Impact of 5-fluorouracil rechallenge on subsequent response and survival in advanced colorectal cancer: pooled analysis from three consecutive randomized controlled trials

The aim of this analysis is to evaluate the effect of 5-fluorouracil (5-FU) rechallenge on subsequent response and survival in patients with advanced colorectal cancer (CRC). Between April 1992 and August 1998, 613 patients were enrolled into 3 consecutive prospective randomized controlled trials assessing first-line infused 5-FU in patients with advanced CRC. All patients had a planned maximum treatment period of 6 months. Those with responding or stable disease at the end of 6 months were observed off treatment. On subsequent disease progression, patients were retreated with 5-FU alone (5-FU group) or 5-FU plus mitomycin C (MMC group). Ninety-three patients have been retreated (5-FU group, n = 71; MMC group, n = 22). The median age was 60 years (range, 38-79 years), and the median time to rechallenge was 11.7 months (5-FU group, 11.7 months; MMC group, 11.4 months). Seventeen percent of patients had an objective response to rechallenge (5-FU group, 13%; MMC group, 27%). The median survival was 14.8 months (5-FU group, 15.2 months; MMC group, 10.5 months; log-rank test, P = 0.23) and the median failure-free survival was 5.4 months (5-FU group, 5.6 months; MMC group, 3.7 months; log-rank test, P = 0.06). On multivariate analysis, a prolonged treatment-free interval of > 12 months (hazard ratio [HR], 0.57; 95% CI, 0.35-0.94; P = 0.027) and good performance status of 0/1 (HR, 0.38; 95% CI, 0.22-0.68; P = 0.001) were associated with better overall survival. In conclusion, a proportion of patients who experienced a prolonged period of tumor control with first-line infused 5-FU therapy and had a planned treatment interruption, retained 5-FU sensitivity and had prolonged survival with 5-FU rechallenge.     

A phase III trial on the therapy of advanced pancreatic carcinoma. Evaluations of the Mallinson regimen and combined 5-fluorouracil, doxorubicin, and cisplatin

One hundred eighty-seven patients with histologically proven advanced pancreatic adenocarcinoma were randomly assigned to therapy with 5-fluorouracil (5-FU) alone, to the Mallinson regimen (combined and sequential 5-FU, cyclophosphamide, methotrexate, vincristine, and mitomycin C), or to combined 5-FU, doxorubicin, and cisplatin (FAP). Patients with both measurable and nonmeasurable disease were included and the primary study end point was survival. Among 41 patients with measurable disease, objective response rates were 7% for 5-FU alone, 21% for the Mallinson regimen, and 15% for FAP. The median interval to progression for each of the three regimens was 2.5 months. Survival curves intertwined with the median survival times for 5-FU alone and the Mallinson regimen at 4.5 months and for FAP at 3.5 months. Compared with 5-FU alone, both the Mallinson regimen and FAP produced significantly more toxicity. Neither the Mallinson regimen nor FAP can be recommended as therapy for advanced pancreatic carcinoma. Any chemotherapy for this disease should remain an experimental endeavor.     

Treatment of advanced-stage colorectal adenocarcinoma with fluorouracil and high-dose leucovorin calcium: a pilot study

Thirty-one evaluable patients with measurable advanced colorectal carcinoma were entered into a pilot study that used weekly fluorouracil (5-FU) at the dose of 600 mg/m2 by bolus infusion administered midway during a two-hour leucovorin calcium infusion of 500 mg/m2. This regimen was repeated weekly for six doses. Twenty-seven of these patients (87%) were considered to be refractory to prior 5-FU therapy and four (13%) were previously untreated. All 31 patients successfully completed at least one 6-week cycle of this regimen with acceptable toxicity. The combined complete (CR) and partial response (PR) rate was 45% with another 25% of patients remaining stable. The 95% confidence levels for the responding patients are 27.6% and 62.7%, respectively. The remaining 30% of the patients had all received prior 5-FU therapy and progressed. All of the responding patients and 80% of the patients with stable disease received two or more cycles of this regimen after a 3- to 4-week interval off therapy. The median time to disease progression was 16.1 months for responding patients and 6.7 months for those patients with stable disease. The median survival for the responders was 20.6 months and for those with stable disease 9.8 months. The median survival for the nonresponding patients was 3.9 months. Toxicity included diarrhea in 70% of patients, skin rash (erythema) in 10%, stomatitis in 15%, nausea and vomiting in 25%, and myelosuppression in 10%. This study confirms and extends previous observations that demonstrate the improved efficacy of 5-FU when used with high-dose leucovorin in advanced colorectal carcinoma.     

