levoleucovorin and Carcinoma--Non-Small-Cell-Lung

Aflibercept, also known as vascular endothelial growth factor (VEGF)-Trap, is a recombinant, decoy receptor fusion protein, rationally designed to block angiogenesis by targeting not only all forms of VEGF-A, but also VEGF-B and placental growth factor. It inhibits VEGF-induced angiogenesis in preclinical models. In tumor models, aflibercept is associated with the reduction of tumor vasculature and size, and the inhibition of ascites formation. Clinical studies are investigating the use of aflibercept alone and in combination with other antineoplastic therapies for the treatment of various cancers. Phase I and II studies have provided proof of principle, and support the continuing clinical investigation of aflibercept. Results from the phase III study, VITAL, of aflibercept in the second-line setting in patients with advanced non-small cell lung cancer [NCT00532155] demonstrated efficacy in progression-free survival and overall objective response rate, but overall survival was not significantly improved. A full report awaits publication. The Phase III VANILLA trial in metastatic pancreatic cancer [NCT00574275] showed no improvement in overall survival. Most recently, the phase III VELOUR study [NCT00561470] of aflibercept plus FOLFIRI compared with placebo plus FOLFIRI in patients with metastatic colorectal cancer following failure of an oxaliplatin regimen showed significant improvements in overall survival, progression-free survival, and response rate and the complete results have been submitted to a peer-reviewed journal. This review summarizes preclinical and clinical data for aflibercept and discusses future directions and clinical trials for this agent.

Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Colorectal Neoplasms; Disease-Free Survival; Drug Screening Assays, Antitumor; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Vascular Endothelial Growth Factor A

Angiogenesis is one of the hallmarks of cancer. Among the identified angiogenic factors, vascular endothelial growth factor (VEGF) is a crucial regulator of angiogenesis in normal and malignant tissue. Increased expression of VEGF has been detected in most tumors of humans, and it is associated with increased risks of recurrence, metastasis, and death. Bevacizumab (Avastin), a recombinant humanized monoclonal antibody targeting VEGF, has been evaluated in various solid tumors. Some pivotal phase III trials demonstrated that the addition of bevacizumab to conventional chemotherapy showed a survival benefit with acceptable toxicity. The United States Food and Drug Administration approved the use of bevacizumab for patients with unresectable colorectal cancer and unresectable non-squamous, non small cell lung cancer. In April 2007, the Japanese Ministry of Health, Labour and Welfare approved bevacizumab for patients with unresectable colorectal cancer. The usage of bevacizumab will be stipulated in combination with 5-fluorouracil containing chemotherapy at a dose of 5 mg/kg or 10 mg/kg given every 14 days. To know its efficacy and safety of bevacizumab is necessary for Japanese patients in the clinical practice.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Camptothecin; Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Drug Administration Schedule; Drug Approval; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Lung Neoplasms; Male; Organoplatinum Compounds; Oxaliplatin; Rectal Neoplasms; Vascular Endothelial Growth Factor A

After over 30 years of theorizing, the use of angiogenesis inhibitors as anticancer therapy has finally moved from the realm of research to reality. Normal adult vasculature is generally quiescent in nature, with endothelial cells dividing approximately every 10 years. In contrast, the growth of tumours requires constant vascular growth and remodelling in order for solid tumours to grow beyond 1-2 mm3 in size. Vascular endothelial growth factor (VEGF) and its receptors are key regulators of the process of angiogenesis, which make them attractive therapeutic targets. A multitude of VEGF-targeted inhibitory agents are currently being investigated for the treatment of cancer. This review article focuses on recent developments in the use of angiogenesis inhibitors for the treatment of breast, lung, and colorectal cancers.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Camptothecin; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Fluorouracil; Humans; Hypertension; Kidney Neoplasms; Leucovorin; Lung Neoplasms; Neoplasms; Neovascularization, Pathologic; Receptors, Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Although 5-FU administered as a single agent in different intravenous bolus schedules has been shown to have minimal activity in non-small cell lung cancer (NSCLC), several lines of experimental evidence suggest that 5-FU in combination regimens may be synergistic with the 'anchor' drug of the combination. Moreover, the recent availability of oral formulations of 5-FU together with the ability to modulate the anabolic and catabolic metabolism of 5-FU with leucovorin and dihydropyrimidine dehydrogenase (DPD) inhibitors, respectively, may provide a substantial improvement in the ease of administration and the efficacy of fluoropyrimidine therapy. Several oral fluoropyrimidines are under investigation. Orzel [UFT (uracil:tegafur) plus oral leucovorin] is the first oral DPD-inhibitory fluoropyrimidine. Orzel administered daily achieves similar concentrations of 5-FU obtained with continuous-infusion 5-FU. This paper reviews the clinical experience with UFT and Orzel in the treatment of NSCLC.

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Combinations; Humans; Leucovorin; Lung Neoplasms; Tegafur; Treatment Outcome; Uracil

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Colorectal Neoplasms; Combined Modality Therapy; Digestive System Neoplasms; Fluorouracil; Humans; Immunologic Factors; Interferon-alpha; Leucovorin; Lung Neoplasms; Neoplasm Staging; Neoplasms; Survival Analysis; Treatment Failure

UFT is an oral antineoplastic drug combining uracil and tegafur in a 4:1 molar ratio. Tegafur acts as a prodrug of 5-fluorouracil (5-FU), being slowly metabolized by cytochrome P450 to 5-FU. Uracil competitively inhibits the metabolism of 5-FU, resulting in increased plasma and tumor 5-FU concentrations. At equimolar doses, higher peak plasma 5-FU concentrations are achieved with UFT plus oral leucovorin with similar systemic 5-FU exposure compared with low-dose continuous 5-FU infusions. The elimination half-life of 5-FU following UFT administration is approximately 7 h compared with 0.2 h with i.v. 5-FU. In phase II studies of UFT plus oral leucovorin for the treatment of advanced colorectal cancer, response rates ranged from 25 to 42%. UFT plus oral leucovorin is well tolerated, with manageable diarrhea being the only dose-limiting toxicity; the regimen is not associated with significant myelosuppression, mucositis, hand-foot syndrome or alopecia. UFT, with or without leucovorin, has also been evaluated alone or in combination with other cytotoxic agents for the treatment of advanced lung, breast and gastric cancers. UFT has also been evaluated as adjuvant therapy for colorectal, breast, gastric, head and neck, and superficial bladder cancers. UFT plus leucovorin offers patients an entirely oral cancer treatment, and appears to provide potential advantages over bolus 5-FU regimens with regard to toxicity and convenience of administration. These benefits should be advantageous in the adjuvant setting, as well as in advanced disease settings in which palliation is an important consideration. Ongoing clinical trials will further define the role of this promising oral treatment regimen.

