levoleucovorin and Carcinoma--Hepatocellular

Apatinib is a novel and highly selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2. Previous studies have suggested that apatinib is safe and effective in some solid tumors. We report one case with advanced hepatocellular carcinoma (HCC), who received apatinib combined with transhepatic arterial chemotherapy and embolization (TACE), and chemotherapy respectively. TACE was administered three times once a month, using lipiodol 10ml, oxaliplatin 150mg, and tegafur 1g. The dose of apatinib was 500 mg/d from day 4 to 24. After TACE, the patient received chemotherapy of regimen FOLFOX4, oxaliplatin intravenously at 85 mg/m2 on day 1, calcium levofolinate 200 mg/m2 on day 1 and 2, 5-fluorouracil 400 mg/m2 intravenously and 5-fluorouracil 600 mg/m2 intravenously pumped for 22h on day 1 and 2, cycled every two weeks for seven cycles. He took concurrently apatinib with a dose of 500mg daily from 1 to 10 days per cycle. He was confirmed as partial response (PR) by the Response Evaluation Criteria in Solid Tumors (RECIST). The level of serum alpha-fetoprotein (AFP) decreased from 60500 ng/ml to 12.7 ng/ml, and the progression free survival (PFS) time was more than eight months. It indicated that apatinib may be a superior choice for HCC patients.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Disease-Free Survival; Ethiodized Oil; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pyridines; Tegafur

Primary liver cancer, mainly consisting of hepatocellular carcinoma (HCC), is one of common malignancies worldwide, and prevalent among the Chinese population. A diagnosis of early stage HCC has proven to be very difficult because of its insidious feature in onset and development. At the time of diagnosis, most HCC cases are locally advanced and/or distant metastatic, which results in difficulty to be treated and poor prognosis. For advanced HCC, systemic therapy is frequently adopted as an important palliative method. In recent years, clinical studies and observations have often reported about systemic anti-cancer therapy of advanced HCC, including molecular target therapy, systemic chemotherapy and immunotherapy. In this article, we review these treatment modalities to provide a reference for clinicians.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Deoxycytidine; Fluorouracil; Humans; Immunotherapy; Leucovorin; Liver Neoplasms; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Organoplatinum Compounds; Transforming Growth Factor beta

Colorectal cancers have been the first cancers to benefit from an efficient anti-angiogenic treatment, represented by bevacizumab, which has been approved for first-line metastatic treatment in combination with reference chemotherapies and which is under study in the adjuvant setting. Other gastro-intestinal malignancies appear less responsive to anti-angiogenic therapy, but inhibitors of the VEGF receptors (sorafenib, sunitinib, axitinib) are in development with encouraging results. The safety profile of anti-angiogenic agents is quite different from that of classical chemotherapy and may require a modification of treatment strategies.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoma, Hepatocellular; Colorectal Neoplasms; Esophageal Neoplasms; Fluorouracil; Gastrointestinal Neoplasms; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Neovascularization, Pathologic; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Stomach Neoplasms

Radiofrequency ablation (RFA) of malignant liver lesions is considered a procedure with low morbidity. However, RFA performed close to hilar structures carries the risk of heat-induced biliary tract damage and subsequent septic episodes.. We performed an analysis of complications in 42 patients with 211 liver lesions treated with a combined approach of liver resection and RFA.. One patient died due to postoperative liver failure. There was one case of temporary liver dysfunction, one vena cava thrombosis, and six febrile episodes. Four of the six febrile episodes were related to bile duct injuries. They became evident 3-5 weeks after the procedure. All four patients were treated successfully by the placement of stents within the biliary tract. None of the patients developed a hepatic abscess.. Biliary tract damage is a complication that can occur weeks after RFA. Immediate endoscopic intervention can obviate the occurrence of prolonged septic complications.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract; Carcinoma, Hepatocellular; Catheter Ablation; Chemotherapy, Adjuvant; Cholangiopancreatography, Endoscopic Retrograde; Colorectal Neoplasms; Combined Modality Therapy; Fatal Outcome; Female; Fever; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Failure; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Organoplatinum Compounds; Postoperative Complications; Radiotherapy, Adjuvant; Retrospective Studies; Stents; Thrombosis; Treatment Outcome; Vena Cava, Inferior

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemotherapy, Cancer, Regional Perfusion; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Mitomycin; Mitoxantrone

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Clinical Trials as Topic; Colonic Neoplasms; Doxorubicin; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Methotrexate; Rectal Neoplasms; Semustine; Vincristine

The combination of lenvatinib, toripalimab and hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) suggested encouraging antitumour activity in our retrospective study. We hereby prospectively establish the efficacy, safety and predictive biomarkers of the combination therapy as a first-line treatment in patients with high-risk advanced hepatocellular carcinoma (HCC).. This phase II, single-centre, single-arm trial enrolled advanced HCC participants with high-risk. Of 51 screened participants, 36 received lenvatinib, toripalimab plus FOLFOX-HAIC. Participants received 21-day treatment cycles of lenvatinib, toripalimab, and FOLFOX-HAIC. The primary end-point was the progression-free survival (PFS) rate per RECIST at six months.. Thirty-six participants (86.1% with high-risk features) were enrolled in our study. The primary end-point was met with a PFS rate of 80.6% (95% CI, 64.0%-91.8%) at six months. The median PFS was 10.4 months (95% CI, 5.8-15.0), and the median OS was not reached at the prespecified final analysis and was 17.9 months (95% CI, 14.5-21.3) after follow-up was extended. The ORR per RECIST was 63.9%, and per mRECIST was 66.7%. The median duration of response was 14.4 months (95% CI, 8.9-19.9). The most common adverse events were thrombocytopenia, elevated aspartate aminotransferase, and hypertension, and no treatment-related death was reported. Participants with low levels of both CCL28 and BTC had unsatisfactory prognosis.. Lenvatinib, toripalimab and FOLFOX-HAIC showed safe and encouraging antitumour activity for advanced HCC with high-risk features. The levels of CCL28 and BTC might be the predictive biomarkers for the triple combination therapy.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Carcinoma, Hepatocellular; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Oxaliplatin; Phenylurea Compounds; Quinolines; Retrospective Studies; Treatment Outcome

Immune checkpoint inhibitors and chemotherapy can synergistically increase efficacy in a variety of malignancies. We conducted this phase Ib/II study to assess the safety and efficacy of anti-PD-1 antibody camrelizumab in combination with FOLFOX4 for treatment-naive advanced hepatocellular carcinoma (aHCC).. This open-label, multicenter phase Ib/II study (NCT03092895) enrolled patients with aHCC and without prior systemic treatment for treatment with camrelizumab (3 mg/kg) and FOLFOX4 every two weeks. First, six patients were enrolled, followed by an additional 28 patients after dose-limiting toxicity cases were determined to be <33% of patients. The primary endpoint was tolerability and safety of treatment.. A total of 34 aHCC patients were enrolled and received study treatment. No dose-limiting toxicity were observed in the first six patients enrolled. Twenty-nine (85.3%) of the total 34 patients had grade ≥3 treatment-related adverse events (TRAEs), with the most common ones being decreased neutrophil count (55.9%) and decreased white blood cell count (38.2%). No TRAEs-related deaths occurred. The objective response and disease control rate were 29.4% (95% CI, 15.1-47.5) and 79.4% (95% CI, 62.1-91.3), respectively. The median duration of response, progression-free survival, and overall survival was 6.9 months (range, 3.3-11.5), 7.4 months (95% CI, 3.9-9.2), and 11.7 months (95% CI, 8.2-22.0), respectively.. Camrelizumab combined with FOLFOX4 for first-line treatment of patients with aHCC showed good safety and tolerability, with promising preliminary antitumor activity.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds

Arginine starvation depletes the micronutrients required for DNA synthesis and interferes with both thymidylate synthetase activity and DNA repair pathways in preclinical models of hepatocellular carcinoma (HCC). Pegylated arginine deiminase (ADI-PEG 20), an arginine degrader, potentiates the cytotoxic activity of platinum and pyrimidine antimetabolites in HCC cellular and murine models.. This was a global, multicenter, open-label, single-arm, phase 2 trial of ADI-PEG 20 and modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in patients who had HCC with Child-Pugh A cirrhosis and disease progression on ≥2 prior lines of treatment. The primary objective was the objective response rate assessed according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary objectives were to estimate progression-free survival, overall survival, safety, and tolerability. Eligible patients were treated with mFOLFOX6 intravenously biweekly at standard doses and ADI-PEG-20 intramuscularly weekly at 36 mg/m. In total, 140 patients with advanced HCC were enrolled. The median patient age was 62 years (range, 30-85 years), 83% of patients were male, 76% were of Asian race, 56% had hepatitis B viremia, 10% had hepatitis C viremia, 100% had received ≥2 prior lines of systemic therapy, and 39% had received ≥3 prior lines of systemic therapy. The objective response rate was 9.3% (95% confidence interval [CI], 5.0%-15.4%), with a median response duration of 10.2 months (95% CI, 5.8 months to not reached). The median progression-free survival was 3.8 months (95% CI, 1.8-6.3 months), and the median overall survival was 14.5 months (95% CI, 13.6-20.9 months). The most common grade ≥3 treatment-related events were neutropenia (32.9%), white blood cell count decrease (20%), platelet count decrease (19.3%), and anemia (9.3%).. Concurrent mFOLFOX6 plus ADI-PEG 20 exhibited limited antitumor activity in patients with treatment-refractory HCC. The study was terminated early, and no further evaluation of the combination will be pursued.. Arginine is an important nutrient for hepatocellular carcinoma (HCC). The depletion of arginine with pegylated arginine deiminase (ADI-PEG 20), an arginine degrader, appeared to make chemotherapy (FOLFOX) work better in animal models of HCC and in patients with HCC on an early phase clinical trial. To formally test this hypothesis in the clinical setting, a large, global, phase 2 clinical trial was conducted of ADI-PEG 20 and FOLFOX in the treatment of patients with refractory HCC. The study showed limited activity of ADI-PEG 20 and FOLFOX in advanced HCC and was stopped early.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Female; Fluorouracil; Humans; Hydrolases; Leucovorin; Liver Neoplasms; Male; Middle Aged; Polyethylene Glycols

Among patients with hepatocellular carcinoma (HCC), 85% of patients have an advanced disease stage at diagnosis and curative therapies cannot be performed. Prognosis has been quite poor as until recently there was no proven effective chemotherapy. Our group found that all-trans-retinoic acid (ATRA) could improve the efficacy of platinum in HCC in vivo and in vitro, thus we wish to validate the efficiency of ATRA in clinical practice.. This is a double-blinded, 1:1 randomized, controlled, multicenter clinical trial. Three hundred and sixty-eight patients with HCC and extrahepatic metastases will receive palliative chemotherapy at the Eastern Hepatobiliary Surgery Hospital, First Hospital of Jilin University and Fujian Provincial Cancer Hospital. Subjects will be randomly assigned to one of the two arms, either ATRA + oxaliplatin + 5-fluorouracil/leucovorin (FOLFOX4) or FOLFOX4 alone. ATRA 20 mg will be given orally three times/day for 3 days prior to the initiation of FOLFOX4. ATRA will be discontinued at the end of FOLFOX4.. Overall survival rate is the primary endpoint. Secondary endpoints are time to progression according to the modified response evaluation criteria in solid tumors (mRECIST) criteria, acute and chronic adverse events, and quality of life.. Chinese Clinical Trial Registry, ChiCTR-IIR-17012916 . Registered on 9 October 2017.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; China; Disease Progression; Double-Blind Method; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Multicenter Studies as Topic; Organoplatinum Compounds; Palliative Care; Progression-Free Survival; Randomized Controlled Trials as Topic; Time Factors; Tretinoin