Mitomycin C plus infusional 5-fluorouracil in platinum-refractory gastric adenocarcinoma: an extended multicenter phase II study

OBJECTIVE: To assess the toxicity and activity of bolus mitomycin C (MMC) in combination with a 24-hour continuous infusion of 5-fluorouracil (5-FU) in gastric cancer patients who had received at least one prior chemotherapy regimen. PATIENTS AND METHODS: Patients were treated with MMC (10 mg/m(2)) on days 1 and 22, 5-FU (2.6 g/m(2)) as a 24-hour infusion, and folinic acid 500 mg/m(2) weekly for 6 weeks. RESULTS: Thirty-four patients with gastric cancer, 16 after failure of first-line chemotherapy and 18 after failure of at least two prior chemotherapies, were included. In the intent-to-treat analysis, 9 (26.5%) of the 34 patients had a partial response and 10 (29.4%) a disease stabilization (disease control rate 56%). The median time to progression was 3.3 months (CI95: 2.8-3.7), and the median overall survival was 7.2 months (CI95: 5.9-8.4). Grade III/IV thrombocytopenia occurred in 14.7% of patients (n = 5), while the most frequent nonhematological grade III/IV toxicities were mucositis and diarrhea, each affecting 9% of patients. CONCLUSIONS: As the tested regimen was generally safe and well tolerated by the patients, MMC plus infusional 5-FU/folinic acid may be a potential second-line regimen for patients with advanced gastric cancer.     

A phase II trial of 5-fluorouracil, doxorubicin, mitomycin C, and leucovorin in advanced gastric carcinoma

To determine the feasibility and toxicity of combining leucovorin (CF) with a 5-fluorouracil (5-FU) combination chemotherapy regimen currently accepted by many as standard treatment for gastric cancer, CF (500 mg/m2) was administered in combination with the Georgetown 5-FU, doxorubicin, and mitomycin C (FAM) regimen. Thirty-two patients with advanced adenocarcinoma of the stomach were evaluable for toxicity and 26 patients with measurable disease were evaluable for response. Fifty-four percent of patients were previously treated with chemotherapy or radiation therapy. The response rate was 38% (95% confidence interval, 21% to 59%). The median duration of response was 6 months (range, 2 to 23+ months). The estimated median survival time was 6.8 months for patients with measurable disease and 11.5 months for all 32 patients. Although diarrhea is dose limiting when 5-FU and CF are administered weekly for 6 of 8 weeks, diarrhea occurred rarely on this combination regimen with 5-FU and CF administered only 4 of every 8 weeks. The dose-limiting toxicity of FAM-CF was cumulative myelosuppression, which also occurs with the standard FAM regimen. As a result, the administered dose intensity of 5-FU decreased as patients continued on study. Thus, a randomized comparison of FAM with FAM-CF would not determine whether CF modulation increases the efficacy of 5-FU when it is administered in optimal doses to patients with gastric cancer.     

Protracted infusional 5-fluorouracil plus high-dose folinic acid combined with bolus mitomycin C in patients with gastrointestinal cancer: a phase I/II dose escalation study

The aim of this study was to define the maximum tolerated dose (MTD) of bolus mitomycin C (MMC) in combination with 24 h-continuous infusion of 5-flourouracil (FU) plus folinic acid, and to assess the toxicity and activity in patients with previously treated colorectal and gastric cancer. Escalating doses of MMC starting from 6 mg m(-2) in 2 mg m(-2)-steps to a maximum of 10 mg m(-2) were applied on days 1 and 22, given to fixed doses of 5-FU (2.600 mg m(-2)) as 24 h infusion and folinic acid 500 mg m(-2) prior to 5-FU weekly for 6 weeks. At least three patients were treated at each dose level. A total of 16 patients have been included in the phase I study. At the highest dose level (MMC 10 mg m(-2)), grade III thrombocytopenia, dyspnoea, mucositis and diarrhoea were observed in one patient each (17 %). In the phase II study 45 patients, 33 with colorectal cancer and 12 with gastric cancer, 23 patients after failure of first- and 22 patients after at least second-line or subsequent chemotherapy have been treated. Seven partial responses (PR) were registered (16%), one (3%; CI(95%), 0-16) in colorectal and six (50%; CI(95%), 21-79%) in gastric cancer patients. In all, 17 (38%) achieved disease stabilisation, 15 colorectal (45%, CI(95%), 28-64%) and two gastric cancer patients (17%; CI(95%), 2-48%). The median progression-free survival was 3.1 months (range, 0.9-9.1) in colorectal and 4.6 months (range, 0.7-12.4) in gastric cancer. The median overall survival time was 6.6 months (range, 1.9-15.6) in colorectal and 7.1 months (range, 1.7-20.8) in patients with gastric cancer. This regimen was considered to be safe and well tolerated for pretreated patients with gastrointestinal adenocarcinoma. In gastric cancer,MMC plus infusional 5-FU/folinic acid may be a potential second-line regimen with promising antitumour activity.     

