the standard treatment for advanced colorectal cancer. The aim of this study was to determine the efficacy and safety of combining irinotecan and S-1 (IRIS) in patients with advanced colorectal cancer.. Irinotecan was administered as an intravenous infusion at a dose of 120 mg/m(2) on day 1 and 15. And S-1 was administered orally on days 1-14 of a 28-day cycle. S-1 was given orally at a dose that did not exceed 40 mg/m(2) based BSA: BSA < 1.25 m(2), 40 mg twice daily; 1.25-1.5 m(2), 50 mg twice daily, and BSA > 1.5 m(2), 60 mg twice daily, for 14 consecutive days.. A total of 38 patients were enrolled. An intent-to-treat analysis showed a complete response and partial response to occur in 13.2% and 50.0%, respectively. The disease control rate was 84.2%. The median progression-free survival and overall survival were 10.0 months and 29.1 months, respectively. The rates of grade 3/4 toxicity over 4 cycles were the following: neutropenia, 15.8%; leucopenia, 7.9%; anorexia, 15.8%; diarrhea, 10.5%.. IRIS is an effective, well tolerated and convenient treatment regimen for patients with advanced colorectal cancer.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Body Surface Area; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Irinotecan; Male; Middle Aged; Oxonic Acid; Survival; Tegafur; Treatment Outcome

Fluorouracil and folinic acid with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) are widely used as first-line or second-line chemotherapy for metastatic colorectal cancer. However, infusional fluorouracil-based regimens, requiring continuous infusion and implantation of an intravenous port system, are inconvenient. We therefore planned an open-label randomised controlled trial to verify the non-inferiority of irinotecan plus oral S-1 (a combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate; IRIS) to FOLFIRI as second-line chemotherapy for metastatic colorectal cancer.. Between Jan 30, 2006, and Jan 29, 2008, 426 patients with metastatic colorectal cancer needing second-line chemotherapy from 40 institutions in Japan were randomly assigned by a computer-based minimisation method to receive either FOLFIRI (n=213) or IRIS (n=213). In the FOLFIRI group, patients received folinic acid (200 mg/m(2)) and irinotecan (150 mg/m(2)) and then a bolus injection of fluorouracil (400 mg/m(2)) on day 1 and a continuous infusion of fluorouracil (2400 mg/m(2)) over 46 h, repeated every 2 weeks. In the IRIS group, patients received irinotecan (125 mg/m(2)) on days 1 and 15 and S-1 (40-60 mg according to body surface area) twice daily for 2 weeks, repeated every 4 weeks. The primary endpoint was progression-free survival, with a non-inferiority margin of 1.333. Statistical analysis was on the basis of initially randomised participants. This study is registered with ClinicalTrials.gov, number NCT00284258.. All randomised patients were included in the primary analysis. After a median follow-up of 12.9 months (IQR 11.5-18.2), median progression-free survival was 5.1 months in the FOLFIRI group and 5.8 months in the IRIS group (hazard ratio 1.077, 95% CI 0.879-1.319, non-inferiority test p=0.039). The most common grade three or four adverse drug reactions were neutropenia (110 [52.1%] of 211 patients in the FOLFIRI group and 76 [36.2%] of 210 patients in the IRIS group; p=0.0012), leucopenia (33 [15.6%] in the FOLFIRI group and 38 [18.1%] in the IRIS group; p=0.5178), and diarrhoea (ten [4.7%] in the FOLFIRI group and 43 [20.5%] in the IRIS group; p<0.0001). One treatment-related death from hypotension due to shock was reported in the FOLFIRI group within 28 days after the end of treatment; no treatment-related deaths were reported in the IRIS group.. Progression-free survival with IRIS is not inferior to that with FOLFIRI in patients receiving second-line chemotherapy for metastatic colorectal cancer. Treatment with IRIS could be an additional therapeutic option for second-line chemotherapy in metastatic colorectal cancer.. Taiho Pharmaceutical Co Ltd and Daiichi Sankyo Co Ltd.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Prodrugs; Tegafur

The combination of an oral fluoropyrimidine derivative, S-1, and irinotecan is expected to be a promising regimen for advanced colorectal cancer. This study was performed to determine the maximum tolerated dose (MTD) and recommended dose (RD) of irinotecan combined with S-1 in a 3-week cycle regimen and to observe the safety and efficacy for patients with previously untreated advanced colorectal cancer. Eighty milligrams per m(2) of S-1 was given orally for 14 consecutive days and escalated doses of irinotecan were administered on days 1 and 8 every 3 weeks in the phase I trial. Forty patients were treated at the RD during the phase II trial. Forty-three patients were enrolled between February 2005 and March 2007. The dose-limiting toxicity was diarrhea and abdominal pain. The MTD of irinotecan was 100 mg/m(2) and the RD was determined to be 80 mg/m(2) of irinotecan combined with 80 mg/m(2) of S-1. The phase II trial showed that 22 of 40 patients achieved a complete or partial response and eight had stable disease. The overall response rate was 55.0%. The median progression-free survival time and median survival time were 6.7 and 21 months, respectively. There were no treatment-related deaths. The main toxicities were leukopenia, neutropenia, anorexia and diarrhea. This study suggests the combination of irinotecan and S-1 repeated every 3 weeks is tolerable and effective for patients with previously untreated advanced colorectal cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Combinations; Female; Humans; Irinotecan; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Oxonic Acid; Tegafur

Three-drug combination of fluoropyrimidine, irinotecan and oxaliplatin has shown survival benefits in patients with metastatic colorectal cancer (mCRC). Recently we performed a phase II study of a new 3-drug regimen, TIROX (S-1 plus irinotecan and oxaliplatin) to evaluate efficacy and safety in refractory mCRC patients. Patients with refractory to all of 3 drugs, age > or = 18 years, PS 0-2, > or = 1 measurable lesion(s) and adequate organ functions were eligible. S-1 was given 40 mg/m(2) twice a day on D1-14, oxaliplatin 85 mg/m(2) and irinotecan 150 mg/m(2) on D1 every 3 weeks. The primary endpoint was overall response rate (ORR). Between Mar 2007 and Nov 2007, 19 patients (of 18 planned) were enrolled; median age 50 years; M/F 12/7; PS 0/1/2 5/13/1; colon/rectum 11/8. By intent-to-treat analysis, ORR was 21.1% (95% CI, 8.7-43.7) and disease control rate was 52.6% (95% CI 31.5-72.8) with four PRs and six SDs. Median duration of disease control was 4.3 months (95% CI 1.7-6.9). Median PFS was 2.6 months (95% CI 2.2-2.9) and median OS was 9.8 months (95% CI 5.3-14.4) after median F/U of 15.4 months. G3/4 toxicities per pt included neutropenia (five, 26.3%), febrile neutropenia (two, 10.5%), thrombocytopenia (one, 5.3%), diarrhea (two, 10.5%) and fatigue (two, 10.5%). TIROX seemed to be feasible and efficacious for refractory mCRC patients, and could be an alternative for patients with good PS but no further treatment options.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Female; Humans; Irinotecan; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur; Treatment Outcome

The aim of this study was to determine the maximum tolerated dose, recommended dose and dose-limiting toxicities of irinotecan (CPT-11) plus S-1 in advanced colorectal cancer.. S-1 was administered orally at 80 mg/m(2) per day for 14 consecutive days followed by a 2-week rest. CPT-11 was given intravenously on days 1 and 15 of each course, at an initial dose of 80 mg/m(2) per day, stepping up to 100, 120 or 150 mg/m(2) per day. Courses were repeated every 4 weeks, unless disease progression or severe toxicities were observed.. A total of 21 patients were entered in this study. The maximum tolerated dose of CPT-11 was considered to be 150 mg/m(2), because 2 of 3 patients developed dose-limiting toxicities such as leukopenia, neutropenia, diarrhea and anorexia. The recommend dose of CPT-11 was set at 120 mg/m(2). Tumor response rate was 42.8% and median progression-free survival time was 10 months (95% confidential interval, 6.0-14.0 months).. A combination of S-1 and CPT-11 showed a good safety profile and can be recommended for further phase II studies in patients with colorectal cancer.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Disease Progression; Dose-Response Relationship, Drug; Drug Combinations; Female; Humans; Injections, Intravenous; Irinotecan; Male; Middle Aged; Oxonic Acid; Rectal Neoplasms; Tegafur

To evaluate the efficacy and safety of the combination of oxaliplatin and S-1 (OS) in treating metastatic colorectal cancer.. Eligible patients were those with measurable lesions, no previous history of chemotherapy (except adjuvant chemotherapy), an age of 18-70 years, and an Eastern Cooperative Oncology Group performance status of zero to two. Oxaliplatin 130 mg/m(2) was administered i.v. on day 1, and S-1 40 mg/m(2) b.i.d. was administered orally on days 1-14, every 3 weeks.. Forty-eight patients (median age, 56 years) were enrolled: 23 had colon cancer, seven rectosigmoid colon cancer; and 18 rectal cancer. Of the 48 patients, 31 were diagnosed with metastatic cancer and 17 had relapsed cancer after surgery, with adjuvant chemotherapy or chemoradiotherapy. In total, 413 cycles were administered (median 6 per patient; range 2-24). Toxicity was evaluated in 48 patient and response in 46. Major toxic effects were grade 3/4 thrombocytopenia (13%) and neutropenia (10%). The overall response rate was 54% [95% confidence interval (CI) 40% to 68%]. The median time to progression and median survival time were 8.5 (95% CI 6.2-10.9) months and 27.2 (95% CI 20.3-34.0) months, respectively.. These data indicate that the OS regimen is effective and well tolerated in patients with advanced colorectal cancer.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Female; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur; Time Factors; Treatment Outcome; Young Adult

This is a feasibility trial of oral uracil/tegafur (UFT)/oral leucovorin (LV) and irinotecan (TEGAFIRI) with maximum dose confirmed in Japan. To document the toxicity and define the objective response rate (RR); and determine progression-free and overall survival.. Patients with advanced or metastatic colorectal cancer (CRC) received: UFT 300 mg/m(2), LV 75 mg/body and CPT-11 150 mg/m(2) (UFT and LV given on days 1-14, and CPT-11 on day 1, every 3 weeks). Eligibility: ECOG performance status (PS) 0-1, adequate bone marrow/liver function and serum creatinine level less than institutional normal value.. Eighteen patients enrolled, 17 evaluable for toxicity and response and 1 patients recalled chemotherapy upon registration. Characteristics: 61% male, median age 63.5 years (51-71). Seventy-two per cent PS 0, 50% first line. One hundred and eighty-six cycles have been delivered. The common Grade 3-4 toxicities were neutropenia (35.3%), leukopenia (29.4%), diarrhea (5.9%), anorexia (5.9%), vomiting (5.9%) and dizziness (5.9%). There was no episode of febrile neutropenia. No death occurred on treatment: Overall RR was 41.2% [7/17: 1 complete response (CR) + 6 partial response (PR)]. Progression-free survival (PFS) is 6.9 months, median survival time (MST) is 25.1 months and 1-year survival rate is 70.6%, whereas PFS 15.0 months, MST 43.6+ months and 1-year survival rate 100% in cases with CR or PR.. Approved dose of CPT-11 is 150 mg/m(2) in Japan. As is lower dose with CPT-11, TEGAFIRI for patients with advanced or metastatic CRC in Japan seems to have the similar effect with that reported abroad and indicates prolonged PFS and MST in cases with CR or PR.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Combinations; Feasibility Studies; Female; Humans; Immunoenzyme Techniques; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Staging; Oxonic Acid; Prognosis; Survival Rate; Tegafur; Uracil

S-1 showed clinical activity in colorectal cancer, and the preclinical data of S-1 with oxaliplatin showed synergistic activity in an animal model. This phase I study was conducted to determine the maximum tolerated dose of S-1 with oxaliplatin and to define its recommended dose for the subsequent phase II study.. Patients with untreated colorectal adenocarcinoma were eligible in this study if they had measurable lesions. S-1 was administered on days 1-14, with doses starting from 60 mg/m2 per day and escalating by 10 mg/m2 at each dose level. Oxaliplatin was given at the fixed dose of 130 mg/m2, through 2-h i.v. infusion on day 1. The treatment was repeated every 3 weeks.. A total of 27 patients received six different S-1 dose levels. The dose-limiting toxicities (DLTs) were neutropenia, diarrhea, and vomiting. At dose level 5 (100 mg/m2), two patients experienced DLTs, while none of the third cohorts did. At dose level 6 (110 mg/m2), two patients experienced DLTs, and one of them died from treatment-related toxicity. The accrual was then stopped.. The recommended dose is S-1 100 mg/m2 on days 1-14, with 130 mg/m2 oxaliplatin on day 1, every 3 weeks. This regimen is proposed for the phase II study.