Topics: Administration, Oral; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Drug Combinations; Humans; Leucovorin; Lung Neoplasms; Neoplasms; Stomach Neoplasms; Tegafur; Uracil

Quality of life (QOL) variables are increasingly included as end points in cancer therapy trials, supplementing such traditional end points as survival time in evaluating the effects of cancer treatments. Consensus has been reached that a number of QOL components (symptom status and physical, emotional, role, and social functioning) should be measured. Assessing multiple health-related QOL dimensions, as compared with a global score, provides a more detailed accounting of specific effects of cancer treatment on patient functioning. Southwest Oncology Group QOL assessment policies emphasize patient reports and the need for systematic quality control procedures. The Southwest Oncology Group QOL questionnaire comprises a battery of categorical scales with established psychometric properties. A set of generic core scales is always included in the battery, and treatment- and disease-specific scales are developed for each trial. Other frequently used QOL questionnaires, such as the European Organization for Research and Treatment of Cancer QLQ-C30, the Cancer Rehabilitation Evaluation System questionnaire, and the Functional Assessment of Cancer Therapy are alternative instruments in current use. Quality of life findings from lung cancer clinical trials indicate a prevalence of symptom distress, fatigue, and decline in functional status, although patients also experience symptom management problems without treatment. A summary of preliminary QOL findings for two vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France) trials (randomized and single-arm) in patients with non-small cell lung cancer show that symptom status was as good or better for patients receiving vinorelbine compared with those receiving 5-fluorouracil/leucovorin in the randomized study. Differences in other QOL dimensions were not detected. Findings for the single-arm trial of oral vinorelbine were generally consistent with those of the randomized trial.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Vinblastine; Vinorelbine

Concomitant chemoradiotherapy represents an investigational approach to the treatment of locoregionally advanced non-small cell lung cancer. The theoretical rationale, and clinical experience are reviewed in brief. Clinical trials conducted at the University of Chicago are summarized.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Chicago; Cisplatin; Clinical Trials as Topic; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Combined Modality Therapy; Fluorouracil; Humans; Hydroxyurea; Immunologic Factors; Interferon-alpha; Leucovorin; Lung Neoplasms; Pilot Projects; Randomized Controlled Trials as Topic; Treatment Outcome

S-1, a novel oral fluoropyrimidine, has potent antitumor activity against non-small-cell lung cancer (NSCLC). Meanwhile, leucovorin enhances the efficacy of 5-fluorouracil by inhibiting thymidylate synthase. Therefore, this phase II clinical trial evaluated the safety and efficacy of S-1 plus leucovorin combination therapy for previously treated patients with NSCLC.. Patients with stage IIIB or IV NSCLC were prospectively enrolled if they received 1 or 2 prior chemotherapy regimens. S-1 (40-60 mg) and leucovorin (25mg) were administered together orally twice per day for 7 consecutive days followed by 7 days of rest. This 2-week cycle was repeated for a maximum of 25 cycles until the onset of disease progression or unacceptable adverse events. Endpoints included objective tumor response, progression-free survival, overall survival, and safety.. Among 33 patients, 6 (18.2%), 14 (42.4%), and 11 (33.3%) had partial response, stable disease, and progressive disease, respectively. Median progression-free and overall survival times were 3.5 and 11.7 months, respectively. The common grade 3 toxicities included stomatitis (18.2%), anorexia (12.1%), and neutropenia (9.1%). One patient had pneumatosis cystoides intestinalis, and another experienced paralytic ileus. There were no treatment-related deaths.. S-1 plus leucovorin combination therapy demonstrated promising efficacy and an acceptable toxicity profile in previously treated patients with NSCLC.

Topics: Administration, Oral; Adult; Aged; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Leucovorin; Male; Middle Aged; Oxonic Acid; Tegafur

Oral treatment regimens with few side effects are appealing in the 2nd or 3rd line treatment of non-small cell lung cancer (NSCLC) patients.. The aim was to investigate the efficacy and toxicity of the oral combination etoposide, Uracil-Tegafur (UFT) and leucovorin in 2nd or 3rd line in Caucasian patients with advanced NSCLC.. Etoposide 50 mg/m(2), UFT 250 mg/m(2) and leucovorin 90 mg (fixed dose) were dosed in 3 gifts approximately 8h apart for 14 days followed by 1 week rest every 3 weeks until progressive disease (PD). Primary endpoint was response rate (RR), secondary endpoints toxicity and time to progression (TTP).. The median number of cycles was 3.5 (95% CI 2-5); 9 patients received > or =6 cycles, 4>10 cycles. The median dose intensities for etoposide and UFT were 223 mg/m(2)/week (95% CI 213-232) and 1092 mg/m(2)/week (95% CI 1032-1167), the relative dose intensities 92% and 90%, respectively. Grade 3/4 neutropenia was observed in 12% (4/32), grade 3/4 thrombocytopenia in 15% (5/32), without febrile neutropenia. Non-hematological toxicity grade 3 included hepatic toxicity (6%), lethargy (15%), diarrhea (3%) and nausea (3%). One patient developed grade 4 arterial ischemia. Fourteen percent (95% CI 4-33%) (4/28) had a confirmed partial response, 57% (95% CI 44-81%) (16/28) stable disease and 28% (95% CI 19-56%) (8/28) progressive disease. The median TTP was 3 months (95% CI 1.3-4.4), the median overall survival 6.7 months (95% CI 4.0-9.3).. The combination of UFT, etoposide and leucovorin is active in 2nd or 3rd line therapy of Caucasian NSCLC patients and because of its favourable toxicity profile this treatment warrants further investigation.

Topics: Administration, Oral; Alopecia; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Drug Combinations; Etoposide; Female; Humans; Kaplan-Meier Estimate; Leucovorin; Lung Neoplasms; Male; Neoplasm Recurrence, Local; Neoplasm Staging; Neutropenia; Tegafur; Uracil

Aphase 1 study of gefitinib in combination with oxaliplatin, 5-fluorouracil and leucovorin (IFOX)was conducted to evaluate the safety and feasibility of this regimen.. Patients with advanced solid malignancies were treated with escalating doses of gefitinib (250 mg or 500 mg once daily) in combination with FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin). The initial dose of oxaliplatin was 70 mg/m2 with sequential dose escalation to 85 mg/m2.. Sixteen patients received a total of 138 14-day courses of daily gefitinib in combination with FOLFOX. Escalation of gefitinib from 250 mg/d to 500 mg/d with FOLFOX was well-tolerated. In addition, no severe toxicities precluded subsequent dose escalation of oxaliplatin from 70 mg/m2 to 85 mg/m2 at which no dose-limiting toxicity was seen. No further dose escalation was performed as this represented the oxaliplatin dose administered in the standard FOLFOX-4 regimen. The most predominant toxicity was diarrhea, which was well controlled with oral antidiarrheal agents. Four partial remissions occurred in patients with metastatic colorectal cancer.. Gefitinib as a 500 mg daily continuous dose was well tolerated in combination with full doses of FOLFOX-4.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Fluorouracil; Gefitinib; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Quinazolines