Phase II trial of combination chemotherapy of colonic cancer with 5-fluorouracil, mitomycin C, and hexamethylmelamine

HexMF consists of hexamethylmelamine 150 mg/m2 D2-15, mitomycin C (MMC) 10 mg/m2 D2 and 5-fluorouracil (5-FU) 30 mg/kg/day as a continuous infusion D1-5 in 4-5 week cycles. It was designed as an alternative to treating patients with standard single agents in sequence, thereby preventing the testing of new drugs as part of primary therapy. Median survival was 12+ months for patients with measurable and 18+ months for patients with nonmeasurable colorectal cancer. It was 9+ months from the onset of secondary chemotherapy. Toxicity included severe thrombocytopenia (50%), severe leukopenia (25%), and moderate stomatitis (50%). Only one instance of leukopenia was life-threatening. The MMC and 5-FU infusion skeleton provides an attractive strategy for testing new drugs as primary therapy. HexMF itself has a potentially broad antitumor spectrum and excellent acceptance by patients. It is suitable for additional phase II trials.     

Randomized trial of 5-fluorouracil and mitomycin C with or without streptozotocin for advanced pancreatic cancer. A Southwest Oncology Group study

A prospective randomized trial comparing streptozotocin, mitomycin C, and 5-FU (SMF) with mitomycin C and 5-FU (MF) in patients with advanced pancreatic cancer was performed. In patients with measurable disease the response rates were 34% (19/56) to SMF, and 8% (5/60) to MF (P = 0.009). Median survivals were similar, however, 18 versus 17 weeks (P = 0.356). Median survival of patients responding to chemotherapy was 33 weeks, and for nonresponders it was 17 weeks (P = 0.002). In patients with nonmeasurable disease, median survivals were 21 weeks (SMF) and 18 weeks (MF) (P = 0.797). Patients surviving greater than or equal to 48 weeks, however, appeared to be increased in the SMF arm (14 patients) compared to the MF (7 patients). Toxicity was moderate for both regimens, with SMF having greater gastrointestinal and renal toxicity. Chemotherapy with SMF appears to produce objective responses in patients with pancreatic cancer, but does not improve survival compared to MF.     

Alternative bimonthly cycles of doxorubicin, cyclophosphamide, and etoposide, cisplatin with hematopoietic growth factor support in patients with carcinoma of unknown primary site

BACKGROUND: Because carcinomas of unknown primary origin are highly malignant tumors with a bad prognosis (median survival, 6-12 months) and no current optimal therapy, the authors designed a prospective dose-dense chemotherapy regimen with the objective of improving the results observed in patients who receive conventional treatment. METHODS: Eighty-two patients received alternative bimonthly cycles of doxorubicin 50 mg/m(2) with cyclophosphamide 1000 mg/m(2) (AC) and etoposide 300 mg/m(2) with cisplatin 100 mg/m(2) (EP). Cycles were given at 2-week intervals with granulocyte-macrophage-stimulating factor support (5 microg/kg per day) from Day 4 to Day 10. Patients without measurable lesions were included, because the major end point was survival. RESULTS: The median number of alternative cycles of AC and EP was 4 cycles (range, 1-12 cycles). An objective response was observed in 24 of 62 patients (39%; 95% confidence interval, 30-48%) with measurable lesions, including 6 patients who achieved a complete response. Among 20 patients with nonmeasurable disease, 9 patients (45%) had no evidence of progressive disease at the end of chemotherapy. The overall median survival of 82 patients was 10 months, with 5 patients surviving clinically disease free at 17 months, 29 months, 45 months, 64 months, and 70 months after the end of treatment. Myelosuppression was the most common toxicity. Two toxic deaths occurred. CONCLUSIONS: Using these doses and schedules, a dose-dense chemotherapy regimen did not appear to improve the outcome of patients with carcinoma of unknown primary site. Alternative studies dealing with news drugs will be required.     