Topics: Adolescent; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Combinations; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Recurrence; Tegafur; Treatment Outcome; Young Adult

To determine the efficacy and tolerability of oral fluoropyrimidine S-1 plus irinotecan in patients with previously untreated advanced colorectal cancer.. S-1 was administered orally at 80 mg/m(2)/day for 21 consecutive days followed by a 2-week rest. CPT-11 was given intravenously on days 1 and 15 of each course, at a dose of 80 mg/m(2)/day. Courses were repeated every 5 weeks, unless disease progression or severe toxicities were observed.. A total of 282 courses of treatment were administered to 40 patients, achieving complete response in 1 and partial responses in 24 with an overall response rate of 62.5% (95% CI: 47.5-77.5%). Median progression-free survival was 7.8 months (95% CI: 6.7-9.6 months). The rates of grade 3 or 4 toxicities were as follows: neutropenia 12.5%, anorexia 12.5%, fatigue 10%, and diarrhea 7.5%.. Combined treatment with S-1 and irinotecan is an effective, well-tolerated and convenient regimen in patients with advanced colorectal cancer which is easily maintained.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Drug Combinations; Female; Fluorouracil; Humans; Irinotecan; Male; Middle Aged; Oxonic Acid; Tegafur

From July, 2007 to June, 2008, we prospectively investigated the influence of Hange-shashin-to on the therapeutic and adverse effects of chemotherapy and the changes in quality of life(QOL)scores of the patients with metastatic gastric and colorectal cancer. Twenty patients receiving S-1/Irinotecan (CPT-11) therapy were randomly allocated into group A (with Hange-shashin-to) and B (without Hange-shashin-to). While the anti-tumor effects did not differ significantly between these two groups, severe side effects of more than grade 3 occurred less frequently in group A. Our results suggested that the decrease in QOL scores on day 15 might be alleviated in group A, compared to group B. Therefore, Hange-shashin-to can be one of the useful supportive medicines in the combination therapy of S-1/CPT- 11.

Topics: Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Combinations; Drugs, Chinese Herbal; Female; Humans; Irinotecan; Male; Middle Aged; Oxonic Acid; Quality of Life; Stomach Neoplasms; Tegafur

Both irinotecan (CPT-11) and S-1 are active against colorectal cancer; however, as S-1 is a prodrug of 5-fluorouracil (5-FU), 5-FU and its metabolites might inhibit the antitumour effect of CPT-11. Therefore, we designed a sequential combination, in which CPT-11 infusion was given on day 1 and S-1 was given orally at 80 mg m(-2) per day on days 3-16 every 3 weeks.. Twelve patients entered the phase I study, and the recommended doses were determined as a CPT-11 dose of 150 mg m(-2) and an S-1 dose of 80 mg m(-2).. In all, 36 patients entered the phase II study, of whom 4 and 16 had complete and partial responses. The overall response rate was 55.6% (95% confidence interval, 38.1-72.1%), and median progression-free survival was 7.7 months (95% confidence interval, 4.8-12.6 months). Grade 3 neutropenia was the most common haematological toxicity and occurred in 6.5% of 215 treatment courses. Grade 3 non-haematological toxicities included anorexia (1.4%) and diarrhoea (0.9%). There was no grade 4 toxicity of any kind.. Our results suggest that this regimen is convenient, safe and promising, compared with conventional regimens for patients with metastatic colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Combinations; Female; Humans; Irinotecan; Male; Maximum Tolerated Dose; Middle Aged; Oxonic Acid; Tegafur

The anti-angiogenic efficacy of chemotherapy would seem to be optimized by administering comparatively lower doses of drugs on a more frequent (daily, several times a week, or weekly) or continuous schedule, with no extended interruptions - sometimes referred to as 'metronomic' chemotherapy. This phase I study was performed to determine the recommended dosage (RD) of metronomic chemotherapy using oral fluoropyrimidine S-1 plus weekly irinotecan (CPT-11) in patients with previously untreated advanced or recurrent colorectal cancer. Patients received first-line chemotherapy consisting of 80 mg/m(2) of S-1 given on days 3 to 7, 10 to 14, and 17 to 21 with escalating dosages of CPT-11 (from 40 mg/m(2)) administered intravenously on day 1, 8, and 15 of a 28-day cycle. Standard patient eligibility criteria were used. Based on the concept of metronomic chemotherapy, dose limiting toxicity (DLT) was defined any toxicity that resulted in skipping of CPT-11 administration, or more than 5 days suspension in S-1 administration, in addition to the conventional criteria. If the maximum tolerated dosage (MTD) was defined as the maximum dosage at which no suspension of CPT-11 or S-1 administration occurred, the RD was considered to be the dosage one rank lower than the MTD. On the other hand, in the present study the MTD was defined as the dosage at which at least one suspension of CPT-11 or S-1 administration occurred, the MTD was considered to be the RD. Two of the first 3 patients at level 4 received 60 mg/m(2) of CPT-11 and 80 mg/m(2) of S-1 experienced a suspension in CPT-11 administration, thus level 4 was defined as the MTD and RD. Sixty mg/m(2) of CPT-11 and 80 mg/m(2) of S-1 were the indicated RD for the following phase II study of metronomic chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Combinations; Female; Humans; Irinotecan; Male; Maximum Tolerated Dose; Middle Aged; Oxonic Acid; Tegafur

The purpose of this study was to determine the optimal dose of oxaliplatin, when combined with a fixed dose of S-1 (40 mg/m twice daily on days 1-14) on a 3-week schedule, for patients with advanced and/or metastatic colorectal cancer. Patients were required to have a histologically proven advanced or metastatic colorectal cancer for which they had received no previous chemotherapy. Oxaliplatin was administered intravenously on day 1 every 3 weeks. Patients were divided into two groups to receive two doses of oxaliplatin - 100 mg/m or 130 mg/m. Ten patients were enrolled in the study between March 2006 and July 2006, and were followed up until 50% of the patients progressed. All patients were evaluated for chemotherapy-related toxicity. The maximum tolerated dose was not reached during the first course. One of six patients experienced grade 3 thrombocytopenia at dose level 2 of oxaliplatin. Nonhematological toxicity was mild and tolerable. During the full course of treatment, complete response was achieved in two of the nine evaluated patients and partial response was achieved in one patient. The remaining six patients achieved stable disease during first two courses of therapy, and four patients remained stable at the time of the last follow-up. The median time to progression-free survival was 8.3 months. When combined with a fixed dose of S-1 80 mg/m, oxaliplatin administered at a dose of 130 mg/m is tolerable and recommended for phase II study.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Combinations; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur

Phase I study of combination therapy with peptide vaccine and anti-cancer drug for colorectal cancer has been performed in our hospital. The purpose of this study was to evaluate the safety and immune response of different dose of RNF43-721 emulsified with Montanide ISA 51 in combination with S-1/CPT-11 chemotherapy. The study design was a dose escalation of peptide (0.5, 1.0, 3.0 mg) with three patients' cohort. Nine patients were enrolled. All patients were treated with peptide subcutaneously every week and two courses with S-1/CPT-11 chemotherapy. Vaccinations were well tolerated without any major adverse events. Immunological reactions are not analyzed yet. We herein report a case who has been evaluated to be long SD with this intervention for para-aortic LN metastasis from sigmoid colon cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cancer Vaccines; Colorectal Neoplasms; Combined Modality Therapy; Drug Combinations; HLA-A Antigens; HLA-A24 Antigen; Humans; Immunotherapy; Irinotecan; Male; Oxonic Acid; Peptides; Tegafur; Tomography, X-Ray Computed

Although the prognosis in patients with pancreatic cancer has been poor, we recently reported unusually high response rate and survival benefit of S-1 treatment in patients with pancreatic cancer. The aim of this study was to reveal genetic background of this unique activity of S-1 against pancreatic cancer. S-1 is a novel oral fluoropyrimidine derivative consisting of Tegafur (FT) and dihydropyrimidine dehydrogenase (DPD) inhibitor (5-chloro-2,4-dihydroxypyridine; CDHP). Accordingly, intratumoral DPD mRNA expression level was measured to reveal whether the level in pancreatic cancer was different from other GI cancer and whether it was relevant to chemosensitivity.. Thirty-three recurrent pancreatic cancer patients treated with S-1 were studied. We obtained 15 responders and 13 non-responders according to the change of serum CA19-9. The mRNA was extracted from paraffin-embedded surgical specimens using laser captured microdissection, and relative expression levels of each DPD/beta-actin were measured using a quantitative reverse transcription polymerase chain reaction (RT-PCR) (Taqman) system. Forty-four colorectal cancer patients and 20 gastric cancer patients treated with S-1 were enrolled as control groups. Thymidylate synthase (TS) mRNA expression levels were also measured.. Intratumoral DPD mRNA expression level was significantly higher in pancreatic cancer than that in colorectal cancer (P = 0.0003; median level, 1.38 vs. 0.44) and gastric cancer (P = 0.0061; 1.38 vs. 0.82). No difference in TS mRNA expression levels was observed among cancer types. DPD expression among responded pancreatic cancer was significantly lower than non-responded. (P = 0.012, Mann-Whitney U test).. Intratumoral DPD mRNA expression level in pancreatic cancer was significantly higher than the other malignancies. This result may elucidate possible reasons for the high effectiveness of S-1 in pancreatic cancer.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; CA-19-9 Antigen; Cisplatin; Colorectal Neoplasms; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Female; Humans; Male; Middle Aged; Neoplasm Proteins; Oxonic Acid; Pancreatic Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Neoplasm; Stomach Neoplasms; Tegafur; Treatment Outcome

To determine the maximum tolerated dose, recommended dose and dose-limiting toxicities of irinotecan plus S-1 in advanced colorectal cancer.. S-1 was administered orally at 80 mg/m2/day for 21 consecutive days followed by a 2-week rest. CPT-11 was given intravenously on days 1 and 15 of each course, at an initial dose of 60 mg/m2/day, stepping up to 80, 100, 120 or 140 mg/m2/day. Courses were repeated every 5 weeks, unless disease progression or severe toxicities were observed.. A total of 20 patients were entered in this study. The maximum tolerated dose of CPT-11 was considered to be 100 mg/m2, because 2 of 3 patients developed dose-limiting toxicities, such as anorexia, fatigue and diarrhea. Therefore, the recommended dose of CPT-11 was set at 80 mg/m2. Tumor responses were seen in 8 of 14 patients with measurable lesions.. A combination of S-1 with CPT-11 is safe and can be recommended for further phase II studies in patients with advanced colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Combinations; Female; Humans; Irinotecan; Male; Maximum Tolerated Dose; Middle Aged; Oxonic Acid; Tegafur

A combination of irinotecan with continuous intravenous infusions of 5-fluorouracil (5-FU) and leucovorin (LV) is often used to treat advanced colorectal cancer. However, recent concerns about safety and convenience have prompted the development of new oral fluoropyrimidine derivatives and improved regimens. This phase II study evaluated the efficacy and safety of the oral fluoropyrimidine S-1 plus irinotecan in patients with previously untreated advanced or recurrent colorectal cancer.. Forty eligible patients with histologically confirmed colorectal adenocarcinoma received this treatment. S-1 was administered orally on days 1 to 14 of a 21-day cycle. Patients were assigned on the basis of body surface area (BSA) to receive one of the following oral doses twice daily: 40 mg (BSA < 1.25 m(2)), 50 mg (BSA > or = 1.25 to < 1.50 m(2)), or 60 mg (BSA > or = 1.50 m(2)). Irinotecan (150 mg/m(2)) was administered by intravenous infusion on day 1.. A total of 327 courses of treatment were administered to 40 patients. Five patients had complete responses, and 20 had partial responses. The overall response rate was 62.5% (95% confidential interval, 47.5%-77.5%). Median progression-free survival was 8.0 months (95% confidential interval, 5.2-11.4 months). The rates of grade 3 or 4 toxicity were as follows: neutropenia, 15%; anemia, 7.5%; anorexia, 12.5%; and diarrhea, 7.5%.. Combined treatment with S-1 and irinotecan is an effective, well tolerated, and convenient regimen in patients with advanced colorectal cancer. Our findings suggest that combined treatment with S-1 and irinotecan is a promising regimen, offering benefits in terms of safety and survival as compared with conventional regimens in patients with advanced colorectal cancer.

Topics: Adenocarcinoma; Adult; Aged; Anemia; Anorexia; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Diarrhea; Disease-Free Survival; Drug Combinations; Female; Humans; Irinotecan; Male; Middle Aged; Neoplasm Staging; Oxonic Acid; Survivors; Tegafur; Treatment Outcome

We planned to conduct a phase II clinical study of combination therapy with CPT-11 and S-1. The antitumor effect was the primary endpoint, while the safety, progression-free survival time, and median survival time were the secondary endpoints. The subjects were untreated patients with inoperable advanced colorectal cancer aged 20-75 years. Based on the results of our previous phase I/II study in patients with gastric cancer, the dosage was established in consideration of safety for outpatient therapy. CPT-11 was administered at a dose of 100 mg/m2 (on days 1 and 15) as an intravenous infusion over 90 minutes, and oral S-1 (40 mg/m2) was administered after breakfast and dinner and then withdrawn for 2 weeks. No other serious adverse reactions occurred (either hematological or non-hematological), and all patients could receive therapy safely on an outpatient basis. Interim analysis suggested excellent results, with a response rate of 50%. Combination therapy with CPT-11 and S-1 achieved a high response rate and could be given safely. These findings suggest that the therapy has potential as first-line treatment for inoperable advanced recurrent colorectal cancer.

Topics: Administration, Oral; Adult; Aged; Alopecia; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Humans; Infusions, Intravenous; Irinotecan; Leukopenia; Middle Aged; Nausea; Neutropenia; Oxonic Acid; Remission Induction; Tegafur

Various kinds of combination chemotherapies with 5-FU as a base agent have been performed for patients with advanced or recurrent colorectal cancer. S-1 was a newly developed 5-FU derivative and was orally administered. One of the combination therapies with S-1 plus irinotecan (CPT-11) has also been expected to have a better therapeutic value. Recently this combination therapy has been undertaken by our department, and its clinical use and toxicities are described in this article.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Humans; Infusions, Intravenous; Irinotecan; Leukopenia; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Oxonic Acid; Tegafur; Vomiting, Anticipatory

This is the first phase II study of S-1 monotherapy for patients with metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-containing regimens. The initial dose of S-1 was 35 mg m-2, administered twice daily for 14 days every 3 weeks. Treatment was repeated until the occurrence of disease progression. Twenty-eight patients were enrolled. S-1 was administered to 21 patients as third-line therapy and to the remaining seven patients as fourth-line therapy. Of 26 evaluable patients, the overall response rate was 14.3% (95% CI, 0.4-28.1), and the disease control rate was 42.9% (95% CI, 23.3-62.4). With a median follow-up period of 227 days, median time to progression and overall survival duration were 91 and 414 days, respectively. The 1-year survival rate of all patients was 60.7%. There was no grade 4 toxicity. Grade 3 haematological toxicities were documented only in two patients. In conclusion, S-1 shows potential as a salvage regimen in heavily pretreated colorectal cancer patients. The twice-daily dose of 35 mg m-2 was well tolerated and can be used in designing further combination chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Combinations; Female; Humans; Irinotecan; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Salvage Therapy; Survival Rate; Tegafur; Treatment Outcome

We have previously reported on phase I/II studies of irinotecan plus S-1 therapy for advanced gastric cancer. Based on the safety and efficacy data that were obtained, this phase II study was planned to assess the efficacy of irinotecan plus S-1 for patients with advanced colorectral cancer. A total of 40 patients are enrolled at 13 medical institutions. The objective of this study was to establish a useful chemotherapy regimen for an out-patient setting.