An infusional ambulatory chronotherapy with 5-FU, folinic acid (FOL) and carboplatin was administered to 45 advanced NSCLC patients. The patients were randomised into 3 groups varying according to the time of administration peak of drugs (reference hours: 4 a.m. for 5 FU (and FOL); 4 p.m. for carboplatin; +/-8 h). The reference schedule appeared best tolerated (regarding hematology and mucositis). This study has prospectively validated the chronotolerance concepts of this complex combination chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Chronotherapy; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Lung Neoplasms; Male; Middle Aged; Prospective Studies; Treatment Outcome

Ifosfamide-based chemotherapy has already been the basis of three separate clinical trials. In this study, ifosfamide was administered to lung cancer patients who had failed to respond to previous chemotherapy, to assess its response rate and toxicity.. From January 1993 to December 1996, 21 patients were treated, including eight patients with small cell lung cancer (SCLC) and 13 with non-small cell lung cancer (NSCLC). Patients who had histocytologically confirmed lung cancer, were previously treated with chemotherapy, had a measurable lesion(s), were younger than 75 years of age, had an Eastern Cooperative Oncology Group performance status of 0-3 and adequate marrow, renal and liver function were eligible for inclusion in this study. For SCLC patients, ifosfamide 2.4 g/m2 intravenous (i.v.) infusion was given over 30 minutes on days 1-3 every four weeks. For NSCLC two regimens were used: IFL (ifosfamide 2 g/m2, 5-fluorouracil (FU) 600 mg/m2 and leucovorin 50 mg/m2 i.v. infusion on days 1-3 every four weeks) and LIFE (leucovorin 50 mg/m2, ifosfamide 1 g/m2, 5-FU 400 mg/m2 and epirubicin 12 mg/m2 i.v. infusion on days 1-3 every four weeks). For NSCLC patients, IFL was used for the first two years of treatment and LIFE was used in the last two treatment years. All patients were evaluated for treatment response and toxicity.. The major toxic effect, myelosuppression (grade 3 or 4 leukopenia), occurred in 62.5% of SCLC patients and 23.1% of NSCLC patients during treatment, and in 62.5% and 10% of SCLC and NSCLC patients, respectively, throughout the course. Only one SCLC and one NSCLC patient experienced febrile neutropenia. One toxic death, attributed to febrile neutropenia, was documented in a patient with SCLC. Alopecia was ubiquitous. Other toxicities were uncommon and mild. The overall response rate was 50% in SCLC and 7.7% in NSCLC. The median time to disease progression was 61 days in SCLC and 47 days in NSCLC. Median survival was 172 days in SCLC and 173 days in NSCLC.. The study results suggest that ifosfamide chemotherapy is active with an acceptable toxicity profile in previously treated SCLC patients. However, it lacks efficacy in NSCLC patients who have been previously treated.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Epirubicin; Female; Fluorouracil; Humans; Ifosfamide; Leucovorin; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Salvage Therapy

The Oncopaz Cooperative Group designed a chemotherapy regimen to modulate UFT (Tegafur and Uracil) with leucovorin. The regimen consisted of a high intravenous dose of leucovorin, followed by oral UFT and oral leucovorin twice daily for 14 days. Based on the promising results obtained with this regimen in patients with advanced colorectal cancer, the Oncopaz group performed several phase II trials using this combination with other drugs to treat advanced gastric, lung, head and neck, and breast cancers. When combined with etoposide in gastric cancer, the regimen was shown to be active and well tolerated. However, when used with cisplatin to treat non-small cell lung cancer, a low response rate and high toxicity precluded its recommendation for further study. The addition of carboplatin in the treatment of head and neck cancer demonstrated moderate activity with low toxicity. In an ongoing trial of advanced breast cancer, preliminary results indicate that the combination of idarubicin, UFT, and leucovorin is active, with moderate, primarily hematologic toxicity. Trials of new combinations are warranted to take advantage of the pharmacokinetic properties and oral bioavailability of UFT and leucovorin.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Drug Combinations; Etoposide; Head and Neck Neoplasms; Humans; Leucovorin; Lung Neoplasms; Middle Aged; Stomach Neoplasms; Tegafur; Uracil

The aim of this study was to define the efficacy of a combination of cisplatin, 5-fluorouracil (5-FU), leucovorin, and etoposide (VP-16) in locally advanced or metastatic non-small-cell lung cancer (NSCLC). From September 1991 to November 1994, 28 patients were treated with cisplatin, 100 mg/m2 i.v. on day 1; 5-FU and leucovorin, 500 mg/m2 on days 1, 2, 3, and 4 by i.v. continuous infusion; and VP-16, 70 mg/m2 i.v. on days 1, 2, 3, and 4 (combination, PFL-VP-16). Cycles were repeated every 3 weeks. There were 22 men and six women. The median age was 58 (range, 41-76). All had measurable diseases (one was stage IIIA, six were IIIB, and 21 were IV). None had previously received chemotherapy for metastatic disease. There was one complete response and six partial responses, for an overall response rate of 25% (95% confidence interval 9-41%). The median response duration and the overall survival were 8 and 9 months, respectively. Limiting toxicity was myelosuppression and oral mucositis. Grade 3 or 4 leucopenia was observed in 20% of all of the 95 cycles administered, and oral mucositis in 13%. No grade 3 or 4 renal toxicity occurred, and neurologic toxicities were limited (3% of the 28 patients experienced grade 3). PFL-VP-16 is active and can easily be administered to patients with advanced NSCLC. However, according to the results obtained with this schedule, VP-16 does not increase either response rate or survival compared with the regimen previously described by Vokes et al. (PFL).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Etoposide; Female; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Survival Rate