5-Fluorouracil plus leucovorin in women with metastatic breast cancer. A phase II study

Because leucovorin increases the antitumor activity of 5-fluorouracil (5-FU) in multiple tumor model systems, we performed a clinical trial to evaluate this combination in women who had received one or no prior chemotherapy regimens for metastatic breast cancer. Thirty-six women with measurable metastatic disease were treated with five consecutive days of i.v. leucovorin, 500 mg/m2/day infused over 30 min, followed 1 h later by i.v. bolus 5-FU, 375 mg/m2/day. Repeat cycles were planned at 4-week intervals. Tumor regression occurred in 10 of 36 patients (28%; 95% confidence interval, 14-45%) with a median time to disease progression (TTP) of 8.7 months (range 3.2-16.8 months) in the responding patients. The median TTP and survival for all patients were 3.0 and 12.4 months, respectively. Among 30 patients who had received prior 5-FU, tumor regressions were seen in seven (23%; 95% confidence interval 10-42%). The major dose-limiting toxicity in this study was mucositis, affecting 89% of the patients. Other toxicities were tolerable in the majority of patients. Although the role of leucovorin in breast cancer clinical practice remains undefined, the data from this trial support the hypothesis that leucovorin enhances the cytotoxic activity of 5-FU against human breast cancer.     

Phase II study of epirubicin, mitomycin C, and 5-fluorouracil in hormone-refractory prostatic carcinoma

Management of metastatic prostatic carcinoma when it becomes refractory to hormonal therapy is controversial, and no standard treatment exists. Nevertheless, chemotherapy for hormone-refractory prostatic carcinoma (HRPC) has shown some advantages compared with the best supportive care. In a prospective phase II study, we evaluated the combination of epirubicin (E), mitomycin C (MMC), and 5-fluorouracil (5-FU) in patients with HRPC. Twenty-eight patients with HRPC were treated with a combination of E (30 mg/m2), 5-FU (750 mg/m2), and MMC (5 mg/m2) day 1 and 2, every 4 weeks. Treatment was continued until evidence of disease progression or excessive toxicity. Patients were monitored with serial measurements of prostate-specific antigen (PSA). Forty-seven percent of the patients exhibited a reduction of serum PSA concentration and an objective response; 38% exhibited disease stability, and 15% had disease progression. Toxicity was substantial. The median time to progression was 7.3 months (range, 1.7-16.8 months) and median survival was 14.5 months (range, 1.6-38.4 months). Performance status improved in 80% of patients, and bone pain was relieved in 70%. Thus the combination of E, MMC, and 5-FU shows activity in the treatment of HRPC, giving substantial palliation of symptoms. In one patient, PSA values remained low even when the tumor had progressed.     

Long-term survival of patients with advanced colorectal cancer may not be due to the response to chemotherapy

Our primary objective was to determine the median and overall survival and secondarily the response rate to first- and second-line chemotherapy of patients with advanced colorectal metastatic disease. Three-hundred and seventy-nine patients (median age 60 years, range 30-87 years) were enrolled from April 1993 to March 2000. Median follow-up was 6 years (range 3-10 years), until July 2003. All patients were evaluable for survival and 342 were evaluable for response and toxicity. Thirty-seven patients did not undergo chemotherapy. All patients had confirmed histology as well as metastatic disease based on radiological tests. First-line treatment was administered to 342 patients: leucovorin (LV) 30 mg/m2 and 5-fluorouracil (5-FU) 425 mg/m2. Three different combinations were given as second-line treatment during different chronological periods: i) 5-FU, mitomycin-C and doxorubicin (FAM); ii) 5-FU and cisplatin (CDDP) and iii) 5-FU, LV and irinotecan (CPT-II). Responses were observed as follows: first-line treatment 16.37%, after FAM 25%, following 5-FU-CDDP 26.83% and after 5-FU-LV-CPT-II, 30.61%. Survival of all patients was as follows: median 25 months (range 16.1-33.9 months). The longest survival was of patients on 5-FU-LV-CPT-II. Median survival of patients with stable disease was 19 months and of untreated patients 12 months. Patients with advanced colorectal cancer have a long median (25 months) and overall survival, despite low responsiveness to chemotherapy.     