Topics: Adenocarcinoma; Administration, Oral; Adolescent; Adult; Aged; Ambulatory Care; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Humans; Irinotecan; Middle Aged; Oxonic Acid; Pyridines; Tegafur

Cyclooxygenase-2 (COX-2) is generally elevated in tumors compared with normal tissue and apparently has an important role in tumor development. A number of studies have found high expression of COX-2 to be an unfavorable prognostic factor for overall survival in several cancers. However, the influence of COX-2 expression levels on tumor response to chemotherapy has been relatively little studied. The purpose of this study was to ascertain if COX-2 gene expression is associated with tumor response in the clinical treatment of colorectal cancer with the fluoropyrimidine-based therapy S-1.. Patients with advanced (stage IV) colorectal cancer were treated with S-1 twice daily based on the patient's body surface area (BSA; BSA < 1.25 m2, 80 mg/d; 1.25 m2 < or = BSA < 1.5 m2, 100 mg/d; BSA > or = 1.5 m2, 120 mg/d) for 28 days followed by a 2-week period rest. mRNA was isolated from paraffin-embedded pretreatment primary tumor specimens and expression levels of COX-2 relative to beta-actin as the internal reference gene were measured using a quantitative reverse transcription-PCR (Taqman) system.. The overall response rate in a group of 44 patients treated with S-1 was 40.9%. Sufficient tumor tissue was available from 40 of these patients for COX-2 mRNA quantitation. COX-2 gene expression was significantly lower in the responding tumors compared with the nonresponders (P = 0.012, Wilcoxon test). Patients with COX-2 values above the cutoff value of 3.28 x 10(-3) had a significantly shorter survival than those with COX-2 gene expressions below the cutoff value (adjusted P = 0.031).. Intratumoral COX-2 gene expression is associated with likelihood of response to chemotherapy with S-1 and is a prognostic factor for survival of patients after the start of S-1 chemotherapy.

Topics: Aged; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Cyclooxygenase 2; Drug Combinations; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Male; Membrane Proteins; Middle Aged; Oxonic Acid; Predictive Value of Tests; Prognosis; Prostaglandin-Endoperoxide Synthases; Pyridines; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Survival Analysis; Tegafur; Treatment Outcome

The goal of the current study was to evaluate the objective response rate and toxicity associated with the oral fluoropyrimidine S-1 (a combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate) in patients with previously untreated metastatic colorectal carcinoma.. Thirty-eight patients were enrolled in the study. S-1 was administered orally at a dose of 40 mg/m2 twice daily for 28 days, followed by a 14-day rest period. Treatment was repeated every 6 weeks unless disease progression was observed.. A combined total of 173 courses of S-1 were administered to the 38 enrolled patients. The median number of courses administered to a given patient was 3.5 (range, 1-18). Although no patient exhibited a complete response to treatment, 15 had partial responses (response rate, 39.5%; 95% confidence interval, 24.0-56.6%). In addition, 5 patients had minor responses, and 14 had stable disease. Four patients were found to have progressive disease after two courses of treatment. The median survival time was 358 days (95% confidence interval, 305-490 days), and the 1-year survival rate was 47.4%. The most common adverse reactions included myelosuppression and gastrointestinal toxicity; most cases involved Grade 1 or 2 toxicity, but Grade 3 toxicities (anemia [7.9% of patients], neutropenia [5.3% of patients], diarrhea [2.6% of patients], and abnormal bilirubin levels [7.9% of patients]) also were noted. Neither Grade 4 toxicity nor treatment-related death was observed during the study.. Orally administered S-1 is active against metastatic colorectal carcinoma and has an acceptable toxicity profile. This promising agent has the potential to become a valuable chemotherapeutic option.

Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Drug Combinations; Female; Humans; Male; Middle Aged; Oxonic Acid; Pyridines; Survival Rate; Tegafur; Treatment Outcome

The oral fluoropyrimidine S-1, which consists of a mixture of a 5-fluorouracil (5-FU) prodrug (tegafur), a dihydropyrimidine dehydrogenase inhibitor [5-chloro-2,4-dihydroxypyrimidine (CDHP)], and an inhibitor of orotate phosphoribosyltransferase [potassium oxonate (oxonic acid)], was developed to increase the feasibility and therapeutic index of 5-FU administered orally. The principal objective of this study was to assess the feasibility of administering S-1 on a once-daily-for-28-day schedule every 5 weeks, determine the maximum tolerated dose, characterize the pharmacokinetics of S-1, and seek evidence of anticancer activity.. Patients with advanced solid malignancies were treated with escalating doses of S-1 on a once-daily oral schedule for 28 days every 5 weeks. The maximum tolerated dose was defined as the highest dose in which fewer than two of the first six new patients experienced dose-limiting toxicity. The pharmacokinetic profiles of the tegafur, CDHP, and oxonic acid constituents were characterized.. Twenty patients were treated with 72 courses of S-1 at three dose levels ranging from 50 to 70 mg/m(2)/day. Diarrhea, which was often associated with abdominal discomfort and cramping, was the principal dose-limiting toxicity of S-1 on this protracted schedule. Nausea, vomiting, mucositis, fatigue, and cutaneous effects were also observed but were rarely severe. Myelosuppression was modest and uncommon. A partial response and a 49% reduction in tumor size were observed in patients with fluoropyrimidine- and irinotecan-resistant colorectal carcinoma. The pharmacokinetic data suggested potent inhibition of 5-FU clearance by CHDP, with resultant 5-FU exposure at least 10-fold higher than that reported from equitoxic doses of tegafur modulated by uracil in the oral fluoropyrimidine UFT.. The recommended dose for Phase II studies of S-1 administered once daily for 28 consecutive days every 5 weeks is 50 mg/m(2)/day. The pharmacokinetic data indicate substantial modulation of 5-FU clearance by CDHP. Based on these pharmacokinetic data, the predictable toxicity profile of S-1, and the low incidence of severe adverse effects at the recommended Phase II dose, evaluations of S-1 on this schedule are warranted in malignancies that are sensitive to the fluoropyrimidines.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Combinations; Enzyme Inhibitors; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Orotate Phosphoribosyltransferase; Oxonic Acid; Pyridines; Pyrimidines; Stomach Neoplasms; Tegafur; Time Factors

Cancer of the colon and rectum is one of the most frequent malignancies both in the US and Europe. Standard palliative therapy is based on 5-fluorouracil/folinic acid combinations, with or without oxaliplatin or irinotecan, given intravenously. Oral medication has the advantage of greater patient convenience and acceptance and potential cost savings. S-1 is a new oral fluorinated pyrimidine derivative. In a nonrandomized phase II study, patients with advanced/metastatic colorectal cancer were treated with S-1 at 40 mg m-2 b.i.d. for 28 consecutive days, repeated every 5 weeks, but by amendment the dose was reduced to 35 mg m-2 during the study because of a higher than expected number of severe adverse drug reactions. In total 47 patients with colorectal cancer were included. In the 37 evaluable patients there were nine partial responses (24%), 17 stable diseases (46%) and 11 patients had progressive disease (30%). Diarrhoea occurred frequently and was often severe: in the 40 and 35 mg m-2 group, respectively, 38 and 35% of the patients experienced grade 3-4 diarrhoea. The other toxicities were limited and manageable. S-1 is active in advanced colorectal cancer, but in order to establish a safer dose the drug should be subject to further investigations.

Topics: Aged; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Drug Combinations; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Oxonic Acid; Pyridines; Tegafur; Treatment Outcome

This study set out to evaluate, in patients with metastatic colorectal carcinoma, the efficacy and toxicity of S-1, which contains tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate, based on a biochemical modulation of 5-fluorouracil (5-FU) targeted at inhibition of dihydropyrimidine dehydrogenase (DPD). Sixty-three patients with measurable metastatic colorectal carcinoma were enrolled into the study. None of the patients had received prior chemotherapy except for adjuvant setting. S-1 was administered orally twice daily at a standard dose of 80 mg m(-2) day(-1) for 28 days followed by a 14-day rest. This agent is continued until disease progression, unaccepted toxicity, or patient refusal. Twenty-two (35%) of the 62 eligible patients achieved PR with a 95% confidence interval of 25-48%. Five of the 10 patients with a history of adjuvant chemotherapy achieved partial remission. The median survival time was 12 months. Major adverse reactions included myelosuppressive and gastrointestinal toxicities, though their incidence of grade 3 or 4 being 13% in neutropenia and less than 10% in the others. None of the 53 patients treated as outpatients required hospitalization due to adverse reactions: These results suggest that S-1 achieves similar responses to those of infusional 5-FU plus leucovorin and shows the potential of another biochemical modulation with easily manageable toxicity.

Topics: Administration, Oral; Adult; Aged; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Drug Combinations; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Oxonic Acid; Pyridines; Survival Rate; Tegafur; Treatment Outcome

S-1 is a novel oral fluorouracil antitumor drug that combines three pharmacological agents: tegafur (FT), which is a prodrug of 5-fluorouracil (5-FU); 5-chloro-2,4-dihydroxypyridine (CDHP), which inhibits dihydropyrimidine dehydrogenase (DPD) activity; and potassium oxonate (Oxo), which reduces gastrointestinal toxicity. Phase I and early Phase II clinical trials have already been completed. On the basis of the results of these trials, 80 mg/m2/day, given daily in two divided doses after breakfast and supper, a 28-day consecutive oral regimen is recommended. In this study, we investigated the pharmacokinetics of 5-FU, intact FT, CDHP, and Oxo, after administration of S-1, at a standard dose of 80 mg/m2/day, in advanced cancer patients. Twelve patients were recruited to the study; 5 patients with gastric cancer, 4 with colorectal cancer, and 3 with breast cancer. Among them, analysis was conducted on 12 patients for single administration and on 10 patients for consecutive administration. The initial dose of S-1 for each patient was determined according to his/her body surface area (BSA) as follows: for BSA < 1.25 m2, 80 mg/body/day; for 1.25 m2 < or = BSA < 1.5 m2, 100 mg/day; and for 1.5 m2 < or = BSA, 120 mg/day. For single administration, half of the standard dose was used. For 28-day consecutive administration, the standard dose was given daily in two divided doses. The average single dose per BSA was 35.9 mg/m2 (31.7-39.7 mg/m2). Pharmacokinetic parameters of plasma 5-FU were as follows: Cmax, 128.5 +/- 41.5 ng/ml; Tmax, 3.5 +/- 1.7 h; AUC(0-14), 723.9 +/- 272.7 ng x h/ml; and T(1/2), 1.9 +/- 0.4 h. In the 28-day consecutive regimen, there were no fluctuations in pharmacokinetics nor any drug accumulation. Because the pharmacokinetics of orally administered S-1 is almost similar to that of continuous i.v. infusion of 5-FU, we concluded that S-1 may improve patients' quality of life.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Breast Neoplasms; Colorectal Neoplasms; Drug Combinations; Drug Evaluation; Female; Humans; Male; Middle Aged; Neoplasms; Oxonic Acid; Pyridines; Stomach Neoplasms; Tegafur

A 79-year-old Japanese male with a history of type 2 diabetes mellitus (T2DM) for 16 years was admitted to evaluate possible renal disease. The T2DM was well controlled in this patient using nutrition therapy without the need for any diabetes medication, and both diabetes retinopathy and proteinuria were negative. At the age of 78 advanced colorectal cancer (stage IIIa) was diagnosed and laparoscopic-assisted colectomy was performed. Following this procedure, the patient began treatment with tegafur/gimeracil/oteracil (S-1), 80 mg twice daily for 28 days of 42-day cycle. The patient received S-1 for 6 months, during which time, serum albumin decreased from 3.0 g/dL to 1.1 g/dL, urinary protein increased from negative to 3.0 g/day, and serum creatinine increased from 0.9 mg/dL to 2.1 mg/dL. Treatment with S-1 was discontinued, and furosemide 180 mg and prednisolone 30 mg treatment was initiated; however, serum creatinine levels continued to increase to 7.2 mg/dL and proteinuria continued to increase reaching a nephrotic range. A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity was decreased to 27.0%. Renal biopsy showed Kimmelstiel-Wilson nodules, while immunofluorescence intensity of IgG subclass was IgG1 dominant, which was not compatible with diabetic nephropathy (DN). Plasma exchange was not affected. However, hemodialysis was initiated.The results of this investigation suggest that when S-1 monotherapy is performed in the case with DN, rapidly progressive glomerulonephritis (RPGN) may develop due to a condition similar to thrombotic microangiopathy, even in patients with a minor risk factor of DN.