Sorafenib is the first-line treatment for hepatocellular carcinoma with portal vein invasion; however, it has shown unsatisfactory survival benefit. Sorafenib plus hepatic arterial infusion chemotherapy (HAIC) of oxaliplatin, fluorouracil, and leucovorin (FOLFOX) has shown promising results for these patients in a previous phase 2 study.. To investigate the efficacy and safety of sorafenib plus HAIC compared with sorafenib for hepatocellular carcinoma with portal vein invasion.. This randomized, open-label clinical trial enrolled 818 screened patients. Of the 818 participants, 247 with hepatocellular carcinoma and portal vein invasion were randomly assigned (1:1) via a computer-generated sequence to receive sorafenib plus HAIC or sorafenib. This trial was conducted at 5 hospitals in China and enrolled patients from April 1, 2016, to October 10, 2017, with a follow-up period of 10 months.. Randomization to receive 400 mg sorafenib twice daily (sorafenib group) or 400 mg sorafenib twice daily plus HAIC (SoraHAIC group) (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400 mg/m2 on day 1, and fluorouracil infusion 2400 mg/m2 for 46 hours, every 3 weeks).. The primary endpoint was overall survival by intention-to-treat analysis. Safety was assessed in patients who received at least 1 dose of study treatment.. For 247 patients (median age, 49 years; range, 18-75 years; 223 men and 24 women), median overall survival was 13.37 months (95% CI, 10.27-16.46) in the SoraHAIC group vs 7.13 months (95% CI, 6.28-7.98) in the sorafenib group (hazard ratio [HR], 0.35; 95% CI, 0.26-0.48; P < .001). The SoraHAIC group showed a higher response rate than the sorafenib group (51 [40.8%] vs 3 [2.46%]; P < .001), and a longer median progression-free survival (7.03 [95% CI, 6.05-8.02] vs 2.6 [95% CI, 2.15-3.05] months; P < .001). Grade 3/4 adverse events that were more frequent in the SoraHAIC group than in the sorafenib group included neutropenia (12 [9.68%] vs 3 [2.48%]), thrombocytopenia (16 [12.9%] vs 6 [4.96%]), and vomiting (8 [6.45%] vs 1 [0.83%]).. Sorafenib plus HAIC of FOLFOX improved overall survival and had acceptable toxic effects compared with sorafenib in patients with hepatocellular carcinoma and portal vein invasion.. ClinicalTrials.gov identifier: NCT02774187.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Portal Vein; Protein Kinase Inhibitors; Sorafenib; Treatment Outcome; Young Adult

Arginine depletion interferes with pyrimidine metabolism as well as DNA damage repair pathways. Preclinical data indicates that pairing pegylated arginine deiminase (ADI-PEG 20) with fluoropyrimidines or platinum enhances cytotoxicity in vitro and in vivo in arginine auxotrophs.. This is a single-center, open-label, phase 1 trial of ADI-PEG 20 and modified FOLFOX6 (mFOLFOX6) in treatment-refractory hepatocellular carcinoma (HCC) and other advanced gastrointestinal tumors. A 3 + 3 dose escalation design was employed to assess safety, tolerability, and determine the recommended phase 2 dose (RP2D) of ADI-PEG 20. A RP2D expansion cohort for patients with HCC was employed to define the objective response rate (ORR). Secondary objectives were to estimate progression-free survival (PFS), overall survival (OS), and to explore pharmacodynamics and immunogenicity. Eligible patients were treated with mFOLFOX6 intravenously biweekly at standard doses and ADI-PEG-20 intramuscularly weekly at 18 (Cohort 1) or 36 mg/m. Twenty-seven patients enrolled-23 with advanced HCC and 4 with other gastrointestinal tumors. No dose-limiting toxicities were observed in cohort 1 or 2. The RP2D for ADI-PEG 20 was 36 mg/m. Concurrent mFOLFOX6 plus ADI-PEG-20 intramuscularly at 36 mg/m

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Hepatocellular; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Hydrolases; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Polyethylene Glycols; Progression-Free Survival

To compare the efficacy and safety of chemoembolization alone or chemoembolization combined with hepatic arterial infusion chemotherapy (HAIC), including oxaliplatin (OXA), 5-fluorouracil (5-FU) and folinic acid (CF), in inoperable hepatocellular carcinoma (HCC) without distant metastasis.. Eighty-four inoperable HCC patients were enrolled. Thirty-nine patients underwent chemoembolization alone, and the other 45 patients underwent chemoembolization + HAIC (OXA/5-FU/CF) treatment non-randomly. The progression free survival (PFS), objective response rate (ORR), disease control rate (DCR) and adverse reactions were compared between the two groups.. A significant difference in the ORR was observed between the chemoembolization alone and chemoembolization + HAIC groups. There was no statistically significant difference in DCR between the two groups. The median PFS (mPFS) showed a significant difference between the two groups. For patients with BCLC stage A/B disease, with or without vessel invasion, the chemoembolization + HAIC group showed better mPFS when compared to chemoembolization alone, but no significant difference was found in patients with BCLC stage C disease. The parameter of pain (grade III-IV) in the chemoembolization + HAIC group was increased statistically.. Chemoembolization combined with HAIC with OXA/5-FU/CF may be safe and more effective than chemoembolization alone for inoperable HCC patients without distant metastasis.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Chi-Square Distribution; China; Disease-Free Survival; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Organoplatinum Compounds; Oxaliplatin; Proportional Hazards Models; Prospective Studies; Risk Factors; Time Factors; Treatment Outcome

The EACH study assessed the efficacy of oxaliplatin, 5-fluorouracil, and leucovorin (the FOLFOX4 regimen) compared with doxorubicin alone in terms of overall survival (OS), progression-free survival (PFS), and safety in patients with advanced hepatocellular carcinoma (HCC). We present the results of this study in Chinese patients.. In a multicenter, open-label, randomized, phase III study (NCT00471965), 371 patients (279 patients from the People's Republic of China) were randomized 1:1 to receive either FOLFOX4 or doxorubicin until disease progression, intolerable toxicity, death, or surgical resection.. Baseline characteristics of the Chinese patients enrolled in the study were similar for the 2 treatment groups and in comparison with the whole EACH cohort. Median OS at the prespecified time point of treatment was 5.7 months with FOLFOX4 and 4.3 months with doxorubicin (hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.55-0.98; p = .03). At the end of the follow-up period, median OS was 5.9 months with FOLFOX4 and 4.3 months with doxorubicin (HR: 0.75; 95% CI: 0.58-0.98; p = .03). Median PFS was 2.4 months and 1.7 months in the FOLFOX4 and doxorubicin groups, respectively (HR: 0.55; 95% CI: 0.45-0.78; p = .0002). The response rate (RR) and disease control rate (DCR) were significantly higher in the FOLFOX4 group than in the doxorubicin group (RR: 8.6% vs. 1.4%, p = .006; DCR: 47.1% vs. 26.6%, p = .0004). Hematological toxicity was more frequently reported in the FOLFOX4 group.. For Chinese HCC patients enrolled in the EACH study, FOLFOX4 significantly improved the RR and DCR and prolonged survival compared with doxorubicin. Systemic chemotherapy with oxaliplatin-based regimens may play an important role in the treatment of Chinese patients with advanced HCC.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Asian People; Carcinoma, Hepatocellular; Doxorubicin; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Survival Analysis; Treatment Outcome

Hepatic arterial infusion (HAI) of chemotherapy requires the implantation of a transcatheter application system which is traditionally performed by surgery. This procedure, but particularly the adjacent drug application via pump or port is often hampered by specific complications and device failure. Interventionally implanted port catheter systems (IIPCS) facilitate the commencement of HAI without need for laparatomy, and are associated with favorable complication rates. We here present an evaluation of the most important technical endpoints associated with the use of IIPCS for HAI in patients with primary liver cancers.. 70 patients (pts) with hepatocellular (HCC, n=33) and biliary tract cancer (BTC, n=37) were enrolled into a phase II -study. Of those, n=43 had recurrent disease and n=31 suffered from liver-predominant UICC-stage IVb. All pts were provided with IIPCSs before being treated with biweekly, intraarterial chemotherapy (oxaliplatin, 5-Flourouracil, folinic acid). The primary objective of the trial was defined as evaluation of device-related complications and port duration.. Implantation of port catheters was successful in all patients. Mean treatment duration was 5.8 months, and median duration of port patency was not reached. Disease-progression was the most common reason for treatment discontinuation (44 pts., 63%), followed by chemotherapy-related toxicity (12 pts., 17%), and irreversible device failure (5 pts., 7%). A total of 28 port complications occurred in 21 pts (30%). No unexpected complications were observed.. HAI via interventionally implanted port catheters can be safely applied to patients with primary liver tumors far advanced or/and pretreated.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinoma, Hepatocellular; Catheterization; Catheters; Cholangiocarcinoma; Disease Progression; Equipment Failure; Female; Fluorouracil; Hepatic Artery; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Withholding Treatment

To determine whether FOLFOX4 (infusional fluorouracil, leucovorin, and oxaliplatin) administered as palliative chemotherapy to patients with advanced hepatocellular carcinoma (HCC) provides a survival benefit and efficacy versus doxorubicin.. This multicenter, open-label, randomized, phase III study in mainland China, Taiwan, Korea, and Thailand involved 371 patients age 18 to 75 years who had locally advanced or metastatic HCC and were ineligible for curative resection or local treatment. They were randomly assigned at a ratio of one to one to receive either FOLFOX4 (n = 184) or doxorubicin (n = 187). The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), response rate (RR) by RECIST (version 1.0), and safety.. At the prespecified final analysis, median OS was 6.40 months with FOLFOX4 (95% CI, 5.30 to 7.03) and 4.97 months with doxorubicin (95% CI, 4.23 to 6.03; P = .07; hazard ratio [HR], 0.80; 95% CI, 0.63 to 1.02). Median PFS was 2.93 months with FOLFOX4 (95% CI, 2.43 to 3.53), and 1.77 months with doxorubicin (95% CI, 1.63 to 2.30; P < .001; HR, 0.62; 95% CI, 0.49 to 0.79). RR was 8.15% with FOLFOX4 and 2.67% with doxorubicin (P = .02). On continued follow-up, the trend toward increased OS with FOLFOX4 was maintained (P = .04; HR, 0.79; 95% CI, 0.63 to 0.99). Toxicity was consistent with previous experiences with FOLFOX4; proportions of grade 3 to 4 adverse events were similar between treatments.. Although the study did not meet its primary end point, the trend toward improved OS with FOLFOX4, along with increased PFS and RR, suggests that this regimen may confer some benefit to Asian patients, but an OS benefit cannot be concluded from these data.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Doxorubicin; Female; Fluorouracil; Follow-Up Studies; Humans; International Agencies; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Prognosis; Prospective Studies; Survival Rate; Young Adult

The purpose of this study was to evaluate the efficacy of postoperative adjuvant chemotherapy with FOLFOX regimen on the outcome after LT for HCC patients who did not meet the Milan criteria. Ninety-five consecutive HCC patients with liver cirrhosis undergoing LT were enrolled. Fifty-eight who did not meet the Milan criteria were randomized to open-label treatment with or without adjuvant chemotherapy after LT (n = 29/group). The FOLFOX chemotherapy protocol comprised 3-week cycles of oxaliplatin 100 mg/m(2) on day 1, leucovorin (calcium folinate, CF) 200 mg/m(2) on day 1 followed by 3-day, and 5-fluorouracil (5-FU) 2000 mg/m(2) as a 48-h continuous infusion, for up to six courses in the 1st year after transplantation. Median survival was extended by 4.57 months by combination chemotherapy. The 1- and 3-year survival rates were 89.7% and 79.3% with chemotherapy versus 69.0% and 62.1% without chemotherapy. The cumulative 1-year survival was significantly increased by chemotherapy (log-rank test, P = 0.043). The 6-month tumor-free survival rate was 24.1% higher with chemotherapy than without. The recurrence rate after LT was significantly different between the two groups at 6 months (P = 0.036), but not at 3 years (P = 0.102). The chemotherapy regimen was generally well tolerated. Post-LT adjuvant chemotherapy with oxaliplatin/5-FU/CF could not prevent tumor recurrence post-LT but may contribute to improve the survival of HCC patients who do not meet the Milan criteria. These results should be verified in a larger sample with a longer follow-up period.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Prospective Studies; Survival Rate; Treatment Outcome

We have previously reported that intra-arterial chemotherapy prolongs the survival of patients with advanced HCC (aHCC); however, whether the response to intra-arterial chemotherapy depends on the etiology of underlying liver cirrhosis (LC) is still unknown.. The aim of this study was to assess any influences of the etiology of LC on the response to combined intra-arterial chemotherapy for aHCC.. A total of 53 adult Japanese LC patients (46 men and 7 women) with aHCC were treated with combined intra-arterial chemotherapy between 2002 and 2007 at our hospital. All of the patients had a Japan Integrated Staging (JIS) score of 3 or 4. Their tumors were inoperable according to computed tomography findings. Combined intra-arterial chemotherapy was administered via the proper hepatic artery every 5 days for 4 weeks and the chemotherapy regimen was continued for as long as possible.. There were 15 patients with HBV infection (B-LC group), 29 patients with HCV infection (C-LC group), and nine patients with alcoholic cirrhosis (A-LC group). The percentage of patients with a complete or partial response after 4 weeks of chemotherapy was 0% in the B-LC group versus 31.0% in the C-LC group and 44.4% in the A-LC group. The survival of the A-LC and C-LC groups was significantly longer than that of the B-LC group with the median survival time being 688, 368, and 211 days, respectively.. Combined intra-arterial chemotherapy might be more effective for aHCC in patients with A-LC or C-LC than in patients with B-LC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Female; Fluorouracil; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Infusions, Intra-Arterial; Japan; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Survival Rate; Treatment Outcome