Neoadjuvant therapy in patients with Stage IIIA NSCLC is associated with a 50-70% resection rate and a 3-5 year survival of 20-32%, but few trials have required meticulous staging of the mediastinum to ensure homogeneity of the study population. Continuous infusion cisplatin 25 mg/m2/day 1-5, 5-fluorouracil 800 mg/m2/day 2-5, and high-dose leukovorin 500 mg/m2/day 1-5 (PFL) given every 4 weeks achieved a 41% response rate in metastatic NSCLC (Lynch TJ, Kalish LA, Kass F, Strauss G, Elias A, Skarin A, Shulman L, Sugarbaker D, Frei E. Continuous infusion cisplatin, 5-fluorouracil, and leukovorin for advanced non-small cell lung cancer. Cancer 1994; 73: 1171-1176). The regimen was therefore evaluated in 34 patients with pathologic Stage IIIA N2 disease between 3/91 and 10/92.. Staging consisted of chest, liver, brain computerized tomography and bone scan, bronchoscopy and surgical mediastinal node mapping. Patients received PFL for 3 cycles, followed by thoracotomy and thoracic radiotherapy (TRT) to 54-60 Gy.. Median age was 57 (42-68) years. Demographic factors included: male 56%; adenocarcinoma 59%, squamous cell carcinoma 24%; Stage T3N2 26%, T2N2 56%, and T1N2 18%. No treatment related deaths occurred. Radiographically defined response to PFL was 65% (6% complete). Thoracotomy was performed in 28 patients (82%) (6 had no attempt due to disease progression). Complete resection was achieved in 21 (75%) and seven were unresectable. Pathologic complete response was observed in five patients (15%) and an additional unresectable patient had fibrosis-only documented at thoracotomy for an overall clinicopathologic response rate of 76% (18% pathologic CR). Another ten patients had residual primary with or without hilar disease with resolution of previously documented mediastinal involvement. Six (18%) patients remain alive and disease-free with a median follow-up of 46 (33-50) months, four of whom had achieved pathologic complete response at time of surgery.. Long-term event-free survival was associated with complete surgical resection which in turn was associated with clinical response to chemotherapy. There was a possible trend associating pathologic downstaging (absent residual disease in mediastinal nodes), particularly pathologic complete response observed in patients with non-bulky mediastinal disease, with improved event-free survival. Pathologic downstaging might therefore be a useful surrogate endpoint in trials evaluating the preoperative activity of new chemotherapy regimens. While radiographic response generally correlated with findings at surgery, response as determined by histologic examination of resected tissue was generally more extensive and may more accurately reflect the systemic impact of the chemotherapy regimen.

Topics: Adult; Aged; Antidotes; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; Cisplatin; Disease Progression; Female; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Survival Rate; Thoracotomy; Thorax

We performed a phase II study to assess the efficacy and toxicity of the cisplatin-UFT-leucovorin (LV) combination in patients with advanced non-small-cell lung cancer (NSCLC). Twenty-five patients with measurable disease who had not received prior chemotherapy were entered into the trial. The therapeutic regimen consisted of cisplatin 90 mg/m(2) and i.v. LV 500 mg/m(2) on day 1, followed by oral UFT 390 mg/m(2)/day (in two doses on days 1 through 14. Patients also received oral LV 15 mg/12 h on days 2 through 14. Seventeen patients required reduced doses of UFT (200 mg/m(2) due to toxicity. Courses were repeated every 28 days for a minimum of three per patient. Three of 25 patients (12%) achieved a partial response (95% CI: 2.6 to 32.2%), two with 390 mg/m(2)/day and one with 200 mg/m(2)/day of UFT. The main side effects were hematological and gastrointestinal. In the courses including 390 mg/m(2)/day of UFT, grade 3-4 toxicity was leucopenia in 18% of the courses, nausea/vomiting in 27%, and diarrhea and epigastralgia in 13% each. Grade 3-4 toxicities for 200 mg/m(2)/day of UFT were leucopenia 2%, nausea/vomiting 9% and diarrhea 7%. In conclusion, this regimen cannot be recommend for the treatment of advanced NSCLC due to its low response rate and high toxicity.

Topics: Abdominal Pain; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Diarrhea; Drug Administration Schedule; Female; Humans; Leucovorin; Leukopenia; Lung Neoplasms; Male; Middle Aged; Nausea; Remission Induction; Tegafur; Vomiting

To determine the feasibility of ambulatory infusional administration 24 hours per day, 7 days per week of a three-drug regimen of cisplatin or carboplatin, leucovorin, and 5-fluorouracil (5-FU) (PLF) utilizing an alternating weekly sequential design and to introduce infusional etoposide as PLEF to the regimen.. Forty-three patients with diverse malignancies received a sequential infusion of 5-FU 200 mg/M2/day on days 1 to 14 and 21 to 35 with leucovorin admixed for day 1 to 7 and 21 to 28. Cisplatin (20 patients) or carboplatin (23 patients) infusion was administered at a dose of 10 mg/M2/day or 30 mg/M2/day, respectively, day 7 to 14 and 35 to 42. Cycles were planned to be repeated consecutively in the absence of toxicity in patients with stable or responding disease. Sixteen patients also received etoposide 30 mg/M2/day as an admixture concomitant with administration of the platinum analogue. Therefore, the distribution of therapies was PLF 19, CLF 8, PLEF 14, and CLEF 2.. A total of 63 courses of PLF +/- E was administered as outlined above. Hematologic toxicity was minimal with or without the addition of etoposide. Sixteen percent of patients developed an elevated creatinine with a median of 1.6 and a range of 1.6 to 3.2 mg %. Tumor responses were observed in seven of fourteen evaluable patients with squamous cell carcinoma of the lung (all of whom received concomitant etoposide). In addition, one patient with metastatic gallbladder cancer achieved a complete clinical response.. Ambulatory infusional PLF with carboplatin or cisplatin using sequentially alternating delivery of the component antineoplastic agents is feasible and active with minimal toxicity. The addition of infusional etoposide to the PLF regimen does not substantially increase hematologic toxicity. Extended phase II studies in aerodigestive cancers are ongoing and a phase III trial comparing this ambulatory regimen to short-term PLF infusion (5-day) may be justified to compare the relative cost and benefits of the two schedules.

Topics: Adult; Aged; Aged, 80 and over; Ambulatory Care; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Drug Administration Schedule; Etoposide; Female; Fluorouracil; Gastrointestinal Neoplasms; Hematologic Diseases; Humans; Infusions, Intravenous; Leucovorin; Lung Neoplasms; Male; Middle Aged

This prospective randomized trial was performed to compare the effectiveness of intravenous vinorelbine tartrate with intravenous fluorouracil and leucovorin (5-FU/LV) on the primary end points of survival, quality of life (QOL), and relief of cancer-related symptoms in patients with advanced non-small-cell lung cancer (NSCLC). Secondary end points included tumor response rates and time to treatment failure. In addition, the safety of both treatment regimens was evaluated in this multicenter study.. Two hundred sixteen patients with stage IV NSCLC were enrolled onto this study from 18 centers. Vinorelbine was administered at a dose of 30 mg/m2/wk. 5-FU/LV was administered at a dose of 425 mg/m2 and 20 mg/m2, respectively, for 5 consecutive days every 4 weeks. Patients with progressive disease or toxicity were removed from study while responding and stable patients were continued on therapy.. The median survival time of patients who received vinorelbine was 30 weeks, with 25% of patients alive at 1 year, compared with a median survival time of 22 weeks and 16% of patients alive at 1 year for those treated with 5-FU/LV (P = .03, log-rank test). This improvement in survival was associated with a higher objective response rate (12% v 3%) and time to treatment failure (10 weeks v 8 weeks) for vinorelbine versus 5-FU/LV. The dose-limiting toxicity of vinorelbine was granulocytopenia, with 54% of patients experiencing grade 3/4 granulocytopenia. Nonhematologic toxicity of vinorelbine was generally grade 1 or 2. The most common grade 3 toxicities were related to injection-site reactions.. This trial confirms the efficacy of vinorelbine in patients with advanced NSCLC. The clinical activity and relatively favorable toxicity profile of this agent make it a reasonable and useful treatment option in the management of patients with this disease.