Topics: Aged; Asian People; Biopsy; Colorectal Neoplasms; Creatinine; Diabetic Nephropathies; Disease Progression; Drug Combinations; Glomerulonephritis; Humans; Kidney; Male; Neoplasm Staging; Oxonic Acid; Proteinuria; Pyridines; Renal Dialysis; Risk Assessment; Serum Albumin; Tegafur; Withholding Treatment

Although chemotherapy is the main treatment for recurrent colorectal cancer, the utility of radiotherapy as a local treatment has been widely reported. We performed chemoradiotherapy with S-1 for cases with recurrence after surgery, and the outcomes are reported herein.. Chemoradiotherapy with S-1 was performed in 4 cases. S-1 was administered for 2 weeks during the irradiation period, and the off period provided was 1 week.. X-ray irradiation was performed in 2 cases and proton beam irradiation in the other 2. The progression free periods of the 2 cases receiving proton beam irradiation were 31 months and 36 months. In contrast, the progression free periods of the 2 cases given X-ray irradiation were 24 months and 21 months.. It is known that S-1 not only achieves a high anticancer effect via dihydropyrimidine dehydrogenase(DPD)inhibition, which is a major metabolic pathway of 5-FU, but also increases the radiation susceptibility of malignancies. S-1 is regarded as an ideal anticancer agent when used in combination with radiation therapy. Since the local control achieved in our 4 cases was good, chemoradiotherapy with S-1 was considered to be a useful treatment.

Topics: Antimetabolites, Antineoplastic; Chemoradiotherapy; Colorectal Neoplasms; Disease Progression; Drug Combinations; Female; Humans; Male; Middle Aged; Oxonic Acid; Recurrence; Tegafur

Topics: Administration, Oral; Aged; Breast Neoplasms; Capecitabine; Cardiotoxicity; Colorectal Neoplasms; Coronary Vasospasm; Drug Combinations; Drug Substitution; Female; Humans; Male; Middle Aged; Oxonic Acid; Stomach Neoplasms; Tegafur

Metronomic chemotherapy is currently considered an emerging therapeutic option in clinical oncology. S-1, an oral formulation of Tegafur (TF), a prodrug of 5-fluorouracil (5-FU), is designed to improve the antitumor activity of 5-FU in tandem with reducing its toxicity. Clinically, metronomic S-1 dosing has been approved for the standard first- and second-line treatment of metastatic or advanced stage of colorectal (CRC). However, expression of intratumor thymidylate synthase (TS), a significant gene in cellular proliferation, is associated with poor outcome to 5-FU-based chemotherapeutic regimens. In this study, therefore, we examined the effect of a combination of TS silencing by an RNA interfering molecule, chemically synthesized short hairpin RNA against TS (shTS), and 5-FU on the growth of human colorectal cancer cell (DLD-1) both in vitro and in vivo. The combined treatment of both shTS with 5-FU substantially inhibited cell proliferation in vitro. For in vivo treatments, the combined treatment of metronomic S-1 dosing with intravenously injected polyethylene glycol (PEG)-coated shTS-lipoplex significantly suppressed tumor growth, compared to a single treatment of either S-1 or PEG-coated shTS-lipoplex. In addition, the combined treatment increased the proportion of apoptotic cells in the DLD-1 tumor tissue. Our results suggest that metronomic S-1 dosing combined with TS silencing might represent an emerging therapeutic strategy for the treatment of patients with advanced CRC.

Topics: Administration, Metronomic; Animals; Antimetabolites, Antineoplastic; Apoptosis; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Drug Combinations; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Oxonic Acid; RNA Interference; RNAi Therapeutics; Tegafur; Thymidylate Synthase; Time Factors; Transfection; Tumor Burden; Xenograft Model Antitumor Assays

S-1, an oral 5-fluorouracil (5-FU)-based medicine that combines tegafur, gimeracil and oteracil potassium is commonly used as an adjuvant chemotherapeutic drug for the treatment of colorectal cancer.. We enrolled 53 patients who underwent curative resection for colorectal cancer and liver metastasis (synchronous, n=24; metachronous, n=29). The subsequent adjuvant chemotherapy with oral S-1 administration was initiated within 56 days after liver resection. Recurrence was evaluated by imaging studies, that were performed during the first year after liver resection. Of the 53 patients, 25 who did not recur within 1 year were defined as being in the no-recurrence (NREC) group and the remaining 18 patients were defined as being in the early-recurrence (EREC) group. There were no significant differences in gene expression profiling for drug resistance and metabolism between the NREC group and the EREC group.. In synchronous liver metastasis, there was no significant difference in early recurrence between serum carcinoembryonic antigen (CEA) ≤5 ng/ml and serum CEA >5 ng/ml (8/24 vs. 16/24, respectively). In metachronous liver metastasis, the early recurrence rate was significantly higher in patients with CEA >5 ng/ml compared to patients with CEA ≤5 ng/ml (15/29 vs. 14/29, p=0.05). The expression of cytochrome P450 2C19 (CYP2C19) and ATP-binding cassette, sub-family B member 1 (ABCB1) were significantly lower in the EREC group (6/15) compared to the NREC group (9/15) in colorectal cancer with metachronous liver metastasis and with serum CEA >5 ng/ml.. Although the exact reason for down-regulation of these genes in the group with poor prognosis is unknown, the information obtained in this study may be useful in clinical practice for colorectal cancer.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoembryonic Antigen; Colorectal Neoplasms; Drug Combinations; Female; Gene Expression Profiling; Humans; Liver Neoplasms; Male; Middle Aged; Oxonic Acid; Recurrence; Tegafur

The anti-p53 autoantibody is an emerging tumor marker that is commonly produced in response to p53 mutations. The usefulness of this antibody has been suggested in screening for and the monitoring of recurrence in colorectal cancer; however, its significance as a marker during chemotherapy remains largely unknown.. We measured serum anti-p53 antibody levels in patients with unresectable colorectal cancer who underwent first-line systemic chemotherapy. Tumor responses were evaluated by computed tomography. We determined whether temporal changes in this antibody during therapy are associated with radiological responses.. Of the 83 patients in our study, 29 (35%) had elevated serum anti-p53 antibody levels before chemotherapy. Among these, antibody levels decreased in all 14 responders. In contrast, among those patients with elevated pretherapeutic serum anti-p53 antibody levels, 89% showed a paradoxical decrease in antibody levels and exhibited disease progression after chemotherapy. Moreover, serum anti-p53 antibody levels before and after chemotherapy were not associated with survival.. These results suggest that serum anti-p53 antibody levels are of limited value in the evaluation of responses to palliative chemotherapy in patients with colorectal cancer.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Autoantibodies; Bevacizumab; Camptothecin; Capecitabine; Carcinoembryonic Antigen; Cetuximab; Colorectal Neoplasms; Disease Progression; Drug Combinations; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Organoplatinum Compounds; Oxonic Acid; Palliative Care; Pregnancy; Survival Rate; Tegafur; Tumor Suppressor Protein p53

A clinical trial of S-1 with leucovorin (S-1/LV) in metastatic colorectal cancer (CRC) patients demonstrated promising efficacy; however, the gastrointestinal toxicities were so severe that it has not been applied in the clinical setting. On the other hand, alternate-day administration of S-1 has been proposed to attenuate the adverse events without reducing its anticancer activity. Our present study was conducted to confirm the feasibility of alternate-day administration of S-1/LV in in vivo xenograft tumor models.. Mice were treated with S-1/LV in a daily group (2 weeks of administration followed by 2 weeks of withdrawal) or an alternate-day group (administration on alternate days for 4 weeks), then the mice were killed and the xenograft tumors were resected. We compared body weight changes, condition of feces, mucosal injury and myelosuppression and assessed adverse reactions, tumor volume, tumor growth inhibition (TGI) and expression of Ki67, TUNEL, cIAP2 and XIAP to evaluate the antitumor activity and tumor apoptosis.. Severe weight loss, diarrhea, mucosal injury and myelosuppression were observed only in the daily group; however, some myelosuppression was also observed in the alternate-day group. The TGI in the alternate-day group was better than in the daily group, possibly resulting from apoptosis due to the suppression of cIAP2 but not XIAP.. Our findings suggest that alternate-day administration of S-1/LV for CRC treatment can achieve high antitumor activity without severe adverse reactions, and we propose that clinical trials with this regimen should be conducted in CRC patients.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Heterografts; HT29 Cells; Humans; Leucovorin; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Oxonic Acid; Tegafur

Chemotherapy with S-1 and oxaliplatin is a new treatment for metastatic colorectal cancer. We present the first case of S-1, oxaliplatin, and bevacizumab therapy in our hospital. The patient was a 69-year-old woman with ascending colon cancer and multiple lung and liver metastases. She tended to suffer from constipation; stenoses at the cecum and colon cancer were detected by colon fiberscopy. Following surgical resection of the primary tumor, the patient received systemic chemotherapy with S-1, oxaliplatin, and bevacizumab. Following chemotherapy, CT showed no cancer in the lung and cancer reduction in the liver or dissemination. The patient had diarrhea and no appetite at first, so we reduced the oxaliplatin dose by 80%. After reduction of the oxaliplatin dose, we could treat the patient with S-1 and oxaliplatin continuously with no toxicity. S-1 and oxaliplatin chemotherapy is cost-effective, and has less toxicity than other chemotherapies, if proper measures are taken. It seemed to have a non-inferior response rate and disease control compared to other chemotherapies, such as FOLFOX. Thus, this chemotherapy is a valid choice for metastatic colorectal cancer.

Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Drug Combinations; Fatal Outcome; Female; Humans; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur

We recently reported that combination therapy with metronomic S-1 dosing and oxaliplatin (l-OHP)-containing PEGylated liposomes improved antitumor activity in a murine colorectal tumor model. However, little is known about the mechanism underlying such improved therapeutic efficacy. Here we investigated the impact of combined treatment on biodistribution, tumor accumulation and intratumor distribution of test PEGylated liposomes and on the structure of tumor vasculature in a solid tumor. The combined treatment clearly enhanced tumor accumulation and intratumor distribution of a subsequent test dose of PEGylated liposome as a result of on the one hand prolonging blood circulation of test liposome and on the other hand the alteration in tumor microenvironment. The l-OHP-containing PEGylated liposomes contributed predominantly to the enhanced tumor accumulation and altered tumor distribution of test liposome. On the other hand, metronomic S-1 dosing contributed to the altered tumor distribution but not the tumor accumulation of test liposome. The antitumor effect of the combined treatment, reflected by the proportion of apoptotic cells in the tumor, was approximately equally accounted for by each of the two treatments, leading to a roughly additive effect. In conclusion, 1-OHP-containing PEGylated liposome together with S-1 enhanced intratumor influx, leading to improved antitumor activity of subsequently injected 1-OHP-containing PEGylated liposomes and/or S-1. This strategy we propose, which is clinically applicable, may overcome the problems related to the use of EPR effect-based nanocarrier systems.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Colorectal Neoplasms; Drug Administration Schedule; Drug Carriers; Drug Combinations; Drug Therapy, Combination; Liposomes; Liver; Male; Mice, Inbred BALB C; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Polyethylene Glycols; Tegafur; Tissue Distribution

Unresectable metastatic colorectal cancer with very slow tumour growth rate does not necessarily require for strong short-interval chemotherapy. In the present study, we administered monthly chemotherapy and aimed to evaluate the usefulness of the specific treatment schedule in patients with unresectable metastatic colorectal cancer with slow tumour growth rate.. Since 2009, at our Institution, patients' whose serum carcinoembryogenic antigen (CEA) values on the treatment day were not higher than those before initial chemotherapy, and patients who did not wish to undergo intensive chemotherapy, were prospectively scheduled for specific chemotherapy. Between January 2009 and December 2011, 10 patients with unresectable metastatic colorectal cancer who received monthly chemotherapy were enrolled in the current study. During the same period, 14 patients with unresectable metastatic colorectal cancer were administered conventional-interval chemotherapy, oxaliplatin with oral S-1 (SOX) or capecitabine (XELOX), and comprised the control group.. Three patients received first-line, four patients received second-line, and three patients received third-line treatment. All patients were able to receive a single-regimen of chemotherapy for more than a year. The survival of patients who received monthly chemotherapy was significantly better than survival of those who received SOX or XELOX within 30 months after starting chemotherapy (p<0.05).. For patients with very slow tumour growth rates, our monthly chemotherapy may be beneficial.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Drug Combinations; Female; Fluorouracil; Follow-Up Studies; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Peritoneal Neoplasms; Prognosis; Survival Rate; Tegafur

5-Fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX) therapy and 5-FU, leucovorin, and irinotecan (FOLFIRI) therapy are standard chemotherapies to treat advanced/recurrent colorectal cancer. However, these chemotherapies require continuous infusion of 5-FU for a prolonged time of 40 h or more, every two weeks. Accordingly, these chemotherapies require hospitalization and placement of a central venous catheter. Because of frequent catheterization, long-term use of these therapies potentially risks complications such as infection and thrombosis. In contrast, S-1 (tegaful, gimeracil, oteracil) combined with irinotecan (IRIS) therapy involves giving one drug orally and infusing the other for about two hours every two weeks, so placement of a central venous catheter is not necessary. The current study examined the efficacy and safety of IRIS therapy in 90 patients at this Hospital who underwent such therapy to treat advanced/recurrent colorectal cancer.. The study comprised 90 patients who underwent IRIS therapy to treat advanced/recurrent colorectal cancer from December 2004 to December 2011.. The ratio of male-to-female patients was 64:26. The mean age at the start of IRIS therapy was 64.5 years, and patients underwent an average of 11 courses of therapy. The response rate to IRIS therapy was 14.8%, the disease control rate was 60.5%, and the overall survival time was 26.7 months. The incidence of adverse events was 70.0%, and the incidence of grade 3 or more severe adverse reactions was 17.8%.. In comparison to the standard therapies of FOLFOX and FOLFIRI, IRIS therapy had a lower response rate but led to an equivalent overall survival time. IRIS therapy had a low incidence of serious adverse events and allowed patients to continue therapy on an out-patient basis. These findings indicate that IRIS therapy may be a useful form of chemotherapy to treat advanced/recurrent colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Combinations; Female; Humans; Irinotecan; Male; Middle Aged; Neoplasm Recurrence, Local; Oxonic Acid; Tegafur