To investigate the therapeutic index of combining etoposide, doxorubicin (adriamycin), cisplatin, 5-fluorouracil (5-FU), and leucovorin (EAPFL) chemotherapy in the treatment of advanced HCC, a trial of a novel schedule of triweekly administration was conducted.. Sixty-six patients with measurable advanced HCC, adequate liver and renal functions and adequate bone marrow reserves in whom local treatment was not indicated were studied. Triweekly EAPFL treatment consisted of a concomitant boost of etoposide 40 mg/m2 i.v. over 30 min on day 1, 2, and 3, doxorubicin 30 mg/m2 i.v. over 30 min on day 1 to a backbone regimen, triweekly PFL chemotherapy with cisplatin 60 mg/m2, 5-FU 1,200 mg/m2, and leucovorin 120 mg/m2 given simultaneously by a 72-h i.v. infusion. Response, survival, and toxicity were evaluated.. One patient had complete response (1%) and thirteen patients had partial response (20%). The objective response rate was 21% (95% confidence interval 11-31%). The median overall survival and median time to progression were 8.9 months and 3.3 months, respectively. Major treatment toxicities (grade 3-4) were neutropenia (28%), anemia (11%), thrombocytopenia (7%), hepatotoxicity (5%), vomiting (2%), and diarrhea (2%). There was no treatment-related death.. Triweekly EAPFL chemotherapy is a moderately effective regimen with tolerable toxicities in the treatment of advanced HCC.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Doxorubicin; Etoposide; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged

To evaluate the time dependence of intra-arterial 5-fluorouracil (5-FU) therapy for advanced hepatocellular carcinoma (aHCC).. Thirty-seven adult Japanese patients who had aHCC and liver cirrhosis were treated with combined intra-arterial 5-FU, cisplatin (CDDP), and leucovorin (LV). The Japan Integrated Staging score (JIS score) of each patient was 3 or more. The patients were divided into two groups, after which the 15 patients in group S were treated with 6-h infusion chemotherapy (LV at 12 mg/h, CDDP at 10 mg/h, and 5-FU at 250 mg/m2 per 4 h) and the 22 patients in group L were treated with 24-h infusion chemotherapy (LV at 12 mg/h, CDDP at 10 mg/h, and 5-FU at 250 mg/ m2 per 22 h). Continuous infusion chemotherapy was performed via the proper hepatic artery every 5 d for 4 wk using an implanted drug reservoir.. The percentages of patients with a partial response after 4 wk of chemotherapy were 6.7% in group S and 31.8% in group L. The survival of group L was significantly better than that of group S, with the median survival time being 496 d in group L and 226 d in group S (P < 0.05).. Continuous 24-h intra-arterial infusion is more effective for aHCC and can markedly prolong survival time as compared to 6-h infusion.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cisplatin; Disease Progression; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Leukocyte Count; Liver Neoplasms; Male; Middle Aged; Survival Rate

To improve the results of New therapeutic strategies in hepatocellular carcinoma (HCC). We have conducted a phase II study with pegylated liposomal doxorubicin (PLD), 5-fluorouracil (5FU) and folinic acid (FA).. Thirty-one patients with hystologically-confirmed, inoperable HCC, received combination chemotherapy with PLD 25 mg/mq on d 1, 5FU 1200 mg/mq in 48 h continuous infusion, and oral FA 30 mg on d 1 and 2 every 3 wk until disease progression or intolerable toxicity.. The median age was 65 years (range 41-82) and 28 patients were hepatitis C virus seropositive (90%). The majority of patients were Child-Pugh Class B (55%). Two patients showed a partial response (PR), and 16 had stable disease (SD). With a median follow-up of 14 mo, the median time to progression of all evaluable patients was 4 mo (95% CI 1.7-7). Median overall survival was 9 mo (95% CI 3-24 mo). After 1 year, 9 of 18 PR/SD patients were alive. Chemotherapy was well tolerated.. PLD/FU/FA combination seems capable of achieving durable stabilization of HCC. The manageable toxicity supports a role for combination with other anticancer agents.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Disease Progression; Doxorubicin; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Polyethylene Glycols; Treatment Outcome; Vitamin B Complex

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Because HCC usually presents as an advanced disease and occurs in the background of liver cirrhosis, most patients are not suitable for treatment with curative intent, thus effective systemic chemotherapy is required. However, the outcome of systemic chemotherapy has been disappointing in advanced HCC. This study was conducted to test the efficacy and toxicity of the combined regimen of epirubicin, cisplatin, and UFT moderated by leucovorin in advanced or recurrent HCC.. All 53 patients received epirubicin (50 mg/m2 i.v.) on day 1 and cisplatin (60 mg/m2 i.v.) after epirubicin administration. Oral UFT 400-600 mg/day, determined by body surface area, and leucovorin 75 mg/day were administered for 21 consecutive days, followed by a 7-day drug free interval.. Nine had a partial response, representing 16.9% of response rate (95% confidence interval rate; 7.0-26.8%) with median response duration of 17.1 weeks (95% CI; 5.0-29.3 weeks, range; 7.1-51.7 weeks). Fifteen patients had stable disease and the disease progressed in 26 patients. The median overall survival for the patients was 24.6 weeks (95% CI; 17.3-31.9 weeks, range; 3.0-131.3 weeks). The main toxicities were hematologic toxicities including neutropenia, which reached grade 3/4 in 17 patients (38.5%), and grade 3 or 4 thrombocytopenia in five patients (9.4%).. The combination of epirubicin, cisplatin, and UFT moderated by leucovorin showed modest anti-tumor activity with relatively tolerable toxicities. However, a randomized phase III trial based on this regimen is warranted to clarify its survival benefit in patients with advanced HCC.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antidotes; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Dose-Response Relationship, Drug; Epirubicin; Female; Hematologic Diseases; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Survival Analysis; Tegafur; Tomography, X-Ray Computed; Treatment Outcome; Uracil

The postresectional tumor recurrence rate is high in patients with hepatocellular carcinoma (HCC). Tumor portal venous invasion is the most important factor related to recurrence. Adjuvant intraportal infusion chemotherapy (IPIC) was used in HCC patients to improve the outcomes.. Between June 1998 and May 1999, 28 HCC patients (IPIC group) underwent postresectional IPIC daily for 2 days with 5-fluorouracil (650 mg/m(2)), leucovorin (45 mg/m(2)), doxorubicin (10 mg/m(2)), and cisplatin (20 mg/m(2)). Treatment was repeated every 3 weeks for six cycles. Patient outcomes were compared with those of 66 matched HCC patients (control group) who underwent hepatectomy without adjuvant therapy.. The IPIC group received an average of 5.2 cycles of chemotherapy, starting 5 to 24 days after surgery. The most frequent IPIC-related adverse events were upper abdominal pain, vomiting, and myelosuppression. Five-year disease-free and overall survival rates for the IPIC group were 44.6% and 60.7%, respectively. Subgroup analysis of patients with tumor-node-metastasis stage I and II disease identified significantly lower recurrence rates for the IPIC group (33.3%) than the control group (65.0%; P = .025). For patients with stage I and II disease, 5-year disease-free and overall survival rates for the IPIC group (70.6% and 83.3%, respectively) were significantly higher than those of the control group (33.4% and 46.9%, respectively; P < .05). Patients with stage III disease do not benefit from IPIC.. Postoperative IPIC benefits HCC patients with tumor-node-metastasis stage I and II disease. The survival advantages demonstrated justify a selection of patients for future trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Case-Control Studies; Chemotherapy, Adjuvant; Cisplatin; Doxorubicin; Female; Fluorouracil; Hepatectomy; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Portal Vein; Postoperative Period; Survival Rate; Treatment Outcome

Hepatocarcinoma is one of the most common malignant tumours world-wide with poor prognosis. Treatment of locally advanced hepatocarcinoma is still controversial. Transcatheter arterial (chemo-)embolisation of hepatocarcinoma are widely used methods but some aspects regarding their use and usefulness have not yet been clarified. Systemic remedies have not yet been proven to affect patient survival.. To determine if intra-arterial chemotherapy with 5-flurouracil and folinic acid in locally advanced hepatocarcinoma is a viable alternative to existing therapies.. Twenty-four inoperable consecutive patients with locally advanced hepatocarcinoma were enrolled. They all underwent intra-arterial chemotherapy via a surgically implanted port-a-cath, and folinic acid (100 mg/m2) and 5-flurouracil (up to 550 mg/m2) were administered with a 1-week or a 2-week schedule.. Nineteen patients completed the study: 2 showed a complete positive response, 11 a partial response, 6 stable disease, while 4 showed a disease progression. Median survival time was 19 (range 4-85) months. Child A patients showed a significant longer survival.. Intra-arterial chemotherapy using folinic acid and 5-flurouracil may be useful in the treatment of locally advanced hepatocarcinoma in cirrhotic patients even in the presence of thrombosis. This treatment could be also useful in comparing transarterial chemoembolisation to a curative treatment.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Female; Fluorouracil; Humans; Injections, Intra-Arterial; Leucovorin; Male; Middle Aged; Pilot Projects; Survival Analysis; Survival Rate; Treatment Outcome

The prognosis for patients with advanced (stage III and IV) hepatocellular carcinoma (HCC) remains poor. Liver resection and liver transplantation have limited effects on overall survival. Our study was carried out to assess a novel therapeutic approach, which includes transarterial locoregional chemotherapy and in vivo locoregional dual immunostimulation, in patients with unresectable HCC. A group of 20 patients with stage III and IV hepatocellular carcinoma had 10 courses (once per day) of transarterial targeted locoregional immunotherapy with interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), emulsified in a Lipiodol-Urografin mixture. The target organs were the spleen and the liver tumor itself. One course of intrahepatic locoregional targeting transarterial chemotherapy was given 10 days after completion of immunotherapy (mitomycin C, carboplatin, Farmorubicin, Leucovorin, 5-fluorouracil, and IFN-gamma). This was followed after 2 months by another course of transarterial targeted locoregional immunotherapy-chemotherapy. All patients survived the operation and had a mean survival time of 18 months (4-22 months). There was a decrease in the tumor size of 14 of the 20 patients. Serum alpha-fetoprotein (AFP) levels declined in 14 patients, reaching normal levels in 12 patients. These preliminary results indicate that combined locoregional immunotherapy-chemotherapy is a promising therapeutic approach in patients suffering from advanced nonresectable HCC and merits further evaluation.

Topics: Aged; alpha-Fetoproteins; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Hepatocellular; Combined Modality Therapy; Drug Administration Schedule; Epirubicin; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Interferon-gamma; Interleukin-2; Leucovorin; Liver; Liver Neoplasms; Male; Middle Aged; Mitomycin; Necrosis; Pilot Projects; Spleen; Survival Rate; Tomography, Emission-Computed

A phase II trial of 5-fluorouracil (5-FU) [250-450 mg/m2/day x 5 days as an intravenous (IV) bolus] combined with calcium leucovorin (500 mg/m2/day x 5 1/2 days by continuous IV infusion) administered on a 28-day schedule was performed in 15 patients with advanced hepatocellular carcinoma. The median age was 58 years; performance status ranged from 50 to 100%. Of 15 evaluable patients, 1 (7%) had a partial response lasting 2.4 months; 8 (53%) had stable disease with a median duration of 5.7 months; and 6 (40%) had progressive disease with a median time to progression of 2.7 months. Median survival was 3.8 months. Treatment with 5-FU and calcium leucovorin was moderately well tolerated; 9% of the treatment courses were complicated by grade 3 or 4 hematological toxicity, and 10% of the courses were complicated by grade 3 or 4 gastrointestinal toxicity. Despite the efficacy of the combination of 5-FU and leucovorin in advanced colorectal cancer, our results document the general resistance of hepatocellular carcinoma to modulated 5-FU.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged

To conduct a pilot trial of hepatic arterial infusion (HAI) of floxuridine (FUDR), leucovorin, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin (FLAP) in nonresectable hepatocellular cancer (HCC) confined to the liver and assess the effects of hepatitis B (HBV) and hepatitis C (HCV) viral markers on toxicity, response to treatment, and patient survival.. Of 31 HCC patients, 13 were HBV- and HCV-nonreactive, and 18 had evidence of either current or prior HBV and/or HCV infection. Treatment was delivered through percutaneous hepatic arterial catheters, and Infusaid pumps (Shiley Infusaid, Norwood, MA) were placed in responding patients. Cisplatin (100 mg/m2) and Adriamycin (30 to 35 mg/m2) were administered on day 1, followed by a continuous 24-hour HAI of an admixture of floxuridine (60 mg/m2) and leucovorin (15 mg/m2) daily for 4 days. Treatment was repeated every 5 weeks.. Twelve (41%) of 29 assessable patients had a partial response (PR), with a median time to disease progression of 13 months. Six (50%) of 12 HBV-negative (HBV-)/HCV-negative (HCV-) and six of 17 (35%) HBV-positive (HCV+) and/or HCV-positive (HCV+) patients achieved a PR. Eight patients have been maintained in remission for a median duration greater than 15.5 months. The median survival duration of all 31 patients was 15 months, 7.5 months among HBV+ and/or HCV+ patients, and significantly longer among hepatitis-non-reactive patients (P = .007). (A median has not yet been reached.) Granulocylopenia (< 0.1 x 10(3)/microL), thrombocytopenia (< 25 x 10(3)/microL), and hospitalizations for infectious complications were significantly more common among HBV-HCV-reactive than -nonreactive patients: 56%, 50%, and 67% versus 15%, 15%, and 8%, respectively (P < .05 for all).. HAI of FLAP has induced long-term PR and has palliated extensive nonresectable HCC. Positive hepatitis serology appeared to increase bone marrow susceptibility to myelotoxic drugs. Conceivably, one or both viruses may have a direct inhibitory effect on bone marrow progenitors and thereby contribute to the observed myelotoxicity.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Doxorubicin; Female; Floxuridine; Hepatic Artery; Hepatitis B; Hepatitis C; Humans; Infusion Pumps; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Pilot Projects; Survival Rate

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Clinical Trials as Topic; Colonic Neoplasms; Doxorubicin; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Methotrexate; Rectal Neoplasms; Semustine; Vincristine

Multikinase inhibitors (MKIs) represent the main treatment options for advanced hepatocellular carcinoma (aHCC). However, accessibility in developing countries is limited. A chemotherapy, Fluorouracil and Oxaliplatin (FOLFOX), offers a less expensive treatment. Therefore, this study sought to compare the clinical effectiveness of FOLFOX with Sorafenib as a first-line treatment for aHCC in real-life practice.. A retrospective aHCC cohort from four Thai hospitals was investigated for patients who received FOLFOX or Sorafenib between 2013-2019. Multiple imputation by chained equations addressed missing covariate data in a treatment effect model using Weight-adjusted-censoring inverse-probability-weighted regression adjustment; overall survival (OS) and progression-free survival (PFS) were estimated.. A total of 504 patients were included, (Sorafenib [n = 382] and FOLFOX [n = 122]). The treatment effect model estimated a median OS for Sorafenib and FOLFOX of 11.38 and 8.22 months, representing a significantly shorter OS (95% confidence interval) of -3.16 (-6.21, -0.11) months for FOLFOX, p = 0.042. A significant shorter median PFS of FOLFOX to Sorafenib of -2.13 (-3.03, -1.24) months, p < 0.001, was reported.. Despite significantly shorter median OS and PFS than Sorafenib, FOLFOX still extended OS by 8.22 months. This evidence may offer clinical utility to physicians considering treatment options for aHCC in low resource settings.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Retrospective Studies; Sorafenib; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Neoadjuvant Therapy; Oxaliplatin; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Fluorouracil; Hepatic Artery; Humans; Leucovorin; Liver Neoplasms; Oxaliplatin; Propensity Score; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Fluorouracil; Hepatic Artery; Humans; Leucovorin; Liver Neoplasms; Oxaliplatin; Propensity Score; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Colorectal Neoplasms; Fluorouracil; Hepatic Artery; Humans; Leucovorin; Liver Neoplasms; Oxaliplatin; Treatment Outcome

Chemotherapy is a common treatment for advanced hepatocellular carcinoma, but the effect is not satisfactory. The study aimed to retrospectively evaluate the effects of adding all-trans-retinoic acid (ATRA) to infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) for advanced hepatocellular carcinoma (HCC).. We extracted the data of patients with advanced HCC who underwent systemic chemotherapy using FOLFOX4 or ATRA plus FOLFOX4 at the Eastern Hepatobiliary Surgery Hospital, First Hospital of Jilin University, and Zhejiang Sian International Hospital and retrospectively compared for overall survival. The Cox proportional hazards model was used to calculate the hazard ratios for overall survival and disease progression after controlling for age, sex, and disease stage.. From July 2013 to July 2018, 111 patients with HCC were included in this study. The median survival duration was 14.8 months in the ATRA plus FOLFOX4 group and 8.2 months in the FOLFOX4 only group ( P  < 0.001). The ATRA plus FOLFOX4 group had a significantly longer median time to progression compared with the FOLFOX4 group (3.6 months vs. 1.8 months, P  < 0.001). Hazard ratios for overall survival and disease progression were 0.465 (95% confidence interval: 0.298-0.726; P  = 0.001) and 0.474 (0.314-0.717; P  < 0.001) after adjusting for potential confounders, respectively.. ATRA plus FOLFOX4 significantly improves the overall survival and time to disease progression in patients with advanced HCC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Disease Progression; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Oxaliplatin; Retrospective Studies; Tretinoin

Intrahepatic cholangiocarcinoma (iCCA) is a primary liver malignancy with a poor prognosis and limited treatment. Cisplatin with gemcitabine is used as the standard first-line chemotherapy regimen; however, there is still no robust evidence for second-line and successive treatments. Although preliminary evidence suggests a vital role of precision therapy or immunotherapy in a subset of patients, the gene alteration rate is relatively low. Herein, we explored the second-line and successive treatments using hepatic arterial infusion chemotherapy (HAIC) based on FOLFIRI after the failure of gemcitabine and platinum combined with target and immunotherapy in refractory CCAs.. Advanced patients with iCCAs confirmed by diagnostic pathology, who progressed at least on a gemcitabine/platinum doublet and/or other systemic chemotherapy combined with target therapy and immune checkpoint inhibitor, were included. All patients received infusional 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) via HAIC until progression or unacceptable toxicity. The primary objective was the feasibility of treatment, with secondary objectives of disease control rate (DCR) and 6-month survival rate.. A total of 9 iCCA patients treated between Dec 2020 and May 2021 were enrolled; 2 patients suffered from distant metastasis, while 7 had local lymph node metastasis and portal vein or hepatic vein invasion. HAIC was delivered as second-line therapy in 6/9 patients, while a third or successive therapy in 3/9 patients. The patients accepted an average of 2.90 ± 1.69 cycles of HAIC. The objective response rate was 22.2%; the disease control rate was 55.5% (5/9); median progression-free survival was 5 months; and 6-month survival rate was 66.7% (6/9).. Our results provide preliminary evidence that HAIC based on FOLFIRI regimen is efficient and safe in some patients progressing after previous treatment. Therefore, HAIC may be a promising and valuable complementary therapy for advanced CCAs as a second-line and successive therapy. Otherwise, the combination of HAIC with precision medicine may improve clinical benefits (clinical registration number: 2021BAT4857).

Topics: Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinoma, Hepatocellular; Cholangiocarcinoma; Cisplatin; Fluorouracil; Humans; Immune Checkpoint Inhibitors; Irinotecan; Leucovorin; Liver Neoplasms; Treatment Outcome

Not all patients with unresectable hepatocellular carcinoma (uHCC) benefit from treatment with immune checkpoint inhibitors and molecular-targeted agents. The aim of this retrospective study was to assess the efficacy and safety of pembrolizumab plus lenvatinib plus hepatic arterial infusion chemotherapy (HAIC) versus pembrolizumab plus lenvatinib in selected populations of patients with treatment-naive uHCC exhibiting programmed cell death ligand-1 (PD-L1) staining.. Consecutive patients with treatment-naive uHCC exhibiting PD-L1 staining who were treated with pembrolizumab plus lenvatinib plus HAIC (PLH) or pembrolizumab plus lenvatinib (PL) were retrospectively identified from our medical centres from 2018 to 2021. HAIC involved oxaliplatin, fluorouracil, and leucovorin (FOLFOX). Follow-up occurred every 3 weeks for 1 year and then every 6 weeks thereafter. The primary endpoints included overall survival (OS) and progression-free survival (PFS). Secondary endpoints were the frequency of key adverse events (AEs).. In total, 248 treatment-naive patients were retrospectively reviewed, 78 of whom were ineligible on the basis of the current criteria. Thus, 170 patients (PLH: n = 84, median age 52 years [range, 42-67]; PL: n = 86, 53 years [range, 43-69]) were eligible for the analysis. The median follow-up was 18.6 months (range, 1-26). At the final follow-up, the median OS was 17.7 months (95% confidence interval [CI], 15.2-18.3) in the PLH group versus 12.6 months (95% CI, 11.1-13.7) in the PL group (hazard ratio [HR] 0.52; 95% CI, 0.36-0.75; p = 0.001). A significant difference was also detected in the median PFS (10.9 months [95% CI, 8.7-11.4] for PLH vs. 6.8 months (95% CI, 5.2-7.4) for PL; HR 0.61, 95% CI, 0.43-0.85; p = 0.001). Significant differences in the rate of the key AEs were noted between groups (79.8% for PLH vs. 62.8% for PL, p = 0.015), but these AEs were controllable.. Among selected populations of patients with treatment-naive uHCC exhibiting PD-L1 staining, the PLH regimen may substantially improve the survival benefits compared with the PL regimen with a controllable safety profile.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Carcinoma, Hepatocellular; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Phenylurea Compounds; Progression-Free Survival; Quinolines; Retrospective Studies

FOLFOX is a combinational regimen of folinic acid (FnA, FOL), fluorouracil (5-Fu, F) and oxaliplatin (OxP, OX), and has been long considered as the standard treatment of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Recent developments of nano delivery systems have provided profound promise for improving anticancer efficacy and alleviating side effects of FOLFOX. Previously, a nanoformulation (termed Nano-Folox) containing OxP derivative and FnA was developed in our laboratory using nanoprecipitation technique. Nano-Folox induced OxP-mediated immunogenic cell death (ICD)-associated antitumor immunity, which significantly suppressed tumor growth in the orthotopic CRC mouse model when administrated in combination with free 5-Fu.. A nanoformulation (termed Nano-FdUMP) containing FdUMP (5-Fu active metabolite) was newly developed using nanoprecipitation technique and used in combination with Nano-Folox for CRC and HCC therapies.. Synergistic efficacy was achieved in orthotopic CRC and HCC mouse models. It resulted mainly from the fact that Nano-FdUMP mediated the formation of reactive oxygen species (ROS), which promoted the efficacy of ICD elicited by Nano-Folox. In addition, combination of Nano-Folox/Nano-FdUMP and anti-PD-L1 antibody significantly inhibited CRC liver metastasis, leading to long-term survival in mice.. This study provides proof of concept that combination of two nano delivery systems can result in successful FOLFOX-associated CRC and HCC therapies. Further optimization in terms of dosing and timing will enhance clinical potential of this combination strategy for patients.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Carcinoma, Hepatocellular; Cell Line, Tumor; Colorectal Neoplasms; Disease Models, Animal; Drug Compounding; Drug Synergism; Female; Fluorodeoxyuridylate; Fluorouracil; Immunogenic Cell Death; Immunotherapy; Leucovorin; Liver Neoplasms; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasm Metastasis; Organoplatinum Compounds; Reactive Oxygen Species; Tissue Distribution

To compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with a modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX) regimen with that of transarterial chemoembolization as a locoregional treatment for patients with locally advanced hepatocellular carcinoma (HCC).. This retrospective study included adult patients with locally advanced HCC who received first-line treatment with either HAIC-mFOLFOX or conventional transarterial chemoembolization monotherapy from January 2015 to December 2016. The outcomes, including tumor response rates, evaluated via imaging assessment using the modified response evaluation criteria in solid tumors; overall survival; progression-free survival; and safety, were compared. The propensity score-matching methodology was used to reduce the influence of confounding factors on the outcomes.. The study included 131 patients with locally advanced HCC who underwent transarterial chemoembolization and 101 who received HAIC-mFOLFOX as initial treatment. After propensity score matching (n = 67 in each group), patients who received HAIC-mFOLFOX had a higher objective response rate (43.3% vs 13.4%, P = .001), longer median overall survival (13.9 vs 6.0 months, P < .001), and longer median progression-free survival (6.4 vs 2.8 months, P = .001) than those who underwent transarterial chemoembolization. The survival benefit with HAIC-mFOLFOX was strengthened in patients with HCC with vascular invasion (hazard ratio: 0.379; 95% confidence interval: 0.237-0.607). HAIC-mFOLFOX was associated with lower incidences of severe adverse events (8.9% vs 22.9%) and liver toxicity than transarterial chemoembolization.. Compared with transarterial chemoembolization, HAIC-mFOLFOX is a potentially safer and more effective locoregional therapy for patients with locally advanced HCC.