Mitomycin-C and capecitabine as third-line chemotherapy in patients with advanced colorectal cancer: a phase II study

Purpose The aim of this study was to investigate the therapeutic value and safety of third-line treatment with mitomycin-C (MMC) and capecitabine (Xeloda) in patients with advanced colorectal cancer pretreated with combination regimens including 5-fluorouracil (5-FU), folinic acid (FA) and irinotecan (CPT-11) or 5-FU, FA and oxaliplatin (L-OHP).Patients and methods A total of 21 patients (M/F 16/5, median age 60.0 years) with advanced colorectal cancer, all of whom had developed progressive disease while receiving or within 6 months of discontinuing two sequential chemotherapy lines with 5-FU, FA and CPT-11 or 5-FU, FA and L-OHP, were accrued to this study. At the time of their relapse or progression, cytotoxic chemotherapy, consisting of intravenous MMC 7 mg/m² on therapeutic day 1 plus oral capecitabine 1000 mg/m² twice daily on days 1–14, was initiated. After rest for 7 days, capecitabine 1000 mg/m² twice daily was administered on days 22–35 followed by 7 days rest. Treatment courses were repeated every 6 weeks unless there was evidence of progressive disease, unacceptable toxicity or patient refusal of treatment.Results All the patients were assessable for toxicity and 19 for response. The median number cycles of chemotherapy was two (range one to four). Only 1 patient (4.8%) had a partial response, 4 patients (19.0%) had stable disease, and 14 patients (66.7%) progressed. The median follow-up period was 7.3 months and median time to progression was 2.6 months. The median overall survival was 6.8 months. No toxic deaths occurred. Toxicities of third-line treatment were mild and manageable. As NCI/NIH common toxicity criteria, grade 3/4 anemia, neutropenia and thrombocytopenia occurred in two, one and one patients, respectively.Conclusion Our findings suggest that the combination of MMC and capecitabine in patients with advanced colorectal cancer pretreated with combination regimens including 5-FU, FA and CPT-11 or 5-FU, FA and L-OHP is safe. However, this regimen had a poor response rate and no definitive contribution to increasing patients overall survival time. Further evaluation of other salvage regimens seems to be warranted.     

High-dose 5-fluorouracil / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study

BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, FA and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose 5-FU/FA and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose 5-FU/FA/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur.     

Evaluation of two modified ECF regimens in the treatment of advanced gallbladder cancer

Gallbladder cancer is a rare disease and it is associated with a poor clinical outcome and survival. A standard therapy for it has not been established yet. The aim of this study is to evaluate efficacy and safety of two modified ECF regimens in advanced gallbladder cancer patients. Clinical data of 38 patients with advanced gallbladder cancer treated with modified ECF regimen were reviewed retrospectively. Of them, 21 patients received an epirubicin, cisplatin, and 5-FU/LV combination therapy. Seventeen patients received a chemotherapy of epirubicin, cisplatin, and capecitabine. Partial response was achieved in fourteen (36.84%) patients with a median duration of 5 months (range, 3-13 months), while stable disease was achieved in eight patients (21.05%). The median time to progression was 4.0 months (95% CI, 3.62-4.58 months). And the median overall survival was 9.8 months (95% CI, 7.26-12.34 months). Responders demonstrated better survival than non-responders (median survival time: 16 vs. 6.9 months, P = 0.008). The median survival time for epirubicin-, cisplatin- and capecitabine-treated patients was 9.2 versus 8.9 months for epirubicin-, cisplatin- and 5-FU/LV-treated patients. There was no statistical difference between both treatment groups in terms of survival time (P = 0.769). Regimen-related toxicity resulted in at least one treatment delay or dosage reduction in 63.2 and 34.2% patients, respectively. There were no chemotherapy-related deaths during the study. Modified ECF regimen with epirubicin, cisplatin and 5-FU/LV or substituting capecitabine for 5-FU/LV is still a potentially effective therapeutic chemotherapy for patients with advanced gallbladder cancer, and toxicity was manageable. There was no remarkable difference in efficacy between the two regimens.     