To evaluate the efficacy and safety of the regimen of low-dose high intensity focused ultra-sound (HIFU) plus S-1 and oxaliplatin (SOX) in the treatment of metastatic colorectal cancer patients with pelvic masses.. A total of 46 patients with metastatic colorectal cancer were recruited and divided into 2 groups: Twenty patients received concurrent HIFU plus S-1 and oxaliplatin (SOX) while another 26 patients SOX alone. The baseline characteristics, progressive-free survival, overall survival time and adverse events were retrospectively analyzed.. The median PFS was 11.2 months (95% CI 9.8-12.7) in the HIFU+SOX group and 7.1 months (95% CI 5.8-8.4) in the SOX group (P = 0.003). And the overall survival time in two groups were 21.9 months (95% CI 18.0-25.9) and 16.9 months (95%CI 14.1-19.6) (P = 0.072) respectively. Major toxic effects included grade 3/4 neutropenia (15%), anemia (10%), thrombocytopenia (10%), diarrhea (15%) and hand-foot syndrome (10%) in the HIFU+SOX group. And it showed no statistically significant differences with the SOX group.. The combined regimen of HIFU and SOX is effective and well-tolerated in patients of late-stage colorectal cancer with pelvic masses.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Combinations; Humans; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Pelvic Neoplasms; Retrospective Studies; Tegafur; Thrombocytopenia; Treatment Outcome; Ultrasonography

We examined the safety and efficacy of S-1 and oxaliplatin plus bevacizumab (SOX+BV)as first-line therapy for advanced/recurrent unresectable colorectal cancer. The subjects were 14 patients with colorectal cancer who received ≥3 courses of SOX+BV therapy in our department.The dosing regimen for 1 course was as follows: BV (7.5 mg/kg) and oxaliplatin (130 mg/m(2)) were administered via intravenous drip infusion on the first day of the course, and S-1 was orally administered twice a day for 2 weeks, repeated every 3 weeks. All patients completed the study treatment, and the median number of courses completed was 9 courses (range: 3-17 courses). In terms of anti-tumor efficacy, complete remission (CR) was observed in 1 patient (7.1%); partial remission (PR), in 9 patients (64.3%); stable disease (SD), in 3 patients (21.4%); and progressive disease (PD), in 1 patient (7.1%), with a response rate of 71.4% and a disease control rate of 92.9%. The median relapse-free survival based on baseline PD was 12 months, and the median relapse-free survival based on PD according to the Response Evaluation Criteria in Solid Tumors (RECIST) was 10 months.The most common adverse events observed included peripheral sensory neuropathy (100%), fatigue (68.3%), anorexia (57.1%), and leukopenia/neutropenia (35.7%); however, almost all adverse events were Grade≤2 and could be managed.The SOX+BV therapy demonstrated an antitumor efficacy similar to that observed with oxaliplatin, fluorouracil, and folinic acid (FOLFOX)+BV therapy without the use of a central venous port.Therefore, the SOX+BV therapy may be among the effective option as first-line therapy for advanced/recurrent colorectal cancer.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Drug Combinations; Female; Humans; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur

The aim of this study was to evaluate the usefulness of circulating tumor cells (CTCs) after preliminary chemotherapy for prediction of response to further anticancer therapy in patients with initially unresectable metastatic colorectal cancer.. CTCs from 14 consecutive patients with Kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type colorectal cancer with synchronous or metachronous unresectable metastatic lesions were measured using the CellSearch system between January 2009 and December 2011. CTCs were measured before and after chemotherapy. The regimen consisted of four courses (three months) of oxaliplatin with oral S-1 (SOX) + panitumumab.. Ten (71%) out of all patients had no detectable CTCs after chemotherapy. Eight out of these ten patients received further chemotherapy, and liver metastases were completely resected in the other two patients; none of these patients died of cancer within a year after starting chemotherapy. The remaining four patients with CTCs continued to have CTCs after chemotherapy, and all four of these patients died of cancer within eight months after starting chemotherapy. The prognosis of the patients who had no detectable CTCs after the chemotherapy was significantly better than that of those who had CTCs even after the chemotherapy (p<0.01).. CTCs after preliminary chemotherapy may be useful in predicting the response to further anticancer therapy.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Combinations; Female; Follow-Up Studies; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Neoplastic Cells, Circulating; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Panitumumab; Prognosis; Prospective Studies; Survival Rate; Tegafur

The aim of this study was to evaluate the impact of chemotherapy with molecular-targeting agents on liver metastases from colorectal cancer.. Six patients with synchronous colorectal liver metastases who underwent hepatectomy after chemotherapy with S-1 and oxaliplatin (SOX) between January 2010 and December 2011 at the Department of Surgery, Kashiwa Hospital, the Jikei University School of Medicine were enrolled. Two patients received only SOX as chemotherapy, while the others received SOX in combination with one of the three molecular-targeting agents, bevacizumab, cetuximab, and panitumumab.. In the two patients who received SOX alone, liver metastases completely disappeared at more than six months after starting chemotherapy as shown by computed tomographic (CT) scan. However, malignant cells were diffusely detected by pathological examination at the site of liver metastases, as detected by CT scan before chemotherapy. In the other four patients who received SOX in combination with molecular targets, the size of liver metastases appeared unchanged at three months after limited chemotherapy by CT scan. Pathologically, few malignant cells were detected, only at the borderline of the tumor, while most tumor cells inside the tumor were necrotized and been replaced by fibroconnective tissue.. Molecular-targeting agents may induce tumor necrosis rapidly from inside the tumor, which might not be detected by CT scan before surgery.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Drug Combinations; Female; Humans; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Panitumumab; Tegafur; Tomography, X-Ray Computed

The aim of this study was to determine the feasibility of S-1 plus oxaliplatin (SOX) or capecitabine plus oxaliplatin (XELOX) as first-line therapy for patients with initially unresectable metastases from colorectal cancer.. Fourteen patients with colorectal cancer who underwent elective colorectal resection between January 2009 and December 2010 at the Department of Surgery, Kashiwa Hospital, the Jikei University School of Medicine, with initially unresectable metastatic lesions were enrolled in this study. After curative resection for the primary colorectal cancer, they underwent adjuvant chemotherapy with SOX or XELOX, starting at one month after surgery.. Seven patients (50%) received SOX, and the others received XELOX as first-line therapy for initially unresectable metastases from colorectal cancer. Four (29%) patients had complete response for liver metastases over six months after chemotherapy, and liver metastases were subsequently judged to be completely resected by surgery. For the other ten patients, the median progression-free survival was 9.1 months and median overall survival was 24.1 months. There were no patients with grade 3 or 4 adverse reactions throughout the entire chemotherapy.. Oxaliplatin with oral S-1 or capecitabine as first-line therapy for patients with initially unresectable metastases from colorectal cancer is safe and feasible.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Disease-Free Survival; Drug Combinations; Feasibility Studies; Female; Fluorouracil; Humans; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Peritoneal Neoplasms; Tegafur

We recently proposed an S-1 combined with oxaliplatin (SOXL) regimen, a combination treatment consisting of oral metronomic S-1 dosing and intravenous administration of oxaliplatin (l-OHP) containing PEGylated liposomes, which showed potent antitumor activity in vivo. PEGylated liposomes induce what is referred to as the "accelerated blood clearance (ABC) phenomenon" upon repeated administration and consequently lose their long-circulating characteristics. This phenomenon seems to pose an impediment for the clinical application and use of PEGylated liposomal formulations. In the present study, l-OHP-containing PEGylated liposomes in the SOXL regimen significantly attenuated the ABC phenomenon in a dose-dependent manner through suppression of the anti-PEG IgM response, which allowed an enhanced hepatic uptake of subsequently injected test PEGylated liposomes. In tumor-bearing mice, the abrogation of the ABC phenomenon restored intratumor accumulation of subsequently injected PEGylated liposomes. Consequently, the therapeutic efficacy of the SOXL regimen over the combination of the free form of the drugs was credited not only with the selective delivery of drugs to the tumor tissue but also with ensuring an adequate accumulation of subsequent doses within the tumor tissue. The SOXL regimen we proposed may hold promise as a safe and effective treatment regimen for advanced colorectal cancer.

Topics: Administration, Metronomic; Animals; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Combinations; Drug Delivery Systems; Liposomes; Liver; Male; Mice; Mice, Inbred BALB C; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Polyethylene Glycols; Tegafur; Tissue Distribution

Combination chemotherapies of oxaliplatin or irinotecan with fluoropyrimidine and molecular target drug were reported to be active in several clinical studies and so regarded as a first-line standard therapy for unresectable or metastatic colorectal cancer. However, the incidence of adverse events is not so low. We investigated the efficacy and safety of chemotherapy combined bevacizumab with fluoropyrimidine as a first-line treatment for frail patients.. Twenty-six patients with unresectable or metastatic colorectal cancer who were treated with first-line chemotherapy combined bevacizumab with S-1 or 5FU/LV (modified Roswell Park Memorial Institute regimen) at our hospital between October 2007 and December 2010 were retrospectively investigated.. The median age was 72 years (range 66-84). Performance status was 0, 1 and 2 in 8, 17 and 1 patient, respectively. The primary lesion was located in the colon in 14 patients and in the rectum in 12. Twenty patients were with resection of the primary lesion and 6 were without, 8 were with postoperative adjuvant chemotherapy and 18 were without. The number of metastasized organs was 1, 2 and 3 in 17, 9 and 0 patients, respectively. The liver, lung, lymph node and peritoneum were metastasized in 9, 9, 11 and 5 patients, respectively. The KRAS gene was wild in 11, mutated in 7 and unknown in 8 patients. Bevacizumab with S-1 was used in 17 patients and bevacizumab with 5FU/LV was used in 9. Response and disease control rates were 50 and 100%, respectively. The median duration of progression-free survival was 9.1 months and the median time to treatment failure was 9.0 months. The incidences of all grades of neutropenia and hypertension were 31%, those of grade 3 or severer were 12%, and those of other adverse events were low. Grade 3 cerebral hemorrhage, grade 4 pulmonary embolism and grade 5 febrile neutropenia each occurred in 1 patient.. The first-line chemotherapy combined bevacizumab with fluoropyrimidine for frail patients with unresectable or metastatic colorectal cancer in Japan was comparable to the safety and efficacy of combination therapy reported previously in Western countries.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Drug Combinations; Female; Fluorouracil; Frail Elderly; Humans; Leucovorin; Male; Neoplasm Metastasis; Oxonic Acid; Retrospective Studies; Tegafur; Treatment Failure; Vascular Endothelial Growth Factor A

Combination therapy with 2 or more drugs with different mechanisms of action has been considered a promising strategy for the effective treatment of advanced and metastatic cancers. However, the rational design of combination therapy represents a potential prerequisite for its effectiveness. Recently, we showed that the combination of oral metronomic S-1 dosing with oxaliplatin (l-OHP)-containing PEG-coated "neutral" liposomes exerted excellent antitumor activity. In addition, we recently designed a PEG-coated "cationic" liposome for dual-targeting delivery of l-OHP to tumor endothelial cells and tumor cells in a solid tumor. This targeted liposomal l-OHP formulation showed efficient antitumor activity in a murine tumor model, compared with l-OHP-containing PEG-coated "neutral" liposomes. In the present study, we investigated the issue of whether metronomic S-1 dosing with l-OHP-containing PEG-coated "cationic" liposomes creates synergy. Unfortunately, metronomic S-1 dosing resulted in impaired delivery of PEG-coated "cationic" liposomes into tumor tissue, presumably by decreasing the binding sites on tumor blood vessels available for the liposomes. The anticipated cytotoxic synergistic effect of the combination treatment was not achieved. Instead, the combination treatment showed lower antitumor efficacy than l-OHP-containing PEG-coated "cationic" liposomes alone. These results suggest that the combined treatment of S-1 and l-OHP-containing PEG-coated "cationic" liposomes seems to be antagonistic rather than synergistic.

Topics: Administration, Metronomic; Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Biological Availability; Cell Line, Tumor; Chemistry, Pharmaceutical; Colorectal Neoplasms; Drug Antagonism; Drug Combinations; Drug Compounding; Drug Synergism; Injections, Intravenous; Liposomes; Male; Mice; Mice, Inbred BALB C; Nanotechnology; Neovascularization, Pathologic; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Particle Size; Polyethylene Glycols; Technology, Pharmaceutical; Tegafur; Tissue Distribution

The aim of this study is to determine the relationship between circulating tumor cells (CTCs) and response to chemotherapy in patients with unresectable metastatic colorectal cancer.. CTCs of twelve consecutive patients with K-ras wild type colorectal cancer with synchronous and/or metachronous unresectable metastatic lesions were measured by the cell search system between January 2009 and December 2010. CTCs were measured before and after chemotherapy. The regimen consisted of four courses (three months) of SOX (TS-1+L-OHP) + panitumumab.. Four patients (33%) had no detectable CTCs before chemotherapy. For these patients, no CTCs were detected after chemotherapy and their serum carcinoembryonic antigen (CEA) levels decreased after chemotherapy. Four of the other eight patients with positive CTCs had no detectable CTCs after chemotherapy and their serum CEA levels decreased after chemotherapy. The other four of eight patients with positive CTCs continued to have CTCs after chemotherapy and all four patients died of cancer within eight months after starting chemotherapy. On the other hand, all eight patients without CTCs after chemotherapy were alive over a year after starting chemotherapy.. CTCs may be able to predict the response to chemotherapy in patients with unresectable metastatic colorectal cancer.

Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Carcinoembryonic Antigen; Chi-Square Distribution; Colorectal Neoplasms; Disease Progression; Drug Combinations; Female; Humans; Male; Middle Aged; Neoplastic Cells, Circulating; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Panitumumab; Prospective Studies; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Tegafur; Time Factors; Treatment Outcome

Oxaliplatin is effective when used with 5-fluorouracil (5-FU) and leucovorin, or with capecitabine (COX) for the treatment of colorectal cancer. In this experiment, we investigated the optimal combination schedule and antitumor activity of oral S-1 with oxaliplatin combination therapy (SOX) against human colorectal cancer xenografts in vivo. Using human colon cancer COL-1-bearing nude mice, oxaliplatin was administered at a total dose of 8.3 mg/kg on day 1 alone, on day 8 alone, or in divided doses administered on days 1 and 8 with S-1 (6.9 mg/kg, days 1-14). The antitumor activity of SOX, administered according to the divided schedule was significantly superior to both monotherapies (p<0.01), and the toxicity was tolerable. However, administration on day 8 alone failed to significantly increase the antitumor activity, when compared with that of monotherapy, while administration on day 1 alone was toxic in this model. Next, the efficacy of SOX was compared with that of COX (360 mg/kg, days 1-14). The antitumor effect of SOX was significantly superior to that of COX (p<0.01), with an equivalent toxicity; moreover SOX suppressed COL-1 tumor growth for a longer period of time (2.2 times) than did COX. The antitumor activity of SOX against the 5-FU-resistant colorectal cancer cell line KM12C/5-FU was equivalent to that of COX. The evaluation of intermittent SOX administration in a clinical trial might be of critical value.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Drug Administration Schedule; Drug Combinations; Drug Resistance, Neoplasm; Fluorouracil; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur; Xenograft Model Antitumor Assays

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Drug Combinations; Female; Fluorouracil; Humans; Male; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur

The updated randomised phase 2/3 FIRIS study demonstrated the noninferiority of IRIS (irinotecan and S-1) to FOLFIRI (irinotecan, folinic acid, and 5-FU) for metastatic colorectal cancer. Meanwhile, in the subset analysis including patients who previously have undergone oxaliplatin-containing chemotherapy, the IRIS group showed longer survival than the FOLFIRI group. However, the molecular mechanism underlying this result is still unknown.. The National Cancer Institute 60 (NCI60) cell line panel data were utilised to build the hypothesis. A total of 45 irinotecan-naive metastatic colorectal cancer patients who had undergone hepatic resection were included for the validation study. The mRNA expressions of excision repair cross-complementing group 1 (ERCC1), dihydropyrimidine dehydrogenase (DPD), and topoisomerase-1 (TOP1) were evaluated by quantitative RT-PCR. The expressions of ERCC1 and DPD were also evaluated by immunohistochemistry.. Sensitivity to oxaliplatin in 60 cell lines was significantly correlated with that of 5-FU. Resistant cells to oxaliplatin showed significantly higher ERCC1 and DPD expression than sensitive cells. In validation study, ERCC1 and DPD but not TOP1 expressions in cancer cells were significantly higher in FOLFOX (oxaliplatin, folinic acid, and 5-FU)-treated patients (N=24) than nontreated patients (N=21). The ERCC1 and DPD protein expressions were also significantly higher in FOLFOX-treated patients.. The ERCC1 and DPD expression levels at both mRNA and protein levels were significantly higher in patients with oxaliplatin as a first-line chemotherapy than those without oxaliplatin. The IRIS regimens with the DPD inhibitory fluoropyrimidine may show superior activity against DPD-high tumours (e.g., tumours treated with oxaliplatin) compared with FOLFIRI.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cell Line, Tumor; Colorectal Neoplasms; Dihydrouracil Dehydrogenase (NADP); DNA Topoisomerases, Type I; DNA-Binding Proteins; Drug Combinations; Endonucleases; Female; Fluorouracil; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Leucovorin; Male; Middle Aged; National Cancer Institute (U.S.); Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Real-Time Polymerase Chain Reaction; Retrospective Studies; RNA, Messenger; Tegafur; United States; Up-Regulation

The purpose of the study was to evaluate the efficacy and tolerability of S-1 monotherapy in metastatic colorectal cancer (CRC) patients who have failed the standard oxaliplatin-based or irinotecan-based chemotherapy. From 2007 to 2010, metastatic CRC patients who received S-1 monotherapy as salvage treatment were identified from tumor registry at Samsung Medical Center. All patients received ≥ second-line treatment for CRC. S-1 was administered orally from day 1 to day 14, every 3 weeks. The dose of S-1 for each patient was determined according to body surface area (BSA) as follows: for BSA < 1.25 m(2), 80 mg/day; for 1.25 m(2) < BSA < 1.5 m(2), 100 mg/day; and for BSA > 1.5 m(2), 120 mg/day divided by 2 doses. The median age of the 19 patients was 59 years (range: 33-77). Fourteen (73.7%) of 19 patients received S-1 monotherapy as third-line treatment after failing oxaliplatin-based or irinotecan-based chemotherapy. Previous regimens prior to S-1 therapy were as follows: FOLFOX, XELOX, FOLFIRI, XELOX + avastin, and cetuximab + irinotecan. The median number of administered S-1 courses given in the entire studied population was 3 cycles (1-10 cycles). Three patients had confirmed partial response (PR) after 3 cycles of S-1 treatment. After a follow-up duration of 22.3 months (range: 6.7-32.6 months), median time to progression (TTP) was 2.1 (95% CI, 1.8-4.2) months. Median overall survival was 11.3 months (95% CI, 8.8-16.8) from the time of S-1 chemotherapy administration. Two patients had grade 1 hand-foot syndrome (HFS) after first and 2nd cycles of treatments, respectively, but treatments were continued without developing further adverse events. The salvage S-1 monotherapy in metastatic colorectal cancer patients who failed irinotecan-based or oxaliplatin-based chemotherapy was moderately effective and well tolerated.

Topics: Adult; Aged; Camptothecin; Cohort Studies; Colorectal Neoplasms; Drug Combinations; Female; Follow-Up Studies; Humans; Irinotecan; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Retrospective Studies; Salvage Therapy; Tegafur; Treatment Failure

Topics: Aged; Antimetabolites, Antineoplastic; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Drug Combinations; Frail Elderly; Health Status Indicators; Humans; Neoplasm Staging; Oxonic Acid; Tegafur

High levels of intratumoral thymidylate synthase (TS) expression are associated with resistance to 5-fluorourcil (5-FU). In order to establish a new treatment method for 5-FU-resistant tumors, the efficacy of gene therapy was investigated using an adenoviral vector expressing short hairpin RNA (shRNA) targeting TS. A replication-deficient recombinant adenoviral vector expressing shRNA targeting TS was constructed under the control of the human U6 promoter (Ad-shTS). Three 5-FU-resistant cancer cell lines, DLD-1/5FU, KM12C/5FU and NUGC-3/5FU, were used. Transduction with Ad-shTS effectively downregulated TS expression in all three 5-FU-resistant tumor cells. MTT assays demonstrated that treatment with Ad-shTS significantly inhibited the growth of all three 5-FU-resistant tumor cells. Furthermore, combined treatment with Ad-shTS and 5-FU demonstrated significantly greater inhibition of tumor cell growth in comparison to 5-FU treatment alone and Ad-shTS treatment alone. S-1, a combination of tegafur, gimeracil and oteracil potassium, was used for the 5-FU treatment by in vivo experiments. The combined treatment of Ad-shTS and S-1 was found to have the strongest antitumor effect against 5-FU-resistant DLD-1/5FU xenografts in nude mice in comparison to S-1 treatment alone and Ad-shTS treatment alone. Furthermore, the apoptotic index in tumors treated with combined Ad-shTS and S-1 was significantly higher in comparison to that in tumors treated with S-1 alone and that in tumors treated with Ad-shTS alone. Consequently, the combined treatment of the TS-inhibiting adenoviral vector and S-1 has effective antitumor activity against 5-FU-resistant tumors.

Topics: Adenoviridae; Animals; Antimetabolites, Antineoplastic; Apoptosis; Blotting, Western; Cell Proliferation; Colorectal Neoplasms; Combined Modality Therapy; Drug Combinations; Drug Resistance, Neoplasm; Drug Synergism; Fluorouracil; Genetic Therapy; Genetic Vectors; Humans; Male; Mice; Mice, Nude; Oxonic Acid; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Survival Rate; Tegafur; Thymidylate Synthase; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

After approval of bevacizumab in Japan, post-marketing surveillance studies reported on safety. However, few reports have shown the efficacy of bevacizumab as used in daily practice. We evaluated the efficacy and safety of bevacizumab for metastatic colorectal cancer patients in daily practice.. All unresectable metastatic colorectal cancer patients who began receiving bevacizumab in participating facilities from June 2007 to October 2008 were retrospectively analyzed for safety and efficacy. Adverse events were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events. Response Evaluation in Solid Tumors criteria, version 1.0, was used for the tumor response rate.. A total of 212 patients from 17 institutions were assessed. Grade 3 or higher adverse events related to bevacizumab included gastrointestinal perforation in 3, thrombosis in 7, hypertension in 30 and gastrointestinal bleeding in 2. Response rates were 62.5, 30.1 and 11.8% overall among patients receiving bevacizumab as first-, second- and third-line or greater therapy. Median progression-free survival was 14.4 [95% confidence interval (CI): 10.8-18.1], 7.8 (95% CI: 6.5-9.1) and 6.0 (95% CI: 4.6-7.3) months, and median overall survival was 32.5 (95% CI: 24.6-40.3), 16.4 (95% CI: 14.4-18.5) and 11.8 (95% CI: 8.6-15.0) months, respectively.. The general cohort of patients in HGCSG0801 showed a similar efficacy and safety profile of bevacizumab as seen in clinical trials. Although the sample size was small and there were several study limitations, these results suggest that colorectal cancer patients in Japan might safely receive and benefit from bevacizumab in combination with chemotherapy in daily practice, as is seen in patients in other countries.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cohort Studies; Colorectal Neoplasms; Confidence Intervals; Disease-Free Survival; Drug Administration Schedule; Drug Combinations; Epistaxis; Female; Fluorouracil; Gastrointestinal Hemorrhage; Humans; Hypertension; Irinotecan; Japan; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxonic Acid; Proteinuria; Retrospective Studies; Tegafur; Thrombosis; Treatment Outcome

Injectable combination chemotherapy with 5-fluorouracil (5-FU)/Leucovorin (LV), oxaliplatin (OHP), and irinotecan (CPT-11) has been a standard treatment for advanced colorectal cancer (CRC). An oral fluoropyrimidine, S-1 (tegafur, gimeracil, and oteracil), has been developed recently, and a combination of S-1/CPT-11 demonstrated effects comparable to FOLFIRI for the treatment of advanced CRC. Being without continuous infusion lasting for days, combination chemotherapy with oral fluoropyrimidine may limit inconvenience and improve the quality of life (QOL) of patients. There have been few studies evaluating chemotherapy with oral fluoropyrimidine in terms of patient QOL and convenience.. We assessed the patients' QOL by questionnaire, comparing experiences of those treated with S-1/CPT-11 to those treated with mFOLFOX6 in patients with advanced CRC. The questionnaire, selected from EORTC QLQ, FACT-G, and FACT/GOG-Ntx, consisted of six categories: moving activity, willingness, pain and numbness, gastrointestinal symptoms, daily life, and convenience. The questionnaire had 5 questions in each category and a total of 30 questions.. Patients' background and characteristics were similar. No significant difference was observed in response rates and time to progression between the groups. As for adverse effects, there was a case of fatigue (grade 2), five cases of neurotoxicites (grade 1 and 2) in mFOL-FOX6, and a case of diarrhea (grade 3) in S-1/CPT-11. No difference between the two groups was observed in responses to the questionnaire asking about moving activity, willingness, gastrointestinal symptoms, and daily life. As for neurotoxicity and convenience, however, S-1/CPT-11 showed significantly better results than mFOLFOX6.. The present results suggest that questionnaires are useful for assessing patients' QOL with advanced CRC treated chemotherapy. Combination chemotherapy with oral fluoropyrimidine S-1 could provide similar response rates, limit inconvenience, and improve QOL.

