Phase II study of biweekly irinotecan and mitomycin C combination therapy in patients with fluoropyrimidine-resistant advanced colorectal cancer

PURPOSE: Experimental studies have shown that mitomycin C (MMC) acts synergistically with irinotecan. We evaluated the antitumor activity and toxicity of a combination of irinotecan and MMC in patients with metastatic colorectal cancer resistant to fluoropyrimidines. METHODS: Eligible patients had evidence of tumor progression while receiving fluoropyrimidine-based regimens or had disease recurrence within 6 months after the completion of adjuvant treatment with fluoropyrimidines. Irinotecan (150 mg/m(2)) and MMC (5 mg/m(2)) were administered on days 1 and 15 of a 28-day cycle. Treatment was repeated every 4 weeks. RESULTS: Among the 41 patients enrolled, 37 (90%) had received previous chemotherapy for metastatic disease, and 4 had received adjuvant chemotherapy alone. Objective responses were observed in 14 patients (34%, 95% confidence interval 20-49%). The median time to progression was 4.2 months, and the median survival time was 11.9 months. The study treatment was well tolerated; the median number of cycles received was four. Grade 3 or 4 neutropenia, the most common toxic effect, occurred in 20 patients (49%). Grade 3 or 4 thrombocytopenia occurred in four patients (10%) and grade 3 diarrhea in one patient. CONCLUSIONS: Our results suggest that irinotecan and MMC combination therapy is effective and well tolerated in patients with fluoropyrimidine-resistant metastatic colorectal cancer. Further clinical investigation of this regimen is warranted.     

Phase I-II study of irinotecan in combination with mitomycin C in patients with advanced gastrointestinal cancer

This phase I-II study was conducted to determine the maximum tolerated dose and optimal schedule of a combination of irinotecan (CPT 11) and mitomycin C (MMC) in a population of previously treated patients with gastrointestinal malignancies. Four cohorts of patients were recruited with MMC given at 8 mg/m2 for the first 3 levels together with irinotecan at 300 mg/m2, 325 mg/m2, and 350 mg/m2; the fourth dose level was given with MMC at 10 mg/m2 and irinotecan at 325 mg/m2. All treatment was repeated at 21-day intervals. The dose-limiting toxicity was hematologic (thrombocytopenia at level 4), and the recommended doses for subsequent phase II studies are MMC 8 mg/m2 with irinotecan 325 mg/m2. Evidence of efficacy was seen at all dose levels examined and justifies further exploration of this combination in a less heavily pretreated patient population.     

Phase II study of capecitabine and mitomycin C as first-line treatment in patients with advanced colorectal cancer

This study was designed to assess the safety and efficacy of capecitabine and mitomycin C (MMC) in previously untreated patients with advanced colorectal cancer (CRC). Patients received capecitabine 2500 mg m(2) day 1, orally divided in two doses of 1250 mg m(-2) in the morning and evening for 14 days every 21 days and MMC 7 mg m(-2) (maximum total dose 14 mg) as an intravenous bolus every 6 weeks for a total of four courses. The median age was 70 years (range 24-85) and the majority of patients (86.9%) were of performance status 1/2. The most common metastatic site was liver. In all, 84 patients were assessable for response. The overall response rate was 38% (95% CI: 27.7-49.3) and a further 33.3% of patients achieved stable disease over 12 weeks. There was good symptom resolution ranging from 64 to 86%. Grade 3/4 toxicity was as follows: hand-foot syndrome 19.7%; diarrhoea 10%; neutropenia 2.4%; infection 2.3%. Capecitabine and MMC have shown encouraging activity with a favourable toxicity profile, a convenient administration schedule, and could be considered for patients deemed unsuitable for oxaliplatin and irinotecan combinations.     