Topics: Adult; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Fluorouracil; Hepatic Artery; Humans; Leucovorin; Liver Neoplasms; Oxaliplatin; Propensity Score; Retrospective Studies; Treatment Outcome

Definitive reirradiation using a stereotactic technique is an effective local treatment option for both recurrent liver metastases and recurrent primary liver cancers. The tolerance of the liver, bile ducts, and surrounding gastrointestinal luminal organs must be respected to ensure safe retreatment. The risks associated with retreatment to these organs must be carefully balanced with the probability of clinical benefit. We present 2 cases for consideration of repeat irradiation along with the opinions of 4 experts, along with conclusions about recommendations.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Colonic Neoplasms; Disease Progression; Dose Fractionation, Radiation; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Organs at Risk; Radiotherapy Dosage; Re-Irradiation

Portal vein tumor thrombus (PVTT) is common in hepatocellular carcinoma (HCC). Recent studies indicate that more aggressive treatments, including surgical resection or locoregional treatment, may benefit selected HCC patients with PVTT. External radiation therapy and infusion chemotherapy were found to achieve good outcomes; however, the use of low-energy x-ray radiation system (INTRABEAM), intraoperative radiation therapy, and portal vein infusion chemotherapy for PVTT has not been reported. We present a case of HCC with PVTT. The patient underwent hemihepatectomy and thrombectomy along with intraoperative radiotherapy (IORT) using a portable INTRABEAM radiation system. Subsequently, to treat PVTT, portal vein infusion chemotherapy with FOLFOX (leucovorin [Folinic acid], fluorouracil, and oxaliplatin) regimen was administered. There were no obvious post-operative complications. After 20 months follow-up period, no obvious tumor recurrence had been observed, and PVTT gradually disappeared completely.. IORT using the INTRABEAM radiation system combined with portal vein infusion chemotherapy is promising for select patients with PVTT.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Combined Modality Therapy; Fluorouracil; Hepatectomy; Humans; Intraoperative Care; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Portal Vein; Radiotherapy, Adjuvant; Retrospective Studies; Thrombectomy; Venous Thrombosis

Topics: Carcinoma, Hepatocellular; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Oxaliplatin; Portal Vein; Sorafenib

Topics: Carcinoma, Hepatocellular; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Oxaliplatin; Portal Vein; Sorafenib

To compare treatment with hepatic arterial infusion of chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC) with both extrahepatic spread (EHS) and intrahepatic tumor and patients with intrahepatic tumor only.. This single-center retrospective study comprised 116 patients with advanced HCC with both intrahepatic tumor and EHS (EHS group; n = 50) or with intrahepatic tumor only (non-EHS group; n = 66) treated with HAIC including oxaliplatin, fluorouracil, and leucovorin between June 2014 and July 2016. Overall survival (OS) and radiologic responses to treatment were determined and compared between the 2 groups.. Both the objective response rate and the clinical benefit rate were higher in the non-EHS group than in the EHS group (37.9% vs 16% objective response rate, P = .010; 81.8% vs 62% clinical benefit rate, P = .017). Median OS was not statistically different between the 2 groups (14.8 months vs 9.8 months, P = .068). Subgroup analysis of OS found that patients with lung metastases survived for a shorter time (OS 7 months) than patients with other metastatic sites (P = .003) and patients free of metastases (P = .001).. HAIC is a potential treatment option for advanced HCC with limited extrahepatic metastases in a population with hepatitis B virus infection.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; China; Clinical Decision-Making; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Oxaliplatin; Patient Selection; Retrospective Studies; Time Factors; Treatment Outcome; Young Adult

Topics: Carcinoma, Hepatocellular; China; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Oxaliplatin; Portal Vein; Sorafenib

Topics: Carcinoma, Hepatocellular; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Oxaliplatin; Portal Vein; Sorafenib

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

To compare the overall survival (OS) and disease progression free survival (PFS) in patients with advanced hepatocellular carcinoma (Ad-HCC) who are undergoing hepatic arterial infusion (HAI) of oxaliplatin, fluorouracil/leucovorin (FOLFOX) treatment vs. sorafenib.. This retrospective study was approved by the ethical review committee, and informed consent was obtained from all patients before treatment. HAI of FOLFOX (HAIF) was recommended as an alternative treatment option for patients who refused sorafenib. Of the 412 patients with Ad-HCC (376 men and 36 women) between Jan 2012 to Dec 2015, 232 patients were treated with sorafenib; 180 patients were given HAIF therapy. The median age was 51 years (range, 16-82 years). Propensity-score matched estimates were used to reduce bias when evaluating survival. Survival curves were calculated by performing the Kaplan-Meier method and compared by using the log-rank test and Cox regression models.. The median PFS and OS in the HAIF group were significantly longer than those in the sorafenib group (PFS 7.1 vs. 3.3 months [RECIST]/7.4 vs. 3.6 months [mRECIST], respectively; OS 14.5 vs. 7.0 months; p <0.001 for each). In the propensity-score matched cohorts (147 pairs), both PFS and OS in the HAIF group were longer than those in the sorafenib group (p <0.001). At multivariate analysis, HAIF treatment was an independent factor for PFS (hazard ratio [HR] 0.389 [RECIST]/0.402 [mRECIST]; p <0.001 for each) and OS (HR 0.129; p <0.001).. HAIF therapy may improve survival compared to sorafenib in patients with Ad-HCC. A prospective randomized trial is ongoing to confirm this finding.. We compared the hepatic arterial infusion of FOLFOX (a combination chemotherapy) with sorafenib (a tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma, retrospectively. It was found that hepatic arterial infusion of FOLFOX therapy may improve both progression free and overall survival in patients with advanced hepatocellular carcinoma.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Hepatocellular; China; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fluorouracil; Follow-Up Studies; Hepatic Artery; Humans; Immunosuppressive Agents; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Oxaliplatin; Retrospective Studies; Sorafenib; Survival Rate; Treatment Outcome; Vitamin B Complex; Young Adult

Nestin expression has been reported to be associated with the prognosis of many solid tumors including human hepatocellular carcinoma (HCC). The present study aimed to identify the role, if any, of Nestin in the chemotherapeutic treatment of HCC.. We determined Nestin expression in nine HCC cell lines and 220 tissue samples of advanced HCC patients (retrospectively registered) treated with FOLFOX regimens. We examined the correlations between Nestin expression and clinicopatholgical variables and HCC prognosis. Also, we used in vitro and in vivo methods to determine the effects of Nestin expression on HCC cell invasion, migration and chemosensitivity.. Nestin expression was significantly increased in HCC tissues and drug-resistant cell lines, and the presence of high levels of Nestin was associated with poor survival. We also showed that drug-resistance occurred in HCC cells with epithelial-mesenchymal transition (EMT), which in turn enhanced invasion ability. Nestin depletion reversed drug-resistance in the Bel-7402/5-FU and Bel-7402/ADM cell lines. Nestin knockdown enhanced chemotherapeutic efficacy in nude mice. Moreover, Nestin up-regulation in Bel-7402 was associated with the activation of Wnt/β-catenin signaling.. Our findings suggest that Nestin inhibitors may be useful for the chemotherapy of HCC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Leucovorin; Liver Neoplasms; Male; Mice; Mice, Nude; Neoplasm Transplantation; Nestin; Organoplatinum Compounds; Prognosis; Up-Regulation; Wnt Signaling Pathway

This study aimed to investigate the pharmaco-economic implications of FOLFOX4 or sorafenib for advanced hepatocellular carcinoma in China.. To conduct the analysis, we performed a Markov model to simulate the process of advanced HCC treated with sorafenib or FOLFOX4. Clinical data were obtained from the ORIENTAL trial and the EACH trial. Incremental cost-effectiveness ratio was regarded as the primary outcome in the analysis. One-way sensitivity analysis as well as probabilistic sensitivity analysis was performed to explore the impact of essential variables on the results of the analysis.. Treatment with sorafenib provided an effectiveness gain of 0.3935 quality-adjusted life year at an average cost of $18,748.00, whereas chemotherapy of FOLFOX4 brought 0.3808 quality-adjusted life year at a cost of $6876.02. The incremental cost-effectiveness ratio of FOLFOX4 versus sorafenib was $934,801.57/QALY. In a probabilistic sensitivity analysis based on a Monte Carlo simulation of 1000 items, the probabilities of FOLFOX4 and sorafenib being cost-effective were 100% and 0% using a willingness-to-pay threshold of $20,301.00 per quality-adjusted life year.. FOLFOX4 chemotherapy is likely to be a cost-effective option compared with sorafenib in the treatment of advanced hepatocellular carcinoma in China.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; China; Cohort Studies; Cost-Benefit Analysis; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Monte Carlo Method; Niacinamide; Organoplatinum Compounds; Phenylurea Compounds; Quality-Adjusted Life Years; Sorafenib

The aim of the present study was to evaluate a single center experience with hepatic arterial infusion (HAI) in patients with hepatocellular carcinoma.. A retrospective analysis of 20 patients treated for hepatocellular carcinoma between 1994 and 2007.. Most patients were treated with an HAI of doxorubicin and cisplatin combined with 5-fluorouracil and folinic acid. The response was not evaluable in the majority of patients, predominantly because of associated surgical procedure or because only one cycle of HAI was administered. The median progression-free survival was 7.7 months. The median survival of all patients was 12.2 months (5-year survival 5%). Serious adverse events were observed in 5 patients, and one patient died of liver failure in association with the administration of HAI.. The data show the limited efficacy of HAI in patients with hepatocellular carcinoma.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Cisplatin; Czech Republic; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fluorouracil; Follow-Up Studies; Hepatic Artery; Humans; Immunosuppressive Agents; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Pregnancy; Retrospective Studies; Survival Rate; Treatment Outcome; Vitamin B Complex

Vascular endothelial growth factor (VEGF) is a primary driving force for both physiological and pathological angiogenesis and over-expression of VEGF has been detected in hepatocellular carcinoma (HCC). The aim of the present study was to clarify the usefulness of VEGF for monitoring the response to intra-arterial chemotherapy in patients with HCC.. Seventy-three patients with liver cirrhosis (LC) and advanced HCC (aHCC) received hepatic arterial infusion chemotherapy (HAIC: leucovorin (LV) at 12 mg/h, cisplatin (CDDP) at 10 mg/h and 5-fluorouracil (5-FU) at 250 mg/22 h) via the proper hepatic artery every 5 days for 4 weeks using a catheter connected to a subcutaneous drug delivery system.. i) Serum VEGF levels were higher in patients with progressive disease than those in patients with a partial response or stable disease. ii) VEGF levels were higher in patients with alcoholic LC than those in patients with hepatitis C-related or hepatitis B-related LC. iii) VEGF levels were higher in stage IVB patients than those in patients with stage III or IVA disease. iv) VEGF levels were significantly higher in patients with giant or confluent multinodular tumors than those in patients with multiple discrete nodules. v) Serum VEGF levels were higher in patients with vascular invasion than in patients without vascular invasion.. Monitoring the serum VEGF level is useful for predicting the response of aHCC to HAIC, as well as for predicting metastasis, tumor type and vascular invasion.

Topics: Aged; Carcinoma, Hepatocellular; Cisplatin; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Treatment Outcome; Vascular Endothelial Growth Factor A

It has been reported that Th2 cytokines down-regulate antitumor immunity, while activation of Th1 cells promotes such immunity. The aim of this study was to assess changes of host immunity in relation to efficacy in patients with liver cirrhosis (LC) and advanced hepatocellular carcinoma (aHCC) treated by combined intra-arterial chemotherapy (CIAC).. Forty-three adult Japanese LC patients who had aHCC received CIAC. Blood samples were collected before and after CIAC.. Eleven of the 43 patients showed a partial response (group PR) and 21 patients had stable disease (group SD), but 11 patients showed no response (group PD). There were no significant differences of Th1 or Th2 cells between before and after CIAC in each group. However, groups SD and PD had higher levels of Th2 cells than in group PR before and after CIAC. The percentage of regulatory T (Treg) cells in group PD was significantly increased after CIAC compared with before CIAC, whereas groups PR and SD showed significant decrease after CIAC.. The percentage of Th2 cells is useful for predicting the response to CIAC and the percentage of Treg cells is useful for assessment of efficacy in LC patients with aHCC receiving CIAC.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Japan; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Lymphocyte Count; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Predictive Value of Tests; T-Lymphocytes, Regulatory; Th1 Cells; Th2 Cells; Treatment Outcome