Topics: Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Combinations; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxonic Acid; Quality of Life; Surveys and Questionnaires; Tegafur

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Drug Combinations; Drug Therapy, Combination; Fluorouracil; Humans; Irinotecan; Neoplasm Metastasis; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Tegafur

Aberrant gene methylation is frequently observed in various cancers and plays an important role in carcinogenesis, cancer progression and drug responsiveness. The aim of this study is to identify colorectal cancer specific gene methylation determining chemosensitivity to S-1/CPT-11 therapy. The gene methylation of CHFR, p16, RUNX3, E-cadherin, MGMT, hMLH1, ABCG2, UGT1A1 and BNIP3 genes were analyzed in 27 colorectal cancer tissues by quantitative methylation-specific PCR (q-MSP). All 27 patients were postoperatively treated by S-1/CPT-11 therapy targeting the metastatic lesion and the recurrent tumor. Thereafter, the patients were divided into a responder group (RG) or a non-responder group (NRG) according to the effect of the chemotherapy. There were 13 cases of RG (48.1%) and 14 cases of NRG (51.9%). The methylation level in CHFR, RUNX3 and BNIP3 was significantly higher in cancer lesions in comparison to the non-cancerous lesion. Only methylation of the BNIP3 gene was significantly higher in primary cancer tissue of the NRG than the RG. The correlation between the BNIP3 methylation status and time to progression (TTP) suggested that the low methylation group (n=16) resulted in a significantly longer TTP, in comparison to the high methylation group (n=11; P=0.004). The methylation level of BNIP3 showed a significant inverse correlation with the mRNA expression suggesting the DNA methylation suppressed BNIP3 expression (r=-0.466, P=0.021). In conclusion, BNIP3 gene methylation is a possible marker predicting a poor response to the S-1/CPT-11 combined therapy in colorectal cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; CpG Islands; DNA Methylation; Drug Combinations; Drug Resistance, Neoplasm; Epigenesis, Genetic; Female; Gene Silencing; Humans; Irinotecan; Male; Membrane Proteins; Middle Aged; Oxonic Acid; Proto-Oncogene Proteins; Tegafur

Recently, in drug therapy for patients with advanced digestive cancer, S-1 (tegafur x gimeracil x oteracil potassium) alone or S-1 combined with other chemotherapeutic agents (S-1+alpha) is prescribed. However, many patients are often forced to give up long-term S-1 treatment owing to high incidence rates of adverse effects. The purpose of this study was to evaluate the efficacy of superfine dispersed lentinan (SDL) for the suppression of adverse effects of S-1 or S-1+alpha.. The subjects were 72 patients who had unresectable or recurrent advanced digestive cancer. The subject group consisted of 45 men and 27 women, with a median age of 64 (31-85) years; 29 gastric, 25 colorectal, 10 pancreatic and 8 other digestive cancer patients. Thirty -one patients were administered S-1 alone and 41 patients were administered S-1+alpha. SDL (15mg of lentinan/bag/day) was orally administered to all patients for 12 weeks. Adverse events and overall survival time were evaluated according to the CTCAE ver 3.0 and the Kaplan-Meier method, respectively.. Seventy-two patients were enrolled in this study. Adverse events which had an undeniable causal relationship to SDL were observed in 2 patients (2.7 %, constipation [Grade 2] and nausea [Grade 1]) out of 72 patients; all of the events were not severe and disappeared when the SDL administration was discontinued. Adverse events associated with S-1 or S-1+ alpha were observed in 9 patients (12.5% ) (11 events) out of 72 patients. Grade 3 adverse events were observed in 3 patients (4.2% ) (leukopenia, 2; thrombocytopenia, 1). Incidence rates of both hematological and nonhematological adverse events were very low. In no gastrointestinal toxicity associated with S-1 or S-1+alpha was observed, which was estimated to be an effect of SDL combination. Mean survival times in gastric cancer and colorectal cancer patients were 9. 5 months (95%confidential interval [CI], 7.0-22.4 months) and 18.4 months (95% CI, 13.2 -28.5 months), respectively.. From the results of the present study, SDL is considered completely free of anything harmful to advanced digestive cancer patients and is effective for the suppression of adverse effects of S-1 or S-1+alpha therapy. It is suggested that SDL can prolong the administration period of S-1 and, as a result, contribute to prolongation of survival in patients with advanced digestive cancer.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Colorectal Neoplasms; Digestive System Neoplasms; Drug Combinations; Drug Therapy, Combination; Female; Humans; Lentinan; Male; Middle Aged; Oxonic Acid; Pancreatic Neoplasms; Stomach Neoplasms; Tegafur

Metronomic chemotherapy has been advocated recently as a novel chemotherapeutic regimen. Polyethylene glycol (PEG)-coated liposomes are well known to accumulate in solid tumors by virtue of the highly permeable angiogenic blood vessels characteristic for growing tumor tissue, the so-called "enhanced permeability and retention (EPR) effect". To expand the range of applications and investigate the clinical value of the combination strategy, the therapeutic benefit of metronomic S-1 dosing in combination with oxaliplatin (l-OHP)-containing PEG-coated liposomes was evaluated in a murine colon carcinoma-bearing mice model. S-1 is an oral fluoropyrimidine formulation and metronomic S-1 dosing is a promising alternative to infused 5-FU in colorectal cancer therapy. Therefore, the combination of S-1 with l-OHP may be an alternative to FOLFOX (infusional 5-FU/leucovorin (LV) in combination with l-OHP), which is a first-line therapeutic regimen of a colorectal carcinoma. The combination of oral metronomic S-1 dosing with intravenous administration of liposomal l-OHP formulation exerted excellent antitumor activity without severe overlapping side-effects, compared with either metronomic S-1 dosing, free l-OHP or liposomal l-OHP formulation alone or metronomic S-1 dosing plus free l-OHP. We confirmed that the synergistic antitumor effect is due to prolonged retention of l-OHP in the tumor on account of the PEG-coated liposomes, presumably via alteration of the tumor microenvironment caused by the metronomic S-1 treatment. The combination regimen proposed here may be a breakthrough in treatment of intractable solid tumors and an alternative to FOLFOX in advanced colorectal cancer therapy with acceptable tolerance and preservation of quality of life (QOL).

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Colorectal Neoplasms; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Drug Synergism; Humans; Liposomes; Male; Mice; Mice, Inbred BALB C; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Polyethylene Glycols; Tegafur; Treatment Outcome; Tumor Burden

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Combinations; Fluorouracil; Humans; Oxonic Acid; Prodrugs; Randomized Controlled Trials as Topic; Tegafur

In a patient with multiple liver metastases of colorectal cancer whose tumor response had been achieved by 5-FU hepatic arterial infusion, a catheter for arterial infusion chemotherapy was occluded resulting in re-elevation of tumor marker levels. For this reason, a second-line IRIS therapy using S-1 and CPT-11 was started. IRIS therapy reduced tumor marker levels to a degree greater than that of previously achieved with 5-FU hepatic arterial infusion, and a diagnostic imaging allowed a judgment of partial response. Although a ratio of liver tumor volume to liver volume was 57% on admission of this patient, the ratio was reduced to 16% by the 14th course of 5-FU hepatic arterial infusion immediately before the catheter was occluded. The ratio was 18% after the 7th course of IRIS therapy, and the diagnostic imaging showed a partial response. Hepatic arterial infusion therapy is one of the treatment methods characterized by a lower incidence of adverse reactions, relatively low cost, and expectation of high anti-tumor efficacy as compared to chemotherapy such as FOLFIRI. IRIS therapy does not require a port insertion and it costs about a half of FOLFIRI therapy. When used as a second-line therapy for unresectable colorectal cancer, IRIS therapy has demonstrated non-inferiority compared to FOLFIRI in a phase III clinica (l FIRIS) study.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Combinations; Fluorouracil; Humans; Infusions, Intra-Arterial; Irinotecan; Leucovorin; Liver Neoplasms; Male; Oxonic Acid; Tegafur; Tumor Burden

Chemotherapy with irinotecan (CPT-11) or oxaliplatin (l-OHP) in combination with infusional 5-fluorouracil (5-FU) and their cross-over as second-line therapies are standard treatments for metastatic colorectal cancer (MCRC). Molecular target agents, which are used as third-line therapies in Western countries after failure of these three drugs, have not been available in Japan. Monotherapy with S-1 [Tegafur, Oteracil potassium and 5-chloro-2,4-dihydroxypyrimidine (CDHP)] showed activity against colorectal cancer with a response rate of 35% as a first-line therapy. It is not clear whether inhibition of dihydropyrimidine dehydrogenase by CDHP can modulate the activity of 5-FU even after patients initially fail with 5-FU. This retrospective study evaluated the efficacy and safety of monotherapy with S-1 for MCRC after the failure of standard chemotherapy.. The subjects of this study comprised two cohorts; the first was 27 patients with MCRC who had failed with 5-FU and CPT-11 before approval of l-OHP in Japan (cohort 1), and the second was 23 patients who had failed with 5-FU, CPT-11 and l-OHP (cohort 2). S-1 was given orally twice daily (80 mg m(2)/day) for 28 days followed by a 14-day rest.. In cohorts 1 and 2, the response rates were 7% and 0%, and the median progression-free survivals were 2.8 and 2.7 months, and overall survivals after initiation of S-1 were 10.5 and 4.7 months, respectively. The common grade 3 and 4 adverse events in cohorts 1 and 2 were diarrhea 15% and 13%, anorexia 11% and 17% and anemia 26% and 30%, respectively.. S-1 monotherapy did not show promising activity against MCRC after the failures with 5-FU, CPT-11 and l-OHP.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Female; Humans; Irinotecan; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Pyrimidines; Retrospective Studies; Tegafur

Previous studies have assessed the efficacy and safety of combined treatment with irinotecan (7-ethyl-10-[4-[1-piperidino]-1-piperidino]carbonyloxycamptothecin, CPT-11) and S-1, containing tegafur, a prodrug of 5-fluorouracil, in the treatment of colorectal and gastric cancer. The objective of this study was to describe the interaction between CPT-11 and S-1 in 4 patients with colorectal cancer. Coadministration of S-1 changed the pharmacokinetic behavior of CPT-11 and its metabolites. In particular, maximum plasma concentration (Cmax) and area under the plasma concentration curve (AUC) of 7-ethyl-10-hydroxycampothecin (SN-38) was markedly decreased by coadministration of S-1. For SN-38, the median ratio of Cmax and AUC with S-1 to those without S-1 was median 0.34 (range 0.24-0.78) and 0.56 (range 0.23-0.68), respectively. A markedly difference in drug interaction among individual patients was observed. We conclude that the plasma concentration of SN-38 was decreased by oral administration of S-1 in patients with colorectal cancer. This observation might be important for clinical decisions regarding combination therapy.

Topics: Administration, Oral; Aged; Antineoplastic Agents, Phytogenic; Camptothecin; Colorectal Neoplasms; Drug Combinations; Female; Fluorouracil; Humans; Irinotecan; Male; Middle Aged; Oxonic Acid; Prodrugs; Tegafur

Vascular endothelial growth factor (VEGF) and its receptors VEGF-R1, -R2 and -R3 play important roles in tumor angiogenesis and are associated with poor prognosis in several solid tumors. However, their functional significance remains unclarified. Here, we investigated the associations between the expression of these receptors and the clinical outcomes of colorectal cancer (CRC) patients.. An immunohistochemical approach was used to detect VEGF-R1, -R2 and -R3 expression in 91 CRC patients who underwent surgery and received chemotherapy at the National Cancer Center Hospital. Statistical analysis was performed to determine the prognostic significance of these biomarkers.. Immunoreactivity for VEGF-R2 and -R3 was localized in microvessels and that for VEGF-R1 in cancer cells and stromal microvessels. VEGF-R1 staining in cancer cells (>10% staining) was found in 84 patients (92%) and in stromal vessels in 75 patients (82%). VEGF-R2 staining in tumor vessels (>10% staining) was found in 84 patients (92%), whereas VEGF-R3 staining was found in 85 patients (93%). Strong positive staining (>60% staining) of VEGF-R1 in tumor cells, and VEGF-R1, -R2 and -R3 in vessels was identified in 58 (64%), 33 (36%), 52 (57%) and 60 (66%) patients, respectively. Univariate analysis revealed that VEGF-R1 strong positive staining correlated with shorter post-operative survival in patients with Stage II/III disease (P = 0.01), but neither VEGF-R2 nor R3 expression correlated with survival.. VEGF-R1, -R2 and -R3 were highly expressed in CRC cells and stromal vessels. VEGF-R1 strong positive staining correlated with shorter survival after CRC surgery.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Combinations; Female; Fluorouracil; Humans; Immunoenzyme Techniques; Leucovorin; Male; Middle Aged; Neoplasm Staging; Oxonic Acid; Prognosis; Retrospective Studies; Survival Rate; Tegafur; Uracil; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factor Receptor-3

We evaluated the therapeutic effect of TS-1, a novel oral fluoropyrimidine, in combination with leucovorin with in vivo experiments using a murine tumor xenograft model fed a low folate diet. The reduced folate levels in the tumors of mice fed a low folate diet were significantly lower than those in the tumors of mice fed a normal diet. In addition, the basal reduced folate levels in the tumors of mice fed a low folate diet were comparable to those in human colorectal cancer tissues. Furthermore, when leucovorin was orally administered, the reduced folate levels in the tumors of mice fed a low folate diet were more than two-fold higher than those of mice fed the normal diet. The leucovorin-induced potentiation of TS-1 antitumor activity was obviously higher in COL-1 tumor-bearing mice fed a low folate diet than in mice fed a normal diet. The remarkable increase in reduced folate levels following the administration of leucovorin contributed to the leucovorin-induced potentiation of TS-1 antitumor activity in this low-folate-diet animal model. These results suggest that rodent models fed a low folate diet are suitable for in vivo evaluation of reduced folate drugs like leucovorin. In this model, the combination of leucovorin with TS-1 resulted in a higher antitumor efficacy than TS-1 alone or the combination of UFT and leucovorin, suggesting that TS-1 and leucovorin combination therapy may be an effective regimen for patients with colorectal cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Diet; Disease Models, Animal; Drug Combinations; Drug Evaluation; Folic Acid; Humans; Leucovorin; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Oxonic Acid; Tegafur

The 3-drug regimen of CPT-11+5-FU+l-LV is generally used for metastatic and/or recurrent colorectal cancer. We have applied this treatment as the first-line intervention in our hospital. However,when the efficacy is reduced we try chemotherapy using CPT-11+TS-1 for 5 outpatients as second- or third-line chemotherapy. Decreased CEA levels were subsequently observed in 4 of 5 cases. In addition, 2 cases exhibited grade 1 or 2 adverse effects, but no case developed neutropenia. We could expect such effects even for patients after only 5-FU, and this treatment may be performed safely on ambulatory patients.