Randomized phase II study of irinotecan plus mitomycin C vs. oxaliplatin plus mitomycin C in patients with advanced fluoropyrimidine/leucovorin-pretreated colorectal cancer

Introduction: Irinotecan and oxaliplatin are two new agents with promising activity in advanced colorectal cancer. Based on preclinical and clinical evidence that both drugs might act synergistically with mitomycin C, a randomized study using a 'pick the winner' design was undertaken to determine the effectiveness and tolerance of these two combination schedules in patients with fluoropyrimidine/leucovorin-pretreated advanced colorectal cancer. Patients and Methods: Sixty-four patients with metastatic colorectal cancer, who progressed while receiving or within 6 months after discontinuing palliative chemotherapy with fluoropyrimidines/leucovorin were enrolled onto this study. They were randomly assigned to treatment with irinotecan 120 mg/m ² on days 1+15 plus mitomycin C 8 mg/m2 on day 1 (arm A) or oxaliplatin 85 mg/m ² on days 1+15 plus mitomycin C 8 mg/m2 on day 1 (arm B). In both treatment arms, courses were repeated every 4 weeks. Results: The objective response rate in arm A is 7/33 (21.2%; 95% confidence interval, 9.0-38.9%) as compared to 5/31 in arm B (16.1%; 95% CI, 5.5-34.7%). Stable disease was noted in 48.5 vs. 45.2%, whereas the tumor progressed in 30.3 vs. 38.7%, respectively. Similar to the recorded response activities, the difference of the two combination regimens in terms of median time to progression (7.0 vs. 5.2 months) and overall survival (12.0 vs. 11.2 months) was only minor and clincally insignificant. The tolerance of treatment was acceptable in both arms, though severe adverse reactions requiring dose reductions (30 vs.16%) and treatment delays (22 vs. 13% of courses) were more commonly noted with irinotecan/mitomycin C. The most common toxicities in arm A were neutropenia (85%; WHO grade 3/4 in 33%), thrombocytopenia (52%), diarrhea (45%), emesis (52%) and alopecia (92%). In arm B, common toxicities included neutropenia (68%; grade 3/4 in 13%), thrombocytopenia (81%), emesis (52%), and peripheral neutropathy (48%). Conclusions: Both mitomycin C combination regimens seem to provide an acceptable therapeutic index in patients with fluoropyrimidine/leucovorin-pretreated metastatic colorectal cancer. In view of the increasing need for a broader chemotherapeutic armentarium for second-line therapy of this common malignant disease, both regimens may be worthwhile to undergo further clinical investigation.     

Phase II study of capecitabine and irinotecan combination chemotherapy in patients with advanced gastric cancer

The present study was conducted to evaluate the efficacy and safety of a combination regimen of capecitabine plus irinotecan in patients with advanced gastric cancer. Patients with previously untreated metastatic or recurrent, measurable gastric cancer received oral capecitabine 1000 mg m(-2) twice daily from day 1 to 14 and intravenous irinotecan 100 mg m(-2) on days 1 and 8, based on a 3-week cycle. Forty-one patients were enrolled in the current study, among whom 38 were assessable for efficacy and 40 assessable for toxicity. Three complete responses and 16 partial responses were confirmed, giving an overall response rate of 46.3%. At a median follow-up of 269 days, the median time to progression and overall survival were 5.1 and 8.6 months, respectively. Grade 3/4 neutropenia occurred in four patients and grade 3 febrile neutropenia was observed in two patients. Grade 3 diarrhoea and grade 2 hand-foot syndrome occurred in six patients and eight patients, respectively. The combination of capecitabine and irinotecan was found to be well tolerated and effective in patients with advanced gastric cancer. Accordingly, this regimen can be regarded as one of first-line treatment options for advanced gastric cancer.     

Chemotherapy with mitomycin C and capecitabine in patients with advanced colorectal cancer pretreated with irinotecan and oxaliplatin