Infusional 5-fluorouracil and mitomycin C: an effective regimen in the treatment of advanced gastric cancer

BACKGROUND: Weekly infusional 5-fluorouracil (5-FU) and folinic acid (FA) as part of multi-drug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective with low toxicity. The present analysis was carried out to evaluate the safety and efficacy of 5-FU/FA in combination with 3-weekly mitomycin C (MMC) in patients with advanced gastric cancer. PATIENTS AND METHODS: A total of 28 patients with AGC were analysed (first line n=23). They received weekly 24-h 5-FU 2,600 mg/m2 preceded by 2-h FA 500 mg/m2 for 6 weeks followed by a two week rest period. Bolus MMC 10 mg/m2 was applied on days 1 and 22. Patient characteristics were: m/f 17/11; median age 67 years (43-79). The most common metastatic sites were liver and peritoneum (n=12, respectively). RESULTS: A median of 3 and a total of 91 cycles were administered. Mean dose intensity in cycle I was: 5-FU 86%, MMC 87%. Responses were observed in 43%, no change was seen in 29% of the patients. Median overall survival was 9.7 months (10.7 months for patients treated first line). Non-haematological toxicities (NCI CTC grades 3 and 4) were observed in 2 patients, leukopenia and thrombocytopenia grades 3/4 were observed in 50 and 25% of the patients, respectively. CONCLUSIONS: Infusional 5-FU/FA plus MMC may safely be used in patients with AGC in the routine clinical setting. This regimen yields response rates and survival data comparable to platinum-based regimen.     

Retrospective comparison of single-agent chemotherapy with weekly 5-fluorouracil or weekly irinotecan in previously treated patients with metastatic colorectal cancer

This study is a retrospective analysis of response, toxicity and freedom from progression of two single-agent chemotherapy regimens in patients with previously treated metastatic colorectal cancer. Thirty-five patients with histologically confirmed measurable metastatic colorectal cancer received chemotherapy after failure of first-line 5-fluorouracil (5-FU) and leucovorin treatment. The median age was 61 years. Twenty-seven patients had liver metastases, 6 had local recurrence, 1 had retroperitoneal lymph node metastases and 1 had lung metastases. Eighteen patients received weekly 2600 mg/m2 5-FU and 17 patients received weekly 125 mg/m2 irinotecan (CPT-11). Treatment was given until disease progression. Total number of cycles was 202 for 5-FU and 248 for CPT-11. The relative dose intensity was 1.0 for 5-FU and 0.84 for CPT-11. No grade 3-4 toxicity was registered in patients who received 5-FU. Grade 3-4 toxicity rates were as follows in those who received CPT-11: vomiting 1 (5.9%) patient in 1 cycle, diarrhea 3 (17.7%) patients in 3 cycles and neutropenia in 3 (17.7%) patients in 3 cycles. No patients manifested febrile neutropenia. Two patients (11.8%) needed hospital admission because of toxicity: 1 for vomiting and 1 for diarrhea. No objective responses were observed in the 5-FU group of patients. Three patients (17.6%) who received CPT-11, achieved partial response with a median duration of 8 months. Stable disease was registered in 3 (17.6%) and 9 (52.9%) patients in 5-FU and CPT-11 groups respectively (p=0.05). Median time to progression was 3.3 months for patients who received 5-FU and 4.2 months for those treated with CPT-11 (not significant). One-year survival was 22.2% and 54.3% respectively (p=0.05). Conclusion: Weekly chemotherapy with CPT-11 is tolerated with acceptable toxicity and leads to a better response rate than weekly high dose 5-FU. It also significantly improves survival but does not prolong freedom from progression.     