Topics: Aged; Ambulatory Care; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Female; Humans; Irinotecan; Male; Middle Aged; Neoplasm Metastasis; Oxonic Acid; Tegafur

We evaluate the feasibility and efficacy of S-1 in combination with cisplatin (CDDP) for patients with colorectal cancer.. A total of 52 patients with advanced or recurrent colorectal cancer were included. S-1 was given orally twice daily for 21 days and CDDP 30 mg/m(2) on day 1 and 8, followed by a 2-week period of no treatment.. Tumor responses among patients included 18 PR, 12 SD, and 16 PD (n = 46). The overall response rate was 36.4% (18/46). The response rate of the patients with prior chemotherapy was 22.2% (4/18) and 50.0% (12/24) among the patients who had no prior therapy. The median survival periods were 555 days and the median progression free survival periods were 183 days, respectively. S-1 in combination with CDDP shows promising activity with acceptable toxicities against colorectal cancer.. A combination of S-1 and CDDP could be a standard therapy for treating colorectal carcinoma.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Colorectal Neoplasms; Disease-Free Survival; Drug Combinations; Female; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Oxonic Acid; Survival Rate; Tegafur; Treatment Outcome

S-1, a novel oral fluoropyrimidine, is increasingly used for the treatment of human cancer including gastrointestinal carcinomas. Using the 5-FU resistant DLD-1/FU human colon cancer cell xenografts, the present study investigated whether S-1 enhances the therapeutic efficacy of radiation and if so what are the underlying mechanisms. Nude mice bearing tumor xenografts were treated with radiation, S-1, or both. Tumor growth delay was the treatments' endpoint. To determine whether S-1 enhances intrinsic cell radiosensitivity, we performed clonogenic cell survival assay. Also we assessed the expression of thymidylate synthase (TS) using immunohistochemistry assay. While S-1 or 5 Gy were only slightly effective as single agents in delaying tumor growth, the combined treatment was highly effective. Clonogenic cell survival showed that S-1 strongly enhanced cell radiosensitivity. Immunohistochemistry showed that the expression of TS was down-regulated in tumors treated by S-1 plus radiation. Combined S-1 plus radiation treatment resulted in a synergistic effect in the therapy of 5-FU resistant human colon carcinoma xenografts (EF = 2.06). The effect could be attributed to the ability of S-1 to increase cell radiosensitivity (EF = 1.9) and to the down-regulation of TS involved in cellular processes leading to radio- and (or) chemo-resistance.

Topics: Administration, Oral; Animals; Antimetabolites, Antineoplastic; Cell Line, Tumor; Colorectal Neoplasms; Drug Combinations; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Oxonic Acid; Radiation-Sensitizing Agents; Tegafur; Xenograft Model Antitumor Assays

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Camptothecin; Colorectal Neoplasms; Drug Combinations; Humans; Irinotecan; Middle Aged; Oxonic Acid; Tegafur; Time Factors

In this study, we demonstrated that chemoimmunotherapy using S-1, a novel oral fluoropyrimidine anticancer drug, combined with lentinan (LNT), a beta (1 --> 3) glucan, was effective in vivo, and we clarified the augmentation of the function of dendritic cells (DCs) in vivo and in vitro. The survival period of Colon-26-bearing mice treated with S-1 + LNT was significantly more prolonged than that of mice treated with S-1 alone (P < 0.05). On the other hand, LNT did not prolong the survival period when combined with S-1 in Colon-26-bearing athymic mice. The frequency of CD86+ DCs infiltrated into Colon-26 was increased in mice treated with S-1 + LNT, and splenic DCs harvested from mice treated with S-1 + LNT showed more potent T-cell proliferation activity than that of DCs from mice treated with S-1 alone (P < 0.05). Furthermore, the activity of cytotoxic T lymphocytes (CTLs) in splenocytes of S-1 + LNT-treated mice was specific and more potent than that of CTLs from mice treated with S-1 alone (P < 0.05). These results suggest that modulation of specific immunity with LNT has a significant role in enhanced antitumor effects through the modification of DC function. We demonstrated that DCs might play an important role in chemotherapy, and the combination therapy of S-1 and LNT presents a promising chemoimmunotherapy, which might lead to better survival for cancer patients.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Dendritic Cells; Drug Combinations; Fibrosarcoma; Immunotherapy, Adoptive; Lentinan; Lung Neoplasms; Lymphoma; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Neoplasms, Experimental; Oxonic Acid; Pyridines; Rats; Rats, Inbred Strains; Spleen; Survival Rate; T-Lymphocytes, Cytotoxic; Tegafur

The usefulness of TS-1 as second/third-line therapy was evaluated in 7 patients with stage IIIb/IV colorectal cancer in whom the response to prior 5-FU/l-LV+CPT-11 therapy administered at our hospital had been rated as progressive disease (PD). The initial dose level of TS-1 was set at 80 mg/m2. The median follow-up period was 8 months. The response rate to TS-1 therapy was 14.3% (1/7). Four cases (57.1%) were rated as showing partial response (PR) or no change (NC). The median time to treatment failure (TTF) was 117 days. Thus, relatively satisfactory tumor dormancy was achieved in IFL-resistant cases. All adverse reactions observed were grade 2 or less severe. These results suggest that TS-1 used as the second/third-line therapy will contribute to improving the prognosis of patients with advanced or recurrent colorectal cancer.

Topics: Adenocarcinoma; Aged; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Drug Evaluation; Female; Humans; Male; Middle Aged; Oxonic Acid; Prognosis; Pyridines; Tegafur

Thymidylate synthase (TS), the target enzyme of the fluoropyrimidine class of drugs, has a 28-bp repeat polymorphism in the promoter region that has been associated with response of tumors to 5-fluorouracil-based therapy. Patients homozygous for the double repeat (2R/2R) in the TS gene have an overall better outcome from treatment than patients homozygous for the triple repeat (3R/3R). However, due to loss of heterozygosity at the TS locus on chromosome 18 in cancer cells, heterozygous 2R/3R individuals can acquire the 2R/loss or the 3R/loss genotype in their tumors. The purpose of this study was to determine whether the response of colorectal cancer to fluoropyrimidine therapy is associated with the resulting tumor TS genotype when loss of heterozygosity occurs in tumor DNA. A total of 30 colorectal cancer patients treated with the fluoropyrimidine-based combination S-1, all of whom had stage IV disease, were studied. The response rate to S-1 in this group of patients was 13 of 30 (43%). The heterozygous 2R/3R genotype was found in 22 of 30 normal tissues, whereas 10 (45%) of the matched cancer tissues showed only the 2R-sequence band (2R/loss), and 7 cancer tissues (32%) showed only the 3R-sequence band (3R/loss). The response rate of the 2R/loss tumor genotype patients was 80% (8 of 10) compared with 14% (1 of 7) in the 3R/loss genotype group (P = 0.029). Patients with tumor 3R/loss genotypes had significantly lower survival than 2R/loss genotypes. Heterozygous patients with a 2R/loss tumor genotype had the same survival as 2R/2R patients, whereas patients with a 2R/3R tumor genotype had a short survival similar to homozygous 3R/3R genotypes. These results show that: (a) response to 5-fluorouracil-based therapy is determined by tumor genotype; and (b) the 3R repeat is a direct negative determinant of outcome.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Chromosomes, Human, Pair 18; Colorectal Neoplasms; DNA; DNA, Complementary; Drug Combinations; Electrophoresis; Female; Genotype; Heterozygote; Homozygote; Humans; Loss of Heterozygosity; Male; Middle Aged; Oxonic Acid; Polymerase Chain Reaction; Polymorphism, Genetic; Pyridines; Reverse Transcriptase Polymerase Chain Reaction; RNA; Tegafur; Thymidylate Synthase; Time Factors; Treatment Outcome

We retrospectively evaluated the efficacy of chemotherapy regarding symptom control, toxicity and discharge rate in 39 patients with gastric or colorectal cancer. Treatment consisted of TS-1 (n = 16), TS-1 + CPT-11 (n = 8), CDDP + CPT-11 (n = 5), paclitaxel (n = 8) and MTX + 5-FU (n = 4) for gastric cancer and 5-FU + l-leucovirin (n = 6), 5-FU + CPT-11 (n = 5), MMC + CPT-11 (n = 8) and 5-FU protracted continuous infusion (n = 5) for colorectal cancer. The rates of symptom improvement were the following: pain 60% (10/15), general fatigue 56% (5/9) and abdominal fullness 53% (8/15). 87% (34/39) of the patients were discharged from hospital and continued chemotherapy as outpatients grade 3 toxicities were the following: anemia 10.3%, nausea and/or vomiting 7.7%, diarrhea 5.1%. There was no treatment related death. The rates of outpatient based treatment duration improvement were the following: gastric cancer: 47.6%, colorectal cancer: 72%. These data suggest that these treatments for gastric and colorectal cancer are safe and improve the patients' QOL.

Topics: Adult; Aged; Ambulatory Care; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cisplatin; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Female; Fluorouracil; Humans; Irinotecan; Male; Middle Aged; Outpatients; Oxonic Acid; Paclitaxel; Pyridines; Retrospective Studies; Stomach Neoplasms; Tegafur

In an effort to improve the therapeutic selectivity of 5-fluorouracil (FUra) against colorectal cancer, S-1, a combination agent including a prodrug of FUra with two modulators, was recently developed by Taiho Pharmaceuticals Co. S-1 is a combination of tegafur (FT), 5-chloro-2,4-hydroxypyridine, and potassium oxonate in the molar ratio of 1.0:0.4:1.0, with the latter two components as inhibitors of dihydropyrimidine dehydrogenase and phosphoribosylpyrophosphate transferase, respectively. In this study, the therapeutic selectivity and efficacy of S-1 (oral) was compared with FT (oral) and FUra (i.v. infusion) in rats bearing advanced colorectal cancer by using clinically relevant schedules. The maximum tolerated doses (MTDs) of S-1, FT, and FUra were 31.5, 200, and 25 mg/kg/d for 7 days and 22.5, 150, and 12.5 mg/kg/d for 28 days, respectively. The therapeutic index of S-1 was 4- to 5-fold higher than that of either FT or FUra. S-1 achieved 100% complete tumor regression (CR) at its MTD in both 7-day and 28-day schedules. Furthermore, the high incidences of stomatitis, alopecia, and diarrhea observed with FUra and FT, were not observed with S-1. In an attempt to understand the basis for the observed superior therapeutic selectivity with S-1, we studied pharmacokinetic analysis of FUra, drug-induced apoptosis, suppression of mitosis, and inhibition of thymidylate synthase (TS) after S-1, FUra, or FT administration. The peak plasma FUra concentrations derived from FUra or S-1 (FT) at comparable MTDs were similar, but the plasma level of FUra was higher with S-1 than with FUra. Induction of high and sustained apoptosis was achieved with S-1. Although the initial level of apoptosis induced by FUra was comparable to S-1, it was not sustained. The sustained level of apoptosis appears to correlate with tumor growth inhibition. Mitotic figures were more greatly suppressed with S-1 treatment than with FUra. Studies on TS inhibition indicated that, although both S-1 and FUra caused a 4- to 6-fold induction of total TS protein, single oral administration of S-1 was superior to 24-h infusion of FUra in suppressing free TS. The data are consistent with the observation that the therapeutic efficacy of S-1 (100% cure) over FUra is associated with high and sustained levels of drug-induced apoptosis, greater suppression of mitosis, and inhibition of free TS in tumor tissues.

Topics: Animals; Antineoplastic Agents; Apoptosis; Colorectal Neoplasms; Disease Models, Animal; Drug Combinations; Female; Fluorouracil; Mitosis; Neoplasm Transplantation; Oxonic Acid; Prodrugs; Pyridines; Rats; Rats, Inbred F344; Tegafur; Thymidylate Synthase; Treatment Outcome

S-1 is an oral combined form of 1 M tegafur [a prodrug of 5-fluorouracil (5-FU)], 0.4 M 5-chloro-2,4-dihydroxypyridine (a reversible inhibitor of dihydropyrimidine dehydrogenase) and 1 M potassium oxonate (an inhibitor of orotate phosphoribosyltransferase). S-1 has been shown to exert a potent antitumor effect with low gastrointestinal toxicity in experimental tumor models. We have therefore compared the antitumor effect of oral S-1 with that of continuous infusion of 5-FU in rats bearing transplants of human and murine tumors. Almost complete inhibition of the tumor growth was obtained on 7 day schedules in Yoshida sarcoma-bearing rats by consecutive administration of 30 mg/kg/day of oral S-1 and 40 mg/kg/day infusion of 5-FU. However, a significant difference between the incidence of toxicities of S-1 and 5-FU, including body weight loss and diarrhea, was noted. The rats given the 5-FU infusion had marked weight loss and severe diarrhea, while those given oral S-1 had neither. Although about 50% inhibition of the tumor growth was attained with 15 mg/kg/day of oral S-1 and 30 mg/kg/day infusion of 5-FU in nude rats with xenografted human colon cancer (KM12C), the rate of body weight loss in the 5-FU-treated group was distinctly higher than in the S-1-treated group. The ratio of the 5-fluoronucleotide concentrations in gastrointestinal tissue to that in the tumor was lower in the S-1-treated rats than in the 5-FU-treated rats. In conclusion, the results suggest that oral S-1 might be more effective in the treatment of cancer patients than continuous infusion of 5-FU, from the standpoint of antitumor potency and toxicity.

Topics: Administration, Oral; Animals; Antimetabolites, Antineoplastic; Cell Division; Colorectal Neoplasms; Digestive System; Drug Combinations; Fluorouracil; Humans; Infusions, Intravenous; Neoplasm Transplantation; Oxonic Acid; Pyridines; Rats; Rats, Inbred F344; Sarcoma, Yoshida; Tegafur; Transplantation, Heterologous