AIMS AND BACKGROUND: To assess the activity and tolerability of the combination of mitomycin C and capecitabine in patients with metastatic colorectal cancer after failure of irinotecan and oxaliplatin-containing regimens. METHODS: We retrospectively reviewed 28 patients with pretreated advanced colorectal cancer who had been treated with mitomycin C, 6 mg/m2 on day 1, and capecitabine, 1900 mg/m2 on days 1-14, every 3 weeks. Tumor assessment was performed every 3 cycles, toxicity assessed at each cycle. RESULTS: Main patient characteristics were median age, 61 years (range, 35-73); male/female ratio, 16/12; single metastatic site involvement, 5/28 (18%); > or =3 metastatic sites, 10/28 (36%). Ninety-six courses of therapy were given (median number, 3; range, 1-9). Twenty-six patients were assessable for response, and all were assessable for toxicity. There was 1 partial response (4%) and 12 had stable disease (43%). Median time to progression was 2 months (range, 1-9) and median overall survival was 6 months (range, 1-29+), with a 1-year overall survival rate of 25%. The regimen was very well tolerated without significant hematological toxicity. CONCLUSIONS: Our results are disappointing. Despite the good safety profile, they do not support further investigation or the routine use of this regimen in this setting.     

Phase II study of combination therapy with S-1 and irinotecan in patients with advanced colorectal cancer.

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

Phase II study of irinotecan, 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer

BACKGROUND: We evaluated the efficacy and tolerability of a modified biweekly irinotecan, 5-fluorouracil and leucovorin regimen (modified Douillard regimen) as the first-line therapy in patients with advanced colorectal cancer. METHODS: A total of 80 patients (41 male, 39 female) with recurrent or metastatic colorectal cancer were enrolled between April 2001 and December 2003. The treatment cycle consisted of irinotecan 150 mg/m(2) as a 90 min infusion on day 1, leucovorin 20 mg/m(2) intravenous bolus, immediately followed by a 48 h continuous infusion of 5-fluorouracil 3000 mg/m(2) on day 1. The primary end-point was response rate, and the secondary end-points were time to progression and toxicity profile. RESULTS: An overall objective response rate of 38.7% [95% confidence interval (CI) 27.84-49.66%] was achieved. The median time to progression was 6.1 months (95% CI 4.63-7.57 months) and the median overall survival time was 20.2 months (95% CI 15.50-24.90 months). The median duration of follow-up for patients was 16.9 months. The toxicity profile was more favorable than for the conventional Douillard regimen. CONCLUSION: We conclude that the modified Douillard regimen may be a practical and more tolerable treatment option in patients with advanced colorectal cancer.     

Phase II study of irinotecan as first-line chemotherapy for patients with advanced colorectal carcinoma

BACKGROUND: The objective of this multicenter, open-labeled, Phase II study performed in Spain was to assess the efficacy and safety of irinotecan (CPT-11) as first-line chemotherapy for patients suffering from advanced colorectal carcinoma (CRC). METHODS: Patients with histologically proven CRC and at least one bidimensionally measurable lesion, ages 18-70 years, with a performance status < or = 2, normal analytical values, and no prior chemotherapy or only adjuvant chemotherapy completed before study entry were selected. The treatment schedule was CPT-11 350 mg/m(2) intravenously administered once every 3 weeks. Both tumor response and toxicity were assessed using the World Health Organization and National Cancer Institute common toxicity criteria. Changes in performance status, weight, and symptoms also were measured. RESULTS: Sixty-five patients (44 chemotherapy-na?ve patients and 21 patients who completed prior adjuvant treatment) were enrolled. Of these, 24.7% of patients responded to the treatment, and 41.5% of patients had stable disease. Patients who had not received prior adjuvant chemotherapy had a lower rate of progression on therapy (27.3%) compared with those who had received prior adjuvant chemotherapy (42.9%). The median survival was 19.9 months (range, 0.3-29.3 months). No significant differences were found in the median survival between chemotherapy-na?ve patients and patients who had received previous chemotherapy. Grade 3-4 diarrhea and neutropenia were the most frequent severe toxic events, which were observed in 23.1% and 30.8% of patients and in 5.9% and 10.9% of the cycles, respectively. CONCLUSIONS: The current antitumor efficacy results show that 350 mg/m(2) of CPT-11 administered every 3 weeks is an active and feasible first-line chemotherapy regimen for patients with CRC. Finally, the overall safety data confirmed that CPT-11 is a well tolerated treatment.     