We have shown that continuous intra-arterial combination chemotherapy (IACC) might be more effective for advanced HCC (aHCC) in patients with HCV-related (C-LC) or alcoholic (A-LC) liver cirrhosis (LC) patients than in patients with HBV-related LC (B-LC). This study retrospectively assesses the difference of etiology on host immunity in LC patients with aHCC treated by IACC.. Forty-seven adult LC patients with aHCC were treated by IACC between 2005 and 2008, with inoperable tumors according to CT findings. IACC (LV at 12 mg/hr, CDDP at 10 mg/hr, and 5-FU at 250 mg/22 hr) was delivered via the proper hepatic artery every 5 days for 4 weeks using a catheter connected to a subcutaneously implanted drug delivery system. The control group comprised 13 healthy volunteers.. Twelve of the 47 patients with aHCC had B-LC, 27 had C-LC, and 8 had A-LC. In the B-LC group, 1 out of 12 patients had a Japan Integrated Staging (JIS) score of 2, 4 had a JIS score of 3, 7 had a JIS score of 4, and no patients had a JIS score of 5, while the respective numbers were 6, 9, 10 and 2 in the C-LC group, and 1, 1, 5 and 1 in the A-LC group. The response rates were 37.0%, 37.5% and 8.3% in the C-LC, A-LC and B-LC group, respectively. In the C-LC group, the percentage of Th1 cells before and after chemotherapy was significantly higher than in the control group. In the B-LC group, the percentage of Th2 cells after chemotherapy was significantly higher than that in the control group. However, there were no significant differences of Th1 and Th2 cells between the A-LC group and the control group.. These results indicate that IACC was more effective for aHCC in A-LC patients with normal Th1/Th2 balance and in C-LC patients without Th2 dominance than in B-LC patients who showed Th2 dominance after chemotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Case-Control Studies; Cisplatin; Drug Combinations; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Paclitaxel; Retrospective Studies; Survival Rate; Treatment Outcome

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Colorectal Neoplasms; Combined Modality Therapy; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver; Liver Neoplasms; Organoplatinum Compounds

Hepatoid adenocarcinoma (HAC) is a rare type of extrahepatic carcinoma whose morphology is similar to that of hepatocellular carcinoma (HCC). Metachronous HCC and HAC in the same patient is extremely rare. The case of a 68-year-old man with chronic hepatitis B infection who had both HCC and HAC of the stomach is reported herein. Nine years previously this patient had been diagnosed with HCC and received a right lobectomy. HCC that recurred at the caudate lobe at 6 months after the operation was successfully treated with transarterial chemoembolization. The patient was followed up regularly thereafter without evidence of tumor recurrence for 9 years. In July 2010 his serum alpha-fetoprotein (AFP) level elevated from 6.5 ng/mL to 625.4 ng/mL, and he developed a probable single metastatic lymph node around the hepatic artery without intrahepatic lesions. Subsequent evaluation with upper endoscopy revealed a 4-cm ulcerative lesion on the antrum of the stomach. Subtotal gastrectomy was performed with lymph-node dissection. Histologic examination revealed a special type of extrahepatic AFP-producing adenocarcinoma-HAC with lymph-node metastasis-which indicates that HAC can be a cause of elevated AFP even in patients with HCC. HAC should be considered if a patient with stable HCC exhibits unusual elevation of AFP.

Topics: Adenocarcinoma; Aged; alpha-Fetoproteins; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Chemotherapy, Adjuvant; Fluorouracil; Gastroscopy; Humans; Leucovorin; Liver Neoplasms; Lymph Nodes; Lymphatic Metastasis; Male; Recurrence; Silicates; Stomach Neoplasms; Titanium; Tomography, X-Ray Computed

A 57-year-old Caucasian man with a history of Child's class A hepatitis C, cirrhosis and progressive multifocal hepatocellular carcinoma was treated with sorafenib but progressed after 7 months of stable disease. At progression he was given salvage chemotherapy consisting of 5-fluorouracil and leucovorin and went into complete radiographic remission after 12 cycles of treatment. He did develop a portal vein thrombosis but nevertheless his hepatic lesions continued to resolve. Throughout his therapy α-fetoprotein (AFP) levels decreased only minimally. He did not seek retreatment after 14 cycles of chemotherapy and presented 3 months later with relapsed disease on CT scans with markedly elevated AFP levels. He received one more chemotherapy cycle but was unable to tolerate further treatment, succumbing to his disease 3 months thereafter, and a total of 29 months after he was deemed a sorafenib failure.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Carcinoma, Hepatocellular; Fatal Outcome; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasms, Multiple Primary; Niacinamide; Phenylurea Compounds; Sorafenib; Tomography, X-Ray Computed; Treatment Outcome; Vitamin B Complex

A 58-year-old man was referred to our hospital for a huge tumor occupying the entire right lobe of the liver. An imaging method revealed a 15 cm-sized hepatocellular carcinoma in the right lobe which extended to the internal segment across the middle hepatic vein. The serum AFP level was 15.3 ng/mL, and the level of protein induced by vitamin K absence or antagonist II was 4,340 mAU/mL. We judged it unresectable, then arterial infusion chemotherapy using 5-fluorouracil, cisplatin, and Leucovorin was performed. After 4 courses, the tumor was markedly reduced to 56 mm. We performed an extended right lobectomy. In the operative finding, although the tumor partially reached the internal segment, the middle hepatic vein was preserved. Nine months after operation, no sign of recurrence was found. It is suggested that hepatic arterial infusion therapy is useful for pre-operative therapy of far-advanced hepatocellular carcinoma as a part of combined modality therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Combined Modality Therapy; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged

The only drug that improves survival in hepatocellular carcinoma is sorafenib. FOLFOX-4 regimen is safe and widely used in patients with colorectal cancer, yielding interesting results with little toxicity. We conducted a retrospective study to evaluate the safety and the effectiveness of FOLFOX-4 in cirrhotic or liver transplanted patients with hepatocellular carcinoma ineligible for sorafenib.. Thirty seven patients were enrolled in the study. The medical record of either cirrhotic patients or liver transplanted patients with advanced hepatocellular carcinoma receiving FOLFOX-4 regimen between November 1999 and March 2006 were retrospectively analyzed. Patients received oxaliplatin 85 mg/m(2) as a 2-hour infusion on day one, and leucovorin 200 mg/m(2) as a 2-hour infusion followed by bolus 5-fluorouracil 400 mg/m(2) and a 48-hours infusion of 5-fluorouracil 2400 mg/m(2). Treatment was repeated every 2 weeks until disease progression or unacceptable adverse effects occurred.. Patients had a Child-Pugh class A (n = 16), class B cirrhosis (n = 10) or a liver transplant (n = 11) and received 2 to 37 cycles of chemotherapy (total of 310 cycles). Two (5.4%) cirrhotic patients developed neutropenic sepsis and one (2.7%) toxic death occurred. At first assessment, five patients from Child-Pugh class A (33%) and two from Child-Pugh class B group (20%) achieved a radiological response and/or alpha foeto-protein decrease, and no patient achieved a complete response.. In conclusion, with a manageable toxicity profile in cirrhotic Child-Pugh class A-B or liver transplanted patients, the FOLFOX-4 regimen appears to be a feasible treatment option for patients with advanced hepatocellular carcinoma unfit for sorafenib. These data need to be confirmed in a prospective study.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Disease-Free Survival; Drug Administration Schedule; Feasibility Studies; Female; Fluorouracil; Humans; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Organoplatinum Compounds; Paris; Retrospective Studies; Survival Analysis; Time Factors; Treatment Outcome

The prognosis for hepatocellular carcinoma (HCC) along with portal vein tumor thrombi (PVTT) is poor, and surgery has not been considered an option.. To compare the outcomes and the quality of life (QoL) of patients with HCC and PVTT who underwent hepatic resection and thrombectomy for tumor thrombi in the inferior vena cava and hepatic vein with total hepatic vascular exclusion to the patients who received only chemotherapy.. We retrospectively reviewed the medical records of patients who received hepatectomy and thrombectomy (n=65), and those who received only chemotherapy (n=50). The surgical outcomes, survival, and QoL that was determined using the Functional Assessment of Cancer Therapy-Hepatobiliary instrument were analyzed and compared.. Patients who underwent surgery had a median overall survival of 17 months, compared with patients who underwent chemotherapy for 8 months (P<0.0001). Patients who underwent surgery had a median recurrence-free survival of 14 months, as compared with patients who underwent chemotherapy for 7 months (P<0.0001). The probabilities of 1-year recurrence in the surgery and chemotherapy groups were 27.7 and 70%, respectively (P<0.0001). The QoL total score of the surgery group was significantly higher than that of the control group (P<0.0001). Surgery was slightly, though significantly more cost-effective than chemotherapy based on the quality-adjusted life years.. Hepatectomy and thrombectomy using the total hepatic vascular exclusion, is a viable surgical management for patients with HCC and PVTT, and is associated with longer overall survival and recurrence-free survival and better QoL than chemotherapy alone.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cost-Benefit Analysis; Female; Fluorouracil; Hepatectomy; Hepatic Veins; Hospital Costs; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplastic Cells, Circulating; Organoplatinum Compounds; Quality of Life; Retrospective Studies; Thrombectomy; Treatment Outcome; Vena Cava, Inferior; Venous Thrombosis

The coexistence of liver cirrhosis with hepatocellular carcinoma (HCC) and colon cancer (Ca), which is a rare clinical condition, was treated in a liver transplant recipient.. A 46-year-old man, diagnosed incidentally during an ultrasound (US) examination with a 3.5-cm HCC in segment VII related to chronic hepatitis C virus (HCV), was referred for liver resection. He underwent a laparoscopic protocol evaluation for liver cirrhosis. Liver appearance and biopsy of the left lobe showed Child B/C liver cirrhosis. Because he fulfilled the Milan criteria, we suggested an orthotopic liver transplantation (OLT). During protocol colonoscopy, we discovered an ulcerative sigmoid colon Ca. Three weeks after completing the pre-OLT assessment he underwent an OLT and was discharged home on day 9 on an immunosuppressive regimen of Everolimus, Myfortic, and Prezolone. Two months after transplantation, the patient underwent a sigmoidectomy and for nearly 1 month thereafter received chemotherapy for colon Ca (6 cycles of FOLFOX:Folinic Acid+Fluorouracil+Oxaliplatin). One and a half years after OLT, patient was in good condition but presented with an increased alpha fetoprotein (a-FP) without other findings. A couple of months later we discovered a colon Ca recurrence and 3 small liver metastases. Patient underwent a bowel resection with Hartmann's procedure. Almost immediately after the last operation, he was found to suffer multiple myeloma. He underwent chemotherapy for both malignancies with good responses, but a few months later died of severe sepsis.. The relevant literature regarding treatment of liver cirrhosis complicated with HCC and synchronous colon Ca reveals poor and controversial outcomes. Our patient underwent chemotherapy immediately after colon resection in the presence of with a good functioning liver. Although his condition was satisfactory after OLT, the optimal treatment of such complicated patients is as yet uncertain.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biopsy; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Colonoscopy; Fatal Outcome; Fluorouracil; Hepatitis C, Chronic; Humans; Incidental Findings; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary; Organoplatinum Compounds; Sepsis; Time Factors; Treatment Outcome

Laparoscopic left lateral sectionectomy (LLS) has gained popularity in its use for benign and malignant tumors. This report describes the evolution of the authors' experience using laparoscopic LLS for different indications including living liver donation.. Between January 2004 and January 2009, 37 consecutive patients underwent laparoscopic LLS for benign, primary, and metastatic liver diseases, and for one case of living liver donation. Resection of malignant tumors was indicated for 19 (51%) of the 37 patients.. All but three patients (deceased due to metastatic cancer disease) are alive and well after a median follow-up period of 20 months (range, 8-46 months). Liver cell adenomas (72%) were the main indication among benign tumors, and colorectal liver metastases (84%) were the first indication of malignancy. One case of live liver donation was performed. Whereas 16 patients (43%) had undergone a previous abdominal surgery, 3 patients (8%) had LLS combined with bowel resection. The median operation time was of 195 min (range, 115-300 min), and the median blood loss was of 50 ml (range, 0-500 ml). Mild to severe steatosis was noted in 7 patients (19%) and aspecific portal inflammation in 11 patients (30%). A median free margin of 5 mm (range, 5-27 mm) was achieved for all cancer patients. The overall recurrence rate for colorectal liver metastases was of 44% (7 patients), but none recurred at the surgical margin. No conversion to laparotomy was recorded, and the overall morbidity rate was 8.1% (1 grade 1 and 2 grade 2 complications). The median hospital stay was 6 days (range, 2-10 days).. Laparoscopic LLS without portal clamping can be performed safely for cases of benign and malignant liver disease with minimal blood loss and overall morbidity, free resection margins, and a favorable outcome. As the ultimate step of the learning curve, laparoscopic LLS could be routinely proposed, potentially increasing the donor pool for living-related liver transplantation.