Topics: Adult; Aged; Aged, 80 and over; Agranulocytosis; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Carcinoma, Non-Small-Cell Lung; Female; Fluorouracil; Humans; Injections, Intravenous; Leucovorin; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Prospective Studies; Quality of Life; Survival Analysis; Vinblastine; Vinorelbine

Eighteen patients with non-small cell lung cancer (NSCLC) who had previously received no systemic chemotherapy, were treated on this phase II study with interferon-alfa-2b 8 MU tiw, leucovorin 500 mg/m2 IVPB over 2 hours and 5-Fluorouracil 500 mg/m2 i.v. for 6 weeks followed by a 2-week rest. There were was no rest period for interferon. Median age of patients on this study was 63 years. Fatigue, nausea, and diarrhea were the most common toxicities. There were no grade IV toxicities and no treatment-related deaths. Seven partial responses (39%) with median duration of 4.5 months were seen. An additional patient has had stable disease/minor response for 12+ months. Median survival is 10 months. ALF has activity in NSCLC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Lung Neoplasms; Male; Middle Aged; Recombinant Proteins

Thirty-two patients with advanced non-small cell lung carcinoma (NSCLC) received a chronomodulated 5-day venous infusion of 5-fluorouracil (5 FU) (700 mg/m2/day), folinic acid (F) (300 mg/m2/day), and carboplatin (C) (40, 50, or 55 mg/m2/day), as first chemotherapy. Courses were repeated every 21 days (after a 16-day interval). In total, 158 courses (median: 4, range: 1 through 16; 81 and 58 courses at, respectively, a 40 and 50 to 55 mg/m2 daily dosage of C) were delivered using a multichannel programmable in-time pump (Intelliject, Aguettant) connected to a double lumen implanted venous side-port. The administration was allowed in fully ambulatory convenience. Overall tolerance was excellent. Grade 3 of 4 hematologic toxicity was encountered in 4.6% of courses for thrombopenia and in 7.0% of courses for neutropenia. Nausea or vomiting (grade 3 or 4) occurred in 7.8% of courses. Mucositis, diarrhea, alopecia, or skin grade 3 or 4 toxicity were observed in less than 3% of courses. Treatment delay was needed in only 7.8% of courses and dose reductions were needed in 4.6% of courses for 5 FU and in 6.5% of courses for C. This good tolerance allowed a sustained quality of life and prompted further trials aiming to define the place of this protocol in the multidisciplinary treatment approach of NSCLC.

Topics: Adult; Aged; Ambulatory Care; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Chronobiology Phenomena; Feasibility Studies; Female; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged

In a randomized phase II study by the Cancer and Leukemia Group B, the cisplatin/5-fluorouracil/leucovorin (PFL) combination produced a 29% response rate in advanced, unresectable non-small cell lung cancer. Vinorelbine (Navelbine; Burroughs Wellcome, Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France), a semisynthetic vinca alkaloid, has also demonstrated single-agent activity in this disease. Therefore, a phase I-II study was designed to investigate the addition of vinorelbine in escalating doses to the PFL combination. The objectives of this study were to establish the maximum tolerated dose of vinorelbine in combination with PFL, and to define the overall response rate in a cohort of patients treated with the maximum tolerated dose. The regimen consisted of vinorelbine in escalating doses starting at 20 mg/m2/d intravenously on days 1 and 5, followed by leucovorin 100 mg orally every 4 hours on days 1 to 5,5-fluorouracil 800 mg/m2/d intravenous continuous infusion days 2 to 5 (96 hours), and cisplatin 100 mg/m2 intravenously 12 to 24 hours after administration of the first dose of vinorelbine. Cycles were repeated every 3 weeks. No dose-limiting toxicity was observed in the first five patients treated with the initial vinorelbine dose. Increasing the dose of vinorelbine to 25 mg/m2 in a second cohort of two patients, however, resulted in grade 4 granulocytopenia in both, and grade 4 diarrhea in one. It was concluded that this dose level was not feasible. During a preliminary analysis, one complete response and three partial responses were observed in 16 patients evaluated; one of these patients had a pathologic complete remission. This early analysis indicates activity for the regimen.

Topics: Adult; Aged; Agranulocytosis; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Carcinoma, Non-Small-Cell Lung; Cisplatin; Cohort Studies; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Remission Induction; Vinblastine; Vinorelbine

In a phase I trial, 17 patients were treated with 5-fluorouracil (5-FU) 500 mg/m2 and leucovorin (LV) 500 mg/m2 intravenously weekly for 6 weeks followed by 2 weeks' rest and interferon alfa-2b 1, 3, 5, 8, or 10 million units (MU) subcutaneously tiw with no rest period. The most common toxicities were fatigue (12), diarrhea (10), nausea/vomiting (7), and fever (7). The maximum tolerated interferon dose was 8 MU tiw. Fatigue and increased incidence of other toxicities rather than a single dose-limiting toxicity occurred at the next highest interferon level. ECOG grade III/IV toxicity occurred in 5 patients and included transient supraventricular tachycardia and brief seizure episode (1), dyspnea (1), decreased performance status (1), anemia requiring transfusion (1), and deep vein thrombosis (1). No toxic deaths occurred. Two patients with non-small cell lung cancer (NSCLC) had partial responses lasting 5 and 4 months. Two other patients with NSCLC had either minor response or stable disease, and 1 patient with colon cancer had a significant decline in serum CEA. The recommended alpha interferon dose is 8 MU tiw when given with this schedule of 5-FU/LV.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Lung Neoplasms; Male; Middle Aged; Recombinant Proteins

Cisplatin, 5-fluorouracil, and leucovorin (PFL) have demonstrated synergistic activity in preclinical models. Continuous infusion of these agents maximizes the potential for synergistic interaction and forms the basis of the PFL regimen.. Sixty-one patients with advanced (Stages IIIB and IV) non-small cell lung cancer were entered into the study. Thirty-one were treated with cisplatin 25 mg/m2/day on days 1-5, 5-fluorouracil 800 mg/m2/day on days 2-6, and calcium leucovorin 500 mg/m2/day on days 1-6. Because of severe mucositis, the final 30 patients were treated with the same dosage of cisplatin but with the deletion on day 6 of leucovorin and 5-fluorouracil. Cycles were repeated every 28 days. Response was assessed after two cycles. Responding patients received an additional two cycles. Patients with Stage IIIB disease received radiation therapy to the mediastinum and sites of involved disease.. PFL had an overall response rate of 41%. Median survival was 8.1 months, and median time to treatment failure was 4.2 months. Importantly, 68% (17 of 25) of responses were maximal after just two cycles of chemotherapy. Notable toxicities included mucositis (43% > or = Grade 3) and myelosuppression. Response, time to failure, or survival did not differ between the two schedules. Mucositis was less severe with 4-day PFL.. PFL as given in this manner is an active regimen for the treatment of patients with advanced non-small cell lung cancer. The rapidity of response makes it a regimen for incorporation into protocols for Stage IIIA disease. A neoadjuvant study using PFL is underway.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Lung Neoplasms; Male; Middle Aged; Survival Analysis