A multicenter phase II study of irinotecan in patients with advanced colorectal cancer previously treated with 5-fluorouracil

This multicenter, open-label, phase II study was performed to assess the efficacy and toxicity of irinotecan 350 mg/m2 intravenously every 3 weeks in patients with advanced colorectal cancer (CRC) previously treated with 5-fluorouracil (5-FU). The study enrolled 115 patients and a total of 558 cycles (median, 6 per patient) were administered. The overall objective response rate on an intent-to-treat basis was 18% (with 1 complete response and 20 partial responses), whereas 42 patients (37%) showed stable disease. Median time to progression was 4.8 months and median survival was 13.6 months. Grade 3/4 toxicities included delayed diarrhea (19.1%), nausea/vomiting (10.4%), and neutropenia (8.7%). There were 2 toxic deaths, 1 from delayed diarrhea and 1 from hemorrhage and grade 4 mucositis. In conclusion, the present study confirms the antitumor efficacy of irinotecan monotherapy in patients with CRC pretreated with 5-FU.     

Phase I-II study of irinotecan combined with mitomycin-C in patients with advanced gastric cancer.

Background:Irinotecan (CPT-11) shows synergism withmitomycin-C (MMC) in a preclinical setting. The goals of this study wereto determine the maximum tolerated dose (MTD), the dose limitingtoxicity, the recommended dose (RD), and preliminary anti-tumor activityin a combined CPT-11 and MMC treatment of advanced gastric cancer. Patients and methods:The study was designed to evaluateescalated doses of CPT-11 and MMC administered every two weeks. Fiveescalating dose levels were studied (CPT-11/MMC: 100/5; 125/5; 150/5;150/7; 150/10 mg/m²). Results:Thirty-onepatients were enrolled. Thirty patients were assessable for toxicity andtumor response for 89 treatment cycles. The median age was 60 years(32–73 years), and most patients (90%) had a performancestatus of 0 to 1. Fourteen patients were previously treated and 17 werechemotherapy-naive. The MTD was CPT-11 150 mg/m² plus MMC 10mg/m², in which all three patients experienced grade 4neutropenia, including one episode of prolonged and one of febrileneutropenia, and one patient experienced grade 3 diarrhea during thefirst cycle. Fifteen partial responses were observed. Conclusions:The RD based on this phase I–II study wasCPT-11 150 mg/m² plus MMC 5 mg/m² administeredevery two weeks. This combination demonstrates promising activityagainst advanced gastric cancer and warrants further investigation inanother phase II study.     

Phase I/II study of first-line irinotecan combined with 5-fluorouracil and folinic acid Mayo Clinic schedule in patients with advanced colorectal cancer

Background  

This multicentre phase I/II study was designed to determine the maximum tolerated dose of irinotecan when combined with 5-fluorouracil and folinic acid according to the Mayo Clinic schedule and to evaluate the activity of this combination as first-line therapy in patients with advanced colorectal cancer.     

Phase II study of irinotecan and ifosfamide in patients with advanced non-small cell lung cancer

OBJECTIVES: This phase II study was conducted to investigate the efficacy and safety of irinotecan (CPT-11) and ifosfamide as first-line chemotherapy for advanced non-small cell lung cancer (NSCLC). METHODS: Eligibility criteria included histologically or cytologically confirmed NSCLC (stage IIIb or IV), no prior treatment, and measurable or evaluable disease. CPT-11 (80 mg/m(2)) was administered intravenously on days 1, 8, and 15, while ifosfamide (1.5 g/m(2)) was given on days 1 through 3 every 4 weeks. RESULTS: Forty-four patients (31 men) with a median age of 65 years (range 43-75) and a median ECOG performance status of 1 (range 0-2) were enrolled. The response rate was 29.5% [95% CI: 16.7-45.2%], with 13 partial responses. The median survival was 12.5 months, the median time to progression was 5.3 months, and the 1 and 2-year survival rates were 52.3 and 11.3%, respectively. Toxicity was generally mild; WHO grade 3-4 neutropenia was recorded in 38.6% of the patients, grade 3 diarrhea in 6.8%, and grade 3-4 nausea/vomiting in 0%. CONCLUSIONS: CPT-11 combined with ifosfamide demonstrated anti-tumor activity in advanced NSCLC, with response and survival rates similar to those of cisplatin-based chemotherapy but with a more favorable toxicity profile.     