Topics: Adenocarcinoma; Adenoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Loss, Surgical; Camptothecin; Carcinoma, Hepatocellular; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Gastrointestinal Stromal Tumors; Hepatectomy; Humans; Laparoscopy; Length of Stay; Leucovorin; Liver Neoplasms; Liver Transplantation; Living Donors; Male; Melanoma; Middle Aged; Organoplatinum Compounds; Postoperative Complications; Retrospective Studies; Tissue and Organ Harvesting

This patient is a male in his 30's. He was diagnosed as hepatitis B virus-related huge primary liver cancer, 10cm in diameter, located in segment 4, accompanied with left portal thrombus and multiple lung metastases. Ten months after repeating systemic chemotherapy using gemcitabine (GEM)+carboplatin (CBDCA)+5-FU/leucovorin (LV) and hepatic arterial infusion chemotherapy with cisplatin (CDDP) 4 times, extended left lobectomy with caudate lobe could be successfully performed because of marked reducion of the huge tumor. The pathology revealed almost entirely necrotic changes of the main tumor, and the remaining, viable tumor nests showed combined hepatocellular and cholangiocarcinoma. Systemic chemotherapy was repeatedly given afterwards, which kept the pulmonary metastases stable without growth. The present case suggests that systemic chemotherapy using GEM+CBDCA+5-FU/LV may be useful in the multimodal treatment for the combined hepatocellular and cholangiocarcinoma with distant metastases.

Topics: Adult; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carboplatin; Carcinoma, Hepatocellular; Cholangiocarcinoma; Cisplatin; Combined Modality Therapy; Deoxycytidine; Fluorouracil; Gemcitabine; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male

We have previously reported that 24-h intra-arterial combination chemotherapy (IACC) prolongs the survival of patients with advanced hepatocellular carcinoma (aHCC). However, it has also been reported that 5-fluorouracil (5-FU) exacerbates liver damage in patients with liver cirrhosis (LC). The aim of this study was to clarify the hepatotoxicity of IACC in LC patients with aHCC.. Twenty-one adult Japanese patients (20 men and 1 woman) with aHCC and LC underwent IACC between 2004 and 2007 at our hospital. These patients showed multiple partial responses or stable disease, except for five patients who showed no response and three patients with tumors more than 30 mm in diameter. All patients had inoperable disease on the basis of computed tomography (CT) findings. IACC (leucovorin at 12 mg/h, cisplatin at 10 mg/h, and 5-FU at 250 mg/22 h) was delivered via the proper hepatic artery every 5 days for 4 weeks.. Twelve patients were in Child-Pugh class A (group A), and nine were in class B (group B). The Child-Pugh score was significantly increased after chemotherapy compared with before chemotherapy in both groups. Serum albumin was significantly decreased after chemotherapy, and the number of patients with ascites also increased after chemotherapy. Serum type IV collagen and N-terminal propeptide of type III procollagen were significantly increased after chemotherapy, although there was no significant change in serum aminotransferases.. IACC might cause hepatotoxicity that induces fibrosis without releasing aminotransferases.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Ascites; Carcinoma, Hepatocellular; Cisplatin; Collagen Type IV; Female; Fluorouracil; Hepatic Artery; Humans; Hyaluronic Acid; Infusions, Intra-Arterial; Japan; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Peptide Fragments; Procollagen; Serum Albumin; Tomography, X-Ray Computed; Transaminases

It is known that tumors develop mechanisms to escape from the immune system and to inhibit antitumor responses. The aim of this study was to retrospectively assess changes of host immunity in relation to efficacy in liver cirrhosis (LC) patients with advanced hepatocellular carcinoma (aHCC) treated by combined intra-arterial chemotherapy.. Thirty-seven adult Japanese LC patients with aHCC were treated by intra-arterial combination chemotherapy. The control group was composed of 19 adult Japanese patients with chronic hepatitis C diagnosed by pathological examination of liver biopsy specimens. All control patients were stage 1 according to the fibrosis score of Desment.. Ten of the 37 patients (group PR) showed a partial response and 17 of the 37 patients (group SD) showed stable disease, but 10 of the 37 patients (group PD) showed no response. There were no significant differences in the percentage of Th1 cells between any of the groups either before or after chemotherapy. The percentage of Th2 cells was significantly higher in group PD before and after chemotherapy than in the control group (P < 0.05 by Tukey's test). Although there was no significant difference, the percentage of Th2 cells was higher in group SD than in group PR.. The percentage of Th2 cells increased in LC patients with aHCC as the efficacy of intra-arterial combination chemotherapy decreased. These results indicated that intra-arterial chemotherapy might be not useful for patients with aHCC, because it induces Th2 dominant host immunity.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Case-Control Studies; Cisplatin; Female; Flow Cytometry; Fluorouracil; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Immunity; Infusions, Intra-Arterial; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Retrospective Studies; Survival Rate; Th1 Cells; Th2 Cells; Treatment Outcome

125 patients with hepatic neoplasms were observed during 1998-2008 years. Trisectionectomy was carried out to 84 patients with colorectal metastatic affection of liver, which amounted 67.2% of all cases. Hepatocellular carcinoma was the second most frequent malignancy to be observed--23 patients (18.4%). 6 patients (4.8%) with cholangiocellular carcinoma went further. 12 patients (9.6%) with non-colorectal metastatic tumors of liver were united into one group. In postoperative period adjuvant chemotherapy was carried out to 60 patients with colorectal metastatic affection of liver. In all patients with hepatic tumors undergoing trisectionectomy postoperative lethality amounted 6.4% (n=8), in patients with colorectal metastatic affection of liver--5.95% (n=5), in patients with primary hepatic tumors--3.45% (n=1), in patients with non-colorectal metastatic affection of liver--16.66% (n=2). Lethality was caused by acute hepatic failure in all observations. Postoperative complications were observed in 44.05% of patients with colorectal cancer and in 44.83% of patients with primary hepatic tumors. Hepatic failure was the most frequent complication. In case of colorectal metastatic affection three-year probability of survival amounted 30.94+/-6.6% in patients undergoing trisectionectomy, five-year--10.4+/-8%. Median 16 months. On conditions that adjuvant chemotherapy was carried out, three-year survival probability increased to 40.53+/-8.1%, five-year--to 10.4+/-8%. Median 17 months. One-year survival probability in patients with primary hepatic tumors undergoing trisectionectomy amounted 92.46+/-5.1%, three-year - 59.44+/-12.3%, five-year--44.58+/-15.8%. Median 42 months. Low level of postoperative lethality, allowable level of postoperative complications and good indices of survival probability in long-term period allow considering that trisectionectomy as a surgical technique is absolutely appropriate.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Postoperative Complications; Probability; Survival Analysis; Time Factors; Vitamin B Complex

Transcatheter arterial embolization (TAE) with gelatin sponge particles and iodized oil often yields poor results when used to treat unresectable multifocal hepatocellular carcinoma (HCC). The present study retrospectively investigated the utility of a novel combination chemotherapy regimen for treating multifocal HCC resistant to TAE.. Thirteen consecutive patients with unresectable multifocal HCC and resistance to TAE were treated with combination chemotherapy consisting of arterial chemoembolization with degradable starch microspheres (DSM) (150-4500 mg on Day 1), mitomycin-C (4-8 mg on Day 1), continuous arterial infusion of 5-fluorouracil (1250 mg/120 h), cisplatin (25-50 mg/120 h) and l-leucovorin (125 mg/120 h) for 10-19 weeks.. The response rate was 84.6%, with complete response in one patient and partial response (PR) in 10 patients. In four of 10 patients with PR, the tumor was not observable, although the tumor marker did not completely decline to the normal range. The 1-, 2- and 3-year survival rates were 100, 28.9 and 9.6% in all, and 100, 33.3 and 0% in six patients with portal vein tumor thrombosis (PVTT). The median survival was 22.1 months in all and 17.1 months in six patients with PVTT. Thrombocytopenia of Grade III or higher was observed in eight patients. Laparoscopic splenectomy was performed before therapy in four patients with platelet counts of <70,000/mm(3), and during therapy in five patients with severe thrombocytopenia.. This novel chemotherapy regimen achieved favorable results and may be useful in treating patients with unresectable multifocal HCC resistant to TAE.

Topics: Absorbable Implants; Aged; alpha-Fetoproteins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Cisplatin; Combined Modality Therapy; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Microspheres; Middle Aged; Mitomycin; Neoplasms, Multiple Primary; Retrospective Studies; Splenectomy; Starch; Survival Analysis; Thrombocytopenia

It has been reported that Th2 cytokines down-regulate antitumor immunity, while activation of type 1 T cells promotes antitumor immunity. However, the immunological features of liver cirrhosis (LC) patients with advanced hepatocellular carcinoma (aHCC) treated by intra-arterial chemotherapy are still unclear. The aim of this study was to assess the influence of intra-arterial combination chemotherapy on the Th1/Th2 balance in LC patients with aHCC.. Twenty-one adult Japanese LC patients with aHCC were treated by intra-arterial combination chemotherapy. The control group was composed of 20 adult Japanese patients with chronic hepatitis C diagnosed from examination of liver biopsy specimens. All control patients were over 55 years old and were stage 1 according to the fibrosis score of Desment.. Thirteen of the 21 aHCC patients (group R) showed an objective response, but the other 8 patients (group N) showed no response. There were no significant differences of Th1 cells between group R and group N either before or after chemotherapy. Although there was no significant difference from group R, group N had a significantly higher percentage of Th2 cells than the control group both before and after chemotherapy (p < 0.05 by Tukey's test).. These results indicate that the Th1/Th2 balance might be a useful indicator of the effect of intra-arterial combination chemotherapy in LC patients with aHCC. Inhibition of an increase of Th2 cells might be important for the efficacy of intra-arterial chemotherapy in such patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Drug Monitoring; Female; Fluorouracil; Hepatitis C, Chronic; Hepatitis, Viral, Human; Humans; Infusions, Intra-Arterial; Interferon-gamma; Interleukin-4; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Lymphocyte Count; Male; Middle Aged; Th1 Cells; Th2 Cells

The prognosis of patients with advanced hepatocellular carcinoma (HCC) is poor. We aimed to clarify the prognostic factors in patients with advanced HCC receiving hepatic arterial infusion chemotherapy (HAIC).. Forty-four HCC patients were treated with HAIC, using low-dose cisplatin (CDDP) and 5-fluorouracil (5-FU) with/without leucovorin (or isovorin). Of these 44 patients, 15 received low-dose CDDP and 5-FU, and 29 received low-dose CDDP, 5-FU, and leucovorin or isovorin. Prognostic factors were evaluated by univariate and multivariate analyses of patient and disease characteristics.. Of all patients, 5 and 12 patients respectively, exhibited a complete response (CR) and a partial response (PR) (response rate, 38%). The response rate (48.3%) in the low-dose CDDP and 5-FU with leucovorin/isovorin group was significantly better than that (20%) in the low-dose CDDP and 5-FU group (P = 0.002). The 1-, 2-, 3-, and 5-year cumulative survival rates of the 44 patients were 39%, 18%, 12%, and 9%, respectively. The regimen using low-dose CDDP and 5-FU with leucovorin/isovorin tended to improve survival rates (P = 0.097). Univariate and multivariate analyses showed the same variables--the Child-Pugh score (P = 0.013, P = 0.018), alpha-fetoprotein (AFP) level (P = 0.010, P = 0.009), and therapeutic effect after HAIC (P = 0.003, P = 0.01), respectively, to be significant prognostic factors.. Patients who had advanced HCC with favorable hepatic reserve capacity and a lower AFP level were suitable candidates for HAIC. Moreover, the regimen using low-dose CDDP and 5-FU with leucovorin/isovorin may be suitable for advanced HCC patients, because of the improvement in the response rate and survival compared with the low-dose CDDP and 5-FU regimen without leucovorin/isovorin.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cause of Death; Cisplatin; Dose-Response Relationship, Drug; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Japan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Prognosis; Survival Analysis; Time Factors; Treatment Outcome; Vitamin B Complex

To investigate the feasibility, reliability and therapeutic effectiveness of adjuvant chemotherapy for advanced hepatocellular carcinoma (HCC) after orthotopic liver transplantation (OLT).. The clinical data of adjuvant chemotherapy after OLT in 10 advanced HCC patients were studied retrospectively. FAP chemotherapy regimen was adopted calcium folinate (CF) 200 mg/m(2) and 5-Fluorouracil 500 mg/m(2) iv on D1 to D5, and doxorubicin 40 mg/m(2), cisplatin 30 mg/m(2) iv on D1, with 28 days as a cycle. The opportune time of chemotherapy, chemotherapy regimen, synergistic action between cytotoxic agent and immunosuppressive agent on liver and kidney and side-effects were preliminarily evaluated.. 7/10 patients are surviving, with the longest survival of 32 months, and the shortest 9 months. Three patients died after operation, two at 13 months, one at 20 months after OLT, all died of metastasis. The incidence of one year survival was 9/9. During the period of chemotherapy, the side-effects of adjuvant chemotherapy were moderate.. Chemotherapy which is able to prolong the life-span of patients with advanced HCC after orthotopic liver transplantation is feasible and effective, the side-effects were mild. The choice of opportune time of chemotherapy might influence the outcome.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Cisplatin; Doxorubicin; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Neoplasm Staging; Postoperative Period; Retrospective Studies; Survival Rate