Topics: Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Cyclophosphamide; Drug Administration Schedule; Drug Evaluation; Humans; Leucovorin; Lung Neoplasms

Thirty-one patients with advanced non-small-cell lung cancer (NSCLC) were treated with a combination of folinic acid, fluorouracil, vincristine, and mitomycin (F-FOMi). Eight partial responses (26%), eight stable disease (26%), and 15 progressive disease (48%) were obtained. Patients with performance status (PS) 0-1 had a significantly better response rate than those with PS 2-3. Overall actuarial survival was 10 months. Toxicity was mild and mainly gastrointestinal with mucositis and diarrhea. F-FOMi seems to be comparable to regimens more widely used in the treatment of NSCLC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Female; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Mitomycin; Vincristine

This randomized phase II study was designed to evaluate the activity of intravenous 6-thioguanine (6-TG) as a single agent and the combination of cisplatin and 5-fluorouracil (5-Fu) modulated by oral leucovorin (PFL) in patients with advanced non-small cell lung cancer (NSCLC). Eligible patients had measurable or evaluable stage III B or IV NSCLC, had no received prior chemotherapy and had a performance status of 0-2. Patients were randomized to treatment with intravenous 6-TG at 55 mg/m2 administered over 30 minutes for 5 consecutive days and repeated every 35 days, or PFL chemotherapy with cisplatin 100 mg/m2 on day 1, 5-FU 800 mg/m2/day as a continuous intravenous infusion over 5 days and oral leucovorin administered at 100 mg every 4 hours during the entire duration of the cisplatin and 5-FU infusions. PFL was repeated every three weeks. Ninety-five eligible patients were randomized, 46 to 6-TG and 49 to PFL. Response rates were 4% for 6-TG (95% confidence interval 0.5%-14.8%, 1 partial, and 1 complete response) and 29% (16.6%-43.3%) for PFL (all partial). The median time to treatment failure was 2 and 4 months, respectively, and the median survival times were 6 and 10 months, respectively. Toxicities with 6-TG were, generally, mild to moderate but severe or life-threatening granulocytopenia was observed in 21% of patients. With PFL, mucositis was dose-limiting, and 78% of patients had severe or life-threatening mucositis. This led to dose reduction of 5-FU and leucovorin during subsequent cycles or treatment termination in 82% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intravenous; Leucovorin; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Survival Rate; Thioguanine

Oral folic acid supplementation is essential for patients treated with pemetrexed, to prevent the risk of severe hematologic toxicity. In case of intestinal absorption disorder, no recommendations exist for intravenous folic acid supplementation.. We describe a 74-year-old patient with multimetastatic non-small-cell lung adenocarcinoma, receiving first-line chemotherapy with carboplatin AUC5, pemetrexed 500 mg/m. Intravenous injection of 200 mg levoleucovorin on day 1 of cycle 1 of pemetrexed-based chemotherapy was administered and well tolerated. During the second cycle, the levoleucovorin perfusion was not renewed by omission. The patient was hospitalized for 7 days because of febrile aplasia. Piperacillin-tazobactam was started, and then switched to amoxicillin-clavulanate plus ciprofloxacin. After this episode of post-chemotherapy febrile aplasia, it was decided to systematically supplement the patient with intravenous levoleucovorin, with blood folate concentration monitoring at each cycle. At 16 months after start of treatment, the patient was in complete remission, indicating that the immune-chemotherapy was effective, with no further febrile neutropenia.. This case report highlights intravenous levoleucovorin supplementation as an alternative to oral folic acid if needed during pemetrexed

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Celiac Disease; Dietary Supplements; Folic Acid; Humans; Injections, Intravenous; Levoleucovorin; Lung Neoplasms; Pemetrexed

Topics: Adenocarcinoma of Lung; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Combined Modality Therapy; Female; Fluorouracil; Hepatic Artery; Humans; Immunotherapy; Infusions, Intravenous; Leucovorin; Lung Neoplasms; Middle Aged; Nivolumab; Oxaliplatin; Prognosis; Radiosurgery

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Brain Neoplasms; Breast Neoplasms; Camptothecin; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Mass Screening; Medical Oncology; Neoplasms; Organoplatinum Compounds; Societies, Medical

Cancer cell lines in standard cell culture medium or in animal models are surrounded by an environment with relatively high folate (HF) levels, compared with folate levels in human plasma. In the present study we adapted 4 colon cancer (C26-A, C26-10, C26-G and WiDr) and 3 squamous cell carcinoma of the head and neck (HNSCC) cell lines (11B, 14C and 22B) to culture medium with low folate (LF) levels (2.5, 1.0 and 0.5 nM, respectively) and investigated whether folate depletion had an effect on sensitivity to antifolates and which mechanisms were involved. All LF cell lines showed a higher sensitivity to 5-fluorouracil (5-FU) alone or in combination with leucovorin (LV) (2-5-fold), to the thymidylate synthase (TS) inhibitors, AG337 (2-7-fold), ZD1694 (3-49-fold), ZD9331 (3-40-fold), LY231514 (2-21-fold) or GW1843U89 (4-29-fold) or to the dihydrofolate reductase (DHFR) inhibitor PT523 (2-50-fold) compared with their HF variants cultured in standard medium containing up to 8 microM folic acid. LV could only increase sensitivity to 5-FU in HNSCC cell lines 14C and 14C/F. The differences in sensitivity could partially be explained by a 2-7-fold increased transport activity of the reduced folate carrier (RFC) in LF cell lines, whereas no significant change in folylpolyglutamate synthetase (FPGS) activity was observed. Furthermore, the protein expression and catalytic activity of the target enzyme TS were up to 7-fold higher in HF colon cancer cells compared with the LF variants (p < 0.05). Although the TS protein expression in LF HNSCC cells was also lower than in HF variants, the TS catalytic activity and FdUMP binding sites were up to 3-fold higher (p < 0.05). Thus, changes in TS levels were associated with differences in sensitivity. These results indicate that folate depletion was associated with changes in TS and RFC levels which resulted in an increase in sensitivity to 5-FU and antifolates. The folate levels in LF medium used in this study are more representative for folate levels in human plasma and therefore these data could be more predictive for the activity of 5-FU and antifolates in a clinical setting than results obtained from cell lines cultured in HF medium or in animal models.