Phase II study of flavopiridol in patients with advanced colorectal cancer.

BACKGROUND: Flavopiridol, a synthetic flavone that inhibits cell cycle progression, has demonstrated activity in colon cancer in xenografts and in a phase I trial. We evaluated flavopiridol in a phase II trial in patients with previously untreated advanced colorectal cancer (ACRC). PATIENTS AND METHODS: Twenty chemotherapy-na?ve patients with ACRC received flavopiridol at a dose of 50 mg/m(2)/day via a 72-h continuous infusion every 14 days. Response was assessed by computed tomography or magnetic resonance imaging every 8 weeks. RESULTS: Twenty patients were enrolled; 19 were evaluable for toxicity and 18 for response. There were no objective responses. Five patients had stable disease lasting a median of 7 weeks. The median time to progression was 8 weeks. Median survival was 65 weeks. The principal grade 3/4 toxicities were diarrhea, fatigue and hyperglycemia, occurring in 21%, 11% and 11% of patients, respectively. Other common toxicities included anemia, anorexia and nausea/vomiting. CONCLUSIONS: Flavopiridol in this dose and schedule does not have single-agent activity in patients with ACRC. Recent preclinical data suggest that flavopiridol enhances apoptosis when combined with chemotherapy. Trials that evaluate flavopiridol in combination with active cytotoxic drugs should help to define the role of this novel agent in ACRC.     

Treatment of advanced gastric cancer with 5-fluorouracil versus mitomycin C

Thirty-eight patients of advanced adenocarcinoma of the stomach were randomly administered intensive courses; of either 5-FU or mitomycin C by intravenous route, The 5-FU administration resulted in a slightly better response than mitomycin C, although the toxic effects of the two drugs were more or less the same. The selection of drug regime in the present study has been based on cost, availability, potential toxicity, and minimal alteration of the patients' life style.     

Phase II study of liposomal doxorubicin in patients with advanced colorectal cancer

Doxil is a liposomal preparation of doxorubicin that results in prolonged pharmacologic exposure in vivo to the active agent. We sought to test the hypothesis that this new formulation would result in improved efficacy in patients with colorectal cancer. Patients with advanced colorectal cancer who had received prior therapy were eligible for the trial. Treatment consisted of Doxil 45 mg/m2 intravenously every 3 weeks. Seventeen patients entered the trial and they received a median of two cycles of treatment. None of the patients had a partial response to treatment. Stable disease was the best response, and one patient received therapy for 17 cycles before her disease progressed. The therapy was well tolerated, with only two patients having the dose decreased because of hand-foot syndrome. Four patients experienced allergic reactions during the infusion, but with appropriate premedication and slowing of the infusion, treatment was able to be resumed without difficulty. No greater than grade I neutropenia or thrombocytopenia developed in any patient. Although Doxil was well tolerated at this dose and schedule, it was not an active agent in this group of patients. Doxil alone or in combination with other agents is worthy of further study in cancers responsive to doxorubicin.     

丝裂霉素加顺铂治疗难治性晚期乳腺癌

Objective： The mitomycin C and cisplatin combination was investigated in patients with advanced breast cancer who had been exposed to anthracyclines, vinorelbine and taxanes. Methods： Three-weekly regimen consisted of mitomycin, 6 mg/m^2 administered intravenously on day 1, and cisplatin, 25 mg/m^2 intravenously on day 1-3. Results： Thirty-eight patients aged 25-75 years （median, 46 years） were treated with an overall response rate of 31.6%. The median time to progression （TTP） was 4.0 months. Median TTP for 12 patients with a complete or partial response was 9.0 months, while stable disease and progression of disease 4.0 months, P=0.002. Grade 3/4 side effects of neutropenia, thrombocytopenia and nausea/vomiting were documented in 4 （10.5%）, 4 （10.5%） and 3 （7.9%） patients, respectively. The median overall survival was 13＊ months. Conclusion： Mitomydn C/cisplatin doublet showed antitumor activity for anthracydine-, vinorelbine- and taxane-resistant breast cancer comparable to other regimens. This well-tolerated regimen provides an affordable option for patients in China.