Folinic acid, 5-fluorouracil and mitomycin C in metastatic breast cancer patients previously treated with at least two chemotherapy regimens

PURPOSE: To assess the activity and safety of combined folinic acid (FA), 5-fluorouracil (5-FU) and mitomycin C (MMC) in metastatic breast cancer patients previously treated with at least two chemotherapy regimens. PATIENTS AND METHODS: A total of 104 consecutive patients were enrolled for treatment with FA 100 mg/m(2) plus 5-FU 400 mg/m(2) i.v. on days 1-5, and MMC 3 mg/m(2) on days 3-5 (FFM). The cycles were repeated every 21 days until progression, severe toxicity or patient refusal. RESULTS: Of the 104 patients, 96 were evaluable for response and toxicity. The overall response rate was 43% (95% confidence interval 32.8-53.2%); 40 patients achieved stable disease (42%) and 15 progressed (15%). In a retrospectively defined subgroup of patients with clinical resistance to taxanes (12 patients) or anthracyclines (14 patients), the response rate was 42%. The median time to progression was 8 months (3-18 months), and the median overall survival was 10.5+ months (2-36 months). The most common treatment-related adverse events were stomatitis, neutropenia, nausea/vomiting and diarrhea. Stomatitis, neutropenia and thrombocytopenia were the only grade 4 treatment-related adverse events, and occurred in no more than 3% of patients. CONCLUSION: The tested FFM regimen seems to offer a valid option for patients with metastatic breast cancer who have been pretreated with two or more chemotherapeutic lines or who have failed on regimens containing anthracyclines or taxanes.     

Extensive cytoreductive surgery followed by intra-operative hyperthermic intraperitoneal chemotherapy with mitomycin-C in patients with peritoneal carcinomatosis of colorectal origin

Peritoneal seeding from colorectal cancer has a very poor prognosis and is relatively resistant to systemic chemotherapy. We performed a phase I/II trial to investigate the feasibility and effectiveness of extensive cytoreductive surgery in combination with intra-operative hyperthermic intraperitoneal chemotherapy (HIPEC) in these patients. 29 patients with peritoneal carcinomatosis of colorectal origin without evidence of distant metastases underwent cytoreductive surgery and intra-operative HIPEC with mitomycin-C (MMC), followed by systemic chemotherapy with 5-fluorouracil (5-FU)/leucovorin. Surgical complications occurred in 11 patients (38%). One patient died directly related to the treatment, resulting in a mortality rate of 3%. MMC toxicity existed mainly of leucocytopenia (in 15 patients; 52%). After a median follow-up of 38 months (range 26-52 months) we found a 2- and 3-year survival rate (Kaplan-Meier) of 45 and 23%, respectively. Extensive cytoreductive surgery and HIPEC is feasible in patients with peritoneal seeding of colorectal cancer. First results suggest that a higher median survival could be achieved compared with conventional palliative surgery and systemic chemotherapy, therefore a randomised phase III study is now being conducted.     

A phase I/II study of leucovorin, carboplatin and 5-fluorouracil (LCF) in patients with carcinoma of unknown primary site or advanced oesophagogastric/pancreatic adenocarcinomas.

Carcinoma of unknown primary site (CUPS) accounts for 5-10% of all malignancies. Forty patients with metastatic CUPS or advanced oesophagogastric/pancreatic adenocarcinomas were recruited. Eligibility included ECOG performance status 0-2, minimum life expectancy of 3 months and measurable disease. The regimen consisted of bolus intravenous 5 fluorouracil (5-FU) and leucovorin (20 mg m-2) days 1-5 and carboplatin (AUC5) on day 3. The leucovorin/carboplatin/5-FU (LCF) was repeated every 4 weeks. The starting dose of 5-FU was 350 mg m-2 day-1 with escalation to 370 and then 400 mg m-2 day -1 after the toxicity at the previous level had been assessed. The maximum tolerated dose (MTD) was defined as the dosage of 5-FU that achieved 60% grade 3/4 toxicity. In addition, objective and symptomatic responses, quality of life and survival were assessed. The MTD of 5-FU in the LCF regimen was 370 mg m-2. The predominant toxicity was asymptomatic marrow toxicity. The 350 mg m-2 level was then expanded. There were two toxic deaths due to neutropenic sepsis, one at 370 mg m-2 after one course and one at 350 mg m-2 after four courses. The objective response rate was 25% with one complete response (CR) and nine partial responses (PRs). The median duration of response was 3.4 months (range 1-10). The CR and eight of the nine PRs were in CUPS patients. Twelve patients developed progressive disease on LCF. Median survival for all 40 patients was 7.8 months (10 months median survival for those treated at 350 mg m-2). The majority of patients described a symptomatic improvement with LCF chemotherapy. The recommended dose of 5-FU for future studies is 350 mg m-2 combined with leucovorin 20 mg m-2 and carboplatin (AUC5).