Topics: Animals; Antimetabolites, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Carrier Proteins; Colonic Neoplasms; Fluorouracil; Folic Acid; Folic Acid Antagonists; Head and Neck Neoplasms; Humans; Leucovorin; Lung Neoplasms; Membrane Proteins; Membrane Transport Proteins; Mice; Multienzyme Complexes; Neoplasms; Peptide Synthases; Reduced Folate Carrier Protein; Tetrahydrofolate Dehydrogenase; Thymidylate Synthase; Tumor Cells, Cultured

Many different cisplatin-based regimens have been used on advanced non-small cell lung cancer (NSCLC) in previous studies but there have been few such references in Taiwan. In this study, we evaluated the efficacy and toxicity of two different regimens including 5-Fluorouracil, Leucovorin, Etoposide and cisPlatin (FLEP) and cisPlatin, Etoposide and Mitomycin (PEM) in the treatment of patients with advanced NSCLC.. We retrospectively analyzed the records of 44 patients with NSCLC who met the selection criteria from February 1995 through April 1998. All of them were confirmed, using histologic tests, that they were in advanced stages, i.e. stage IIIB or IV. Twenty-two patients received FLEP and 22 patients received PEM.. Three patients with FLEP therapy and 3 patients with PEM therapy had partial response. No patient had complete response. The response rate was 13.6% in both groups, respectively. The median survival was 160 +/- 30 (median + SD) days for patients with FLEP therapy and 263 +/- 104 days for patients with PEM therapy. The factors that were associated with longer survival in all patients included response (Stable Disease vs Disease Progression p = 0.004, Partial Response vs Disease Progression p = 0.047) and regimen of chemotherapy (PEM vs FLEP p = 0.008). The major clinically significant toxicity was myelosupression.. The responses to regimens, FLEP and PEM, were low in our study groups that might be due to the low dose of cisplatin and etoposide in our regimens. The patients with response to chemotherapy and PEM therapy had longer median survival than those who underwent FLEP therapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Epirubicin; Etoposide; Female; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Mitomycin; Retrospective Studies; Survival Rate

The prognosis of Stage III unresectable non-small cell lung cancer may be improved by concurrent chemoradiotherapy. In this study, we attempted to evaluate the feasibility, tolerance, efficacy and toxicities of the combination of thoracic radiation and chemotherapy with a novel regimen that included 5-fluorouracil, leucovorin, etoposide and cisplatin (the FLEP regimen) in the treatment of this group of patients.. From July 1995 to September 1996, 20 untreated patients with locally advanced non-small cell lung cancer were enrolled in the study. Radiation at a dose of 44 Gy was initially delivered in daily fractions of 2 Gy 5 days a week to the tumor and mediastinum, followed by a boost to the tumor (20 to 26 Gy according to patients tolerance). Concurrently with thoracic irradiation, patients were treated with chemotherapy consisting of cisplatin at the dose of 60 mg/m2/d for 1 day, etoposide at the dose of 60 mg/m2/d for 2 days, and 5-FU 500 mg/m2/d plus leucovorin 50 mg/d infusion for 48 hours. Cycles of chemotherapy were repeated every 3 weeks for a maximum of 3 cycles.. Seventeen of 20 patients were assessable. The overall response rate was 70.6% (95% confidence interval = 49-92%). No complete response was achieved. The median response duration for all responding patients is not yet estimable, with a range of 3.5 to 15.5+ months. Eleven patients remain progression-free for 4 to 15 months. The median survival for the entire group is not estimable. The major toxicity was esophagitis. Other grade 3 or 4 toxicities were not frequently observed.. Combined-modality therapy with FLEP regimen and radiation is a promising treatment with a high response rate and acceptable toxicity for locally advanced non-small cell lung cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Combined Modality Therapy; Etoposide; Female; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Patient Compliance; Radiotherapy

Both cisplatin (CDDP) and leucovorin (LV) have been shown to enhance cytotoxicity of 5-fluorouracil (FUra) against murine and human neoplasms by increasing intracellular reduced folate concentrations. We were interested in their use in a combination to inhibit non-small cell lung cancer (NSCLC) cell growth and therefore conducted an in vitro study to investigate the cytotoxic activities of combinations of CDDP plus FUra, with and without LV (20 microM), against seven NSCLC cell lines. A tetrazolium assay with application of the classical isobole method was used to test drug combinations. We found that LV enhanced FUra but not CDDP cytotoxicity and that the degree of enhancement was negatively correlated with the effect of FUra. There was an overall additive combination effect of CDDP plus FUra, although there may be synergy at higher effect levels. There was synergy to a combination of CDDP, FUra, and LV, presumably primarily related to the synergistic effects of adding LV to FUra. In summary, LV and CDDP enhanced FUra cytotoxicity in a complementary fashion and there was clear synergy of a combination of CDDP, FUra, and LV against a panel of NSCLC cell lines. Our in vitro results provide a rationale for controlled clinical studies of this three-drug regimen in patients with NSCLC.

Topics: Carcinoma, Non-Small-Cell Lung; Cell Survival; Cisplatin; Drug Synergism; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Tumor Cells, Cultured

Leucovorin (LV) increases the cytotoxic effect of fluorouracil (FUra) and 5-fluoro-2'-deoxyuridine (FdUrd) by enhancing the formation of the fluorodeoxyuridine monophosphate (FdUMP) thymidylate synthase (TS) 5,10-methylenetetrahydrofolate (mTHF) ternary complex. To study the difference in the efficacy of this combination against different tumors, we compared the effect of LV (20 microM) on the cytotoxicity of FUra, FdUrd, and 5-fluorouridine (FUrd) in vitro against cell lines of five colorectal carcinomas (CC), five gastric carcinomas (GC), and four non-small-cell lung carcinomas (NSCLC) using the colony-forming assay. At the concentration used in the experiments, LV alone failed to inhibit colony formation in any of the cell lines tested. The NSCLC cell lines were more resistant to FdUrd than were the CC and GC lines. LV modulated the cytotoxicity of FdUrd in all five CC lines and in three of the five GC lines but failed to do so in any of the NSCLC lines. In addition, following 20 h treatment with 1 microM [3H]-FdUrd, formation of the FdUMP/TS/mTHF ternary complex was enhanced by LV in the LV-sensitized CC and GC cell lines but not in the LV-refractory NSCLC lines. These in vitro data corresponded well to the results of clinical trials. Therefore, the colony-forming assay may be useful for the identification of the sensitivity of tumors according to phenotype.