Several clinical trials in human neoplasms have demonstrated the effectiveness of combination therapy with 5-fluorouracil (FUra), cisplatin (CDDP), and leucovorin (LV). Thymidylate synthase (TS), the target enzyme of FUra, and dihydropyrimidine dehydrogenase (DPD), the rate-limiting catabolic enzyme of pyrimidines, have both been reported to be predictors of the response to FUra-based chemotherapies. Therefore, we aimed to clarify the effects of a combination of the three drugs against hepatoma cells and to determine the role of these two enzymes using in vitro models.. Five human hepatoma cell lines (Hep3B, HepG2, HuH7, PLC/PRF/5 and Chang) were used. Cytotoxicity was determined after exposure to various concentrations and combinations of antitumor agents. The combination effects of FUra and CDDP in terms of synergy, additivity or antagonism were evaluated by median effect analysis. The mRNA levels of TS and DPD were measured by quantitative real-time PCR. Expression of TS and DPD proteins was also investigated.. LV alone did not show any cytotoxicity, although it enhanced the cytotoxicity of FUra, but not that of CDDP. Synergistic enhancement was observed with the combination of FUra and CDDP against all cells. The median combination index at fraction 0.5 was 0.554 (range 0.273-0.616). All cells expressed TS and DPD with median relative quantities of mRNA normalized to that of HuH7 cells of 1.04 (range 1.00-1.32) and 1.18 (range 0.88-1.55), respectively. A strong correlation was found between the IC(50) of FUra and the mRNA level of DPD (r=0.912, P=0.0295).. LV and CDDP enhanced the cytotoxicity of FUra, which provided a rationale for the regimen combining the three drugs for the treatment of hepatocellular carcinoma. DPD plays an important role in the sensitivity to FUra, and the DPD mRNA expression level may be used to predict the response to FUra-based chemotherapy for HCC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cell Survival; Cisplatin; Dihydrouracil Dehydrogenase (NADP); Electrophoresis, Polyacrylamide Gel; Fluorouracil; Humans; Immunoblotting; Leucovorin; Liver Neoplasms; RNA, Messenger; Thymidylate Synthase; Tumor Cells, Cultured

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Cisplatin; Ethanol; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Injections, Intralesional; Leucovorin; Liver Neoplasms; Mitomycin

Intra-arterial infusion chemotherapy (IAIC) can potentially improve survival in some patients with hepatocellular carcinoma (HCC), but the ideal regimen is not yet established. We prospectively evaluated the effects of short-course continuous infusion with the combination of cisplatin, mitomycin C, 5-fluorouracil (5-FU) and leucovorin for unresectable advanced HCC and analyzed their prognostic factors.. Patients with unresectable advanced HCC and not suitable for other therapy were enrolled. Cannulation via the left subclavian artery with the tip of catheter at the proper hepatic artery was done before initialization of IAIC routinely. The regimen consisted of the daily administration of cisplatin (10 mg/m2), mitomycin C (2 mg/m2), leucovorin (15 mg/m2), and daily infusion of 5-FU (100 mg/m2) for 5 days. Only the patients that had received at least 2 courses of IAIC were evaluated.. Two-hundred and 11 courses of IAIC were performed, and each patient received at least 2 cycles of chemotherapy. The overall response rate was 28.3%. We observed a complete response in 5 patients (9.4%), a partial response in 10 patients (18.9%), a minimal response in 5 patients (9.4%), no change in 11 patients (20.8%) and a progressive disease in 22 patients (41.5%). The patients with response to treatment survived longer than the patients without response (24.6 +/- 14.2 months vs 8.7 +/- 5.3 months, p < 0.001). In univariate and multivariate analysis, absence of main vessel thrombosis and alpha-fetoprotein (AFP) reduction percentage > 50% following treatment showed significance in our study. All side effects subsided after conservative treatment.. Continuous IAIC with cisplatin, mitomycin-C, leucovorin, and 5-FU is effective for patients with severe advanced HCC. Absence of main vessel thrombosis, and AFP reduction percentage > 50% following treatment were good predictors of treatment response in our study. All side effects were mild and tolerable.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Drug Administration Schedule; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Mitomycin; Survival Rate

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Hepatocellular; Drug Administration Schedule; Female; Fluorouracil; Gastrointestinal Agents; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Octreotide

Hepatic resection for huge hepatocellular carcinoma (HCC) is challenging. The role of multimodality nonsurgical therapy for HCC larger than 10 cm is unclear.. We retrospectively investigated 131 HCC patients with main tumors larger than 10 cm in diameter seen between October 1990 and October 2001. Fifty-six patients (group A) underwent hepatectomy and 75 patients (group B) underwent nonsurgical multidisciplinary therapy including hepatic arterial infusion, transcatheter arterial embolization, and percutaneous acetic acid injection.. Patients in group B were older, had lower serum albumin levels, and there were more patients with liver cirrhosis and great vessel invasion. Median survivals of group A and B patients were 17 months and 7 months, respectively (p < 0.001). But the 1-, 3-, 5-year survival rates in group B using 38 patients undergoing 3 or more sessions of nonsurgical treatment were not significantly worse than those for group A using 53 patients with followup (57.1%, 19.0%, 16.3% versus 60.7%, 24.5%, 24.5%, respectively). Group A patients had 37.7% and 71.7% recurrence rates at 6 and 12 months, respectively, after operation, and they had a significantly higher frequency of overall extrahepatic recurrence compared with group B patients (43.4% versus 18.7%, p = 0.005). In group B, only 3 of 35 patients younger than 60 years had tumor shrinkage after nonsurgical treatment modalities in comparison to 17 of 40 patients in the elderly group (p = 0.003). Younger patients had a significantly higher prevalence of hepatitis B surface antigen positivity (85.7% versus 47.5%) and infiltrating tumor growth pattern (74.3% versus 45.0%) compared with older patients.. Our study suggests that the advantage of hepatic resection in patients with huge HCC is marginal. An effective adjuvant therapy is needed to improve outcomes after hepatic resection. The experience in using nonsurgical treatment shows that the result is poor in young patients compared with that in elderly patients.

Topics: Acetic Acid; Age Factors; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Cisplatin; Female; Hepatectomy; Humans; Infusions, Intra-Arterial; Injections, Intralesional; Leucovorin; Liver Neoplasms; Male; Middle Aged; Mitomycin; Neoplasm Recurrence, Local; Neoplasm Staging; Patient Selection; Proportional Hazards Models; Retrospective Studies; Survival Analysis; Taiwan; Tomography, X-Ray Computed; Treatment Outcome

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Drug Administration Schedule; Fluorouracil; Humans; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male

Hepatocellular carcinoma (HCC) with vascular invasion and/or intrahepatic metastasis (IM) has a poor prognosis, so advanced HCC may be considered as a contraindication for hepatectomy. We experienced a case of HCC with hepatic venous and portal venous tumor thrombus and multiple IM who survived over 1 year after the operation with combined locoregional chemotherapy. (Case): A 67-year-old male patient was diagnosed with HCC with extracapsular invasion after transarterial embolization (TAE). CT scan revealed the HCC had a right portal venous tumor thrombus and multiple IM. Posterior lobectomy and thrombectomy of hepatic venous and portal venous tumor thrombus and placement of portal venous catheter ware performed. From the first day after operation the patient received continuous intravenous and intraportal 5-FU for 3 weeks. At the first month after operation, TAE and PEIT were given against residual IM. After discharge the patient received hepatic arterial infusion chemotherapy (MTX/CDDP/5-FU/Leucovorin). Fourteen months after operation, the patient is surviving in good physical condition.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Embolization, Therapeutic; Fluorouracil; Hepatectomy; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Methotrexate; Neoplasm Invasiveness; Neoplastic Cells, Circulating; Portal Vein

A patient with advanced unresectable fibrolamellar hepatocellular carcinoma is reported, who was treated with cisplatinum, epirubicin and 5-fluorouracil combination chemotherapy. Tumour regression was achieved, enabling major debulking surgery to be performed. The patient remains in clinical remission 11 months after completing therapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Carcinoma, Hepatocellular; Cisplatin; Combined Modality Therapy; Epirubicin; Fluorouracil; Humans; Leucovorin; Liver; Liver Neoplasms; Male; Tomography, X-Ray Computed; Treatment Outcome

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Carcinoma, Hepatocellular; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Carcinoma, Hepatocellular; Drug Therapy, Combination; Ethanol; Female; Fluorouracil; Humans; Iodized Oil; Leucovorin; Liver Neoplasms; Male; Middle Aged; Tomography, X-Ray Computed; Ultrasonography

Three cases of bile duct necrosis owing to hepatic arterial infusion chemotherapy (HAI) were reported. Regarding HAI, transcatheter hepatic arterial embolization (TAE) was applied in two cases (hepatocellular carcinoma: 1; metastasis: 1) and 5-fluorouracil (continuous) combined with leucovorin (one shot) therapy (LV + 5-FU) was given to one metastatic case. In the data of blood biochemistry, serum alkaline phosphatase, gamma-glutamyl transpeptidase, and leucine aminopeptidase values characteristically elevated without the elevation of total bilirubin value. Hepatic tumors degenerated with necrosis in all cases and no viable cells were histologically recognized. Although the destruction of bile ducts was locally detected adjacent to these tumors in TAE cases and was more widespread in the LV + 5-FU case, these lesions were very similar in each case. Therefore, we concluded that both ischemia and drug toxicity induced bile duct necrosis and the necrosis around the bile duct was the secondary change due to the leaked bile juice.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bile Ducts, Intrahepatic; Carcinoma, Hepatocellular; Embolization, Therapeutic; Fluorouracil; Hepatic Artery; Humans; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Leucovorin; Liver; Liver Neoplasms; Male; Middle Aged; Necrosis

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Drug Evaluation; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged

We utilized the presence of hepatic receptors for galactose-terminal glycoproteins to achieve specific rescue of differentiated hepatocytes from methotrexate toxicity. This was accomplished by administration of a conjugate formed by covalent coupling of the methotrexate antagonist, folinic acid (leucovorin), to galactose-terminating (desialylated) bovine fetuin. Two cultured hepatocyte-derived cell lines were chosen to test rescue from methotrexate toxicity: Hep G2 cells are capable of receptor-mediated endocytosis of galactose-terminating glycoproteins; PLC/PRF/5 cells are not. In the presence of methotrexate alone, both cells lines were reduced in number to 20% of control populations by day 5. Growth rates of both lines returned to normal when free folinic acid was added to the medium containing methotrexate. When asialofetuin-folinic acid conjugate was given to both cell lines in the presence of methotrexate, Hep G2 cells doubled their numbers by day 4 and reached control (without methotrexate) populations by day 8. However, PLC/PRF/5 cells failed to respond to administered asialofetuin-folinic acid conjugate under identical conditions, and the growth curve was the same as that for cells which received methotrexate alone. Conjugates of asialofetuin bound to folic acid (folate derivative requiring dihydrofolate reductase activity for conversion to an active metabolite) and fetuin (non-galactose-terminal glycoprotein) linked to folinic acid also were made for control studies. These conjugates failed to rescue either cell line.

Topics: alpha-Fetoproteins; Asialoglycoprotein Receptor; Asialoglycoproteins; Carcinoma, Hepatocellular; Cells, Cultured; Fetuins; Glycoproteins; Humans; Leucovorin; Liver; Liver Neoplasms; Methotrexate; Receptors, Cell Surface

Topics: Animals; Biodegradation, Environmental; Carcinoma, Hepatocellular; Cell Line; Cells, Cultured; Chromatography, Gel; Cycloheximide; Drug Stability; Electrophoresis; Enzyme Activation; Folic Acid Antagonists; Humans; Leucovorin; Leukemia L1210; Liver Neoplasms; Methotrexate; Mice; Rats; Tetrahydrofolate Dehydrogenase; Triamterene; Trimethoprim

Topics: Adenocarcinoma; Arteries; Brain Neoplasms; Carcinoma, Hepatocellular; Carcinoma, Squamous Cell; Catheterization; Chloramphenicol; Facial Neoplasms; Fever; Fluorouracil; Head and Neck Neoplasms; Humans; Infections; Infusions, Parenteral; Leucovorin; Liver Neoplasms; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Neoplasm Metastasis; Palliative Care; Penicillins; Stomach Neoplasms; Thoracic Neoplasms

Topics: Adenocarcinoma; Adolescent; Aged; Carcinoma, Hepatocellular; Chemical and Drug Induced Liver Injury; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Parenteral; Leucovorin; Liver Function Tests; Liver Neoplasms; Male; Methotrexate; Middle Aged; Mitomycins; Neoplasm Metastasis; Rectal Neoplasms; Sigmoid Neoplasms