Topics: Adenocarcinoma; Carcinoma, Non-Small-Cell Lung; Cell Survival; Colony-Forming Units Assay; Colorectal Neoplasms; Drug Synergism; Floxuridine; Fluorodeoxyuridylate; Fluorouracil; Leucovorin; Lung Neoplasms; Stomach Neoplasms; Tetrahydrofolates; Thymidylate Synthase; Tumor Cells, Cultured

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Dipyridamole; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Lung Neoplasms; Male; Middle Aged; Pilot Projects

Edatrexate (10-ethyl-10-deaza-aminopterin; CGP 30 694) is a methotrexate (MTX) analogue that shows promise against non-small-cell lung cancer (NSCLC) and other tumors. Since edatrexate's mechanism of action is the same as that of MTX, we used leucovorin in an attempt to alleviate its dose-limiting toxicity, stomatitis. In four patients with NSCLC who had experienced significant stomatitis after treatment with edatrexate, cyclophosphamide, and cisplatin, we observed a remarkable reduction in stomatitis following the administration of low-dose leucovorin. On the basis of the results obtained in these individuals, we treated 15 additional patients with this three-drug regimen plus leucovorin rescue. These subjects could tolerate the treatment with lesser degrees of stomatitis and received higher edatrexate doses in subsequent courses as compared with the patients who previously received this regimen without leucovorin rescue. This approach is expected to improve the therapeutic indices of edatrexate and edatrexate-containing chemotherapy regimens by modifying the dose-limiting toxicity of this antineoplastic agent.

Topics: Aminopterin; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Evaluation; Drug Tolerance; Female; Folic Acid Antagonists; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Stomatitis

The present study was designed to analyse the cytotoxic effects of the combination of fotemustine with 5-fluorouracil (5-FU) plus folinic acid (FA). Two human tumor cell lines were used; one line was derived from colon cancer (WIDR) and the other, from a non-small-cell lung cancer (CAL 12). Cytotoxic effects were assessed using the MTT (tetrazolium bromide) semi-automated test in 96-well incubation plates. The effects of various drug combinations were evaluated by the isobologram method. The drug combinations tested included fotemustine concentrations of 20, 30, 40, 50 and 70 micrograms/ml, 5-FU concentrations of 5, 15 and 30 micrograms/ml, and a constant FA concentration of 10(-5) M. A total of 180 different experimental conditions were tested. When cells were exposed to fotemustine prior to treatment with 5-FU, the final cytotoxic effects on both cell lines were additive or synergistic in the majority of cases (P less than 0.001). The 5-FU concentration was a determinant factor that modified the effects of the drug combination from antagonism (at low 5-FU concentrations) to synergism (high 5-FU concentrations; P less than 0.001). The addition of FA (10(-5) M) resulted in a significant shift towards synergistic associations in both cell lines. Administration of 5-FU prior to treatment with fotemustine caused marked antagonism, which 10(-5) M FA could not significantly shift towards simple additivity.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cell Line; Cell Survival; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Interactions; Drug Screening Assays, Antitumor; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Nitrosourea Compounds; Organophosphorus Compounds; Tumor Cells, Cultured

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Mouth Mucosa; Stomatitis; Vinblastine; Vinorelbine

Twenty-three patients with regionally advanced non-small cell lung cancer (NSCLC) (Stage III) were treated with continuous infusion 5-fluorouracil (5-FU) augmented by high-dose oral leucovorin and hydroxyurea and concomitant radiotherapy. This chemoradiotherapy regimen was administered during 5 days of every other week for six cycles (total radiation dose, 6000 cGy). Three patients (13%) had stable disease, 13 patients (57%) had a partial response (PR), and 1 patient (4%) had a complete response (CR). The overall response rate was 61% (95% confidence interval, 41% to 81%). At a median follow-up time of 19 months, the median survival time for all 23 patients was 12 months. The median time to disease progression was 6 months. Twelve patients have had disease progression outside of the chest, and only 3 patients have had intrathoracic disease progression as the site of first failure. The toxicities of this regimen consisted of mild to moderate myelosuppression and moderate degree dermatitis and mucositis. It was concluded that concomitant chemoradiotherapy with this regimen results in high local activity at acceptable toxicity. However, the systemic activity of this regimen was low, resulting in a high distant recurrence rate and a median survival time that was not different from that achieved with standard therapy. Therefore, its use, as defined in this study, cannot be recommended.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Combined Modality Therapy; Drug Administration Schedule; Drug Evaluation; Female; Fluorouracil; Follow-Up Studies; Humans; Hydroxyurea; Leucovorin; Lung Neoplasms; Male; Middle Aged; Pilot Projects; Radiotherapy Dosage

Fourteen patients with inoperable or recurrent non-small cell lung cancer (NSCLC) were treated with 5-fluorouracil (5-FU) plus high-dose leucovorin (LV). The administration schedule was 2 h infusion of LV at a dose of 500 mg/m2 and 30 min infusion of 5-FU at a dose of 600 mg/m2 given 1 h after the start of the LV infusion. This regimen was followed weekly, six times. No objective (complete or partial) response was seen in any of the patients. Ten patients showed no change and there were four with progressive disease. One patient experienced grade 3 leukopenia after two courses of treatment. Another experienced grade 2 leukopenia. One patient experienced grade 2 vomiting and six, skin pigmentation. Other myelosuppressive effects and non-hematologic toxicities, including diarrhea and mucositis, were mild. It was concluded that the schedule of 5-FU with high-dose LV therapy employed could not be expected to produce a response rate greater than or equal to 20% against NSCLC. 5-FU plus high-dose LV therapy was, therefore, considered to be ineffective against NSCLC with the schedule of administration followed.

Topics: Adult; Aged; Carcinoma, Non-Small-Cell Lung; Drug Evaluation; Female; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged

We have carried out a phase II study evaluating the activity of a 5-fluorouracil drug combination in patients with advanced non-small-cell lung cancer. Patients were given 60 mg/m2 of methotrexate i.v. on day 1. On day 2, 750 mg/m2 of 5-fluorouracil was administered as a 24-h infusion daily for 3 days. Also on day 3, 10 mg/m2 of mitomycin was given i.v. along with folinic acid. Folinic acid was started on day 3 initially at a dose of 25 mg/m2 intravenously every 6 h for three doses, followed by a 2-h infusion of 200 mg/m2 daily on days 3 and 4. Therapy was repeated every 28 days. Fourteen of 35 patients (40%) experienced a partial response to chemotherapy. The median survival of the entire group was 19 weeks. Mucositis was a common side effect but severe leukopenia, anemia, renal insufficiency, and skin ulceration were rare. This study demonstrated that 5-fluorouracil infusion therapy has activity in advanced non-small-cell lung cancer but the responses are not durable. Further studies evaluating differing dose schedules and alternate 5-fluorouracil infusion-based drug combinations seems warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Drug Evaluation; Female; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Male; Methotrexate; Middle Aged; Mitomycins; Neoplasm Staging