A phase II study of modified deGramont 5-fluorouracil, leucovorin, and oxaliplatin in previously treated patients with metastatic colorectal cancer

Purpose: To evaluate the toxicity and efficacy of a modified deGramont regimen of 5-fluorouracil (5-FU), leucovorin, and oxaliplatin in patients with advanced colorectal cancer who have progressed on at least one but not more than two prior chemotherapy regimens. Patients and Methods: Patients with stage 4 colorectal cancer were treated with oxaliplatin 85 mg/m² by a 2-hour intravenous infusion, followed by leucovorin 500 mg/m² by a 2-hour intravenous infusion, followed by 5-FU 400 mg/m² by bolus injection, followed by 5-FU 2.4 g/m² administered by a 46-hour continuous infusion. Cycles were administered every 2 weeks. Results: Seventy patients were treated and 68 patients had previously received irinotecan. Eleven percent of patients had a partial response, 33% of CEA-evaluable patients had a ≥50% drop in their CEA level. The median time to progression was 6.2 months, and the median overall survival was 8.7 months. Toxicity was mild to moderate, as 14% of patients experienced grade 3 or 4 neutropenia and 3% of patients experienced grade 3 neuropathy. Conclusion: The modified deGramont regimen of 5-FU, leucovorin, and oxaliplatin is tolerable and is associated with a modest degree of antitumor activity in patients who have progressed on both 5-FU and irinotecan.     

Oxaliplatin Added to Simplified Bimonthly Low-Dose Leucovorin and 5-FU for Pretreated Advanced Colorectal Cancer Is Effective and Not Affected by Different Previous 5-FU Regimens

This phase II study examined bimonthly oxaliplatin (85 mg/m²) added to a continuous infusion of fluorouracil (3000 mg/m² for 46 h following a 400 mg/m² bolus), with leucovorin (LV) (150 mg/m²) administrated in a simplified way to patients with metastatic colorectal cancers (CRC) refractory or resistant to 5-fluorouracil (5-FU). Sixty patients were registered. Of the 52 evaluable patients, 3 (5.8%) achieved a complete response (CR) and 18 (34.6%) achieved a partial response (PR). The overall response rate (CR + PR) was 40.4% (95% confidence interval [CI]: 26.6%-54.2%) for evaluable patients and 35% (95% CI: 22.6%-47.4%) by intention to treat. The median progression-free survival (PFS) was 5.2 months, and the median survival was 14.2 months. No significant differences were seen in response rates and PFS of patient groups pretreated either with high-dose 5-FU/LV by continuous infusion or with intravenous 5-FU/LV by a weekly bolus. From the 421 cycles analyzed, dose-limiting toxicities included cumulative sensory neuropathy and leukopenia, accounting for 11.6% and 10.0%, National Cancer Institute-Common Toxicity Criteria grade 3/4 toxicities per patient, respectively. Two (3.3%) patients experienced hepatic encephalopathy related to high-dose 5-FU. With necessary caution, this regimen was effective for 5-FU-pretreated CRC, regardless of ethnic differences, and it had the advantage of LV being administrated at a low dose in a simplified way.     

A phase II study with CPT-11 plus leucovorin and bolus IV 5-fluorouracil in patients with advanced colorectal carcinoma

Standard chemotherapy in advanced colorectal carcinoma (CRC) has not yet been established. The present study was conducted to assess the efficacy and toxicity profile of CPT-11, leucovorin (LV), and bolus 5-fluorouracil (5-FU) in a weekly schedule. Fifty-five patients were entered with no prior chemotherapy for advanced disease or adjuvant treatment ended at least 6 months preceding study entry, and 45 were assessable for response. Patients were treated with CPT-11 80 mg/m² (7 patients) or 70 mg/m² (48 patients). After completion of CPT-11 infusion, LV 200 mg/m² was administered over 2 hr followed immediately by 5-FU 450 mg/m², IV bolus, weekly for 6 weeks followed by a 2-week rest period. Treatment was continued for four cycles. Because of grade 3 and 4 diarrhea in four of the first seven patients, the study was amended to reduce the starting dose of CPT-11 from 80 to 70 mg/m² weekly. Four complete and 10 partial responses were observed (response rate: 25.5%), the median time to progression (TTP) was 7.7 months, 1-year survival rate was 62.3%, and the median overall survival was 15.0 months. Grade 3 and 4 diarrhea occurred in seven patients (12.7%), four of them treated with CPT-11 80 mg/m². Grade 3 myelotoxicity occurred in five patients (9.0%). Toxic death because of diarrhea, neutropenia, bacteremia, and sepsis occurred in a patient treated with CPT-11 80 mg/m². Our results confirm the efficacy of CPT-11, LV, and 5-FU in a weekly schedule in patients with advanced CRC. Further studies are needed to compare the present regimen with higher doses of CPT-11 with LV plus different schedules of 5-FU administration in the treatment of metastatic CRC.     

A pharmacokinetic study of 5-FU/leucovorin and alpha-interferon in advanced cancer

The present study was designed to study 5-FU pharmacokinetics after interferon. Weekly bolus 5-FU (500 mg/m²), immediately followed by leucovorin (60 mg/m²     

A phase I human trial of mitoguazone and gemcitabine sequential bi-weekly treatment of cancer patients

Our previous studies have demonstrated the existence of synergism in a combination therapy using mitoguazone and gemcitabine when the mitoguazone is administered 24 hours before gemcitabine. Based on the cell culture and animal experimental results, a phase I clinical trial was performed in order to determine the toxicity of the combined treatment. Mitoguazone and gemcitabine were administered sequentially: mitoguazone on day 1 and gemcitabine on day 2. This cycle was repeated every 2 weeks. The dosages of these two drugs were varied between patients. Ten patients were enrolled in the study. Six patients began treatment at dose level 1 (mitoguazone 500 mg/m², gemcitabine 1500 mg/m²), three at dose level 2 (mitoguazone 500 mg/m², gemcitabine 2000 mg/m²), and one at dose level 3 (mitoguazone 600 mg/m², gemcitabine 2000 mg/m²). Dose-limiting toxicity (DLT) was only observed in two patients treated at dose level 1 and one patient treated at dose level 3, while all the other patients only experienced nonhematologic toxicity, such as asthenia and mucositis. Two melanoma patients showed responses (one partial and one minor) to the treatment. One lymphoma patient also showed a brief partial response. This phase I trial indicated that the combination of mitoguazone and gemcitabine had limited but noticeable activity for treatment of cancer patients. Further study on the toxicity and on the effect of the scheduled mitoguazone-gemcitabine combination is needed.     

Phase I trial of gemcitabine and paclitaxel in advanced solid tumors

Purpose. Gemcitabine and paclitaxel are chemotherapeutic agents with clinical antitumor activity in a broad range of malignant solid tumors. Because of preclinical synergy, unique mechanisms of action and resistance, and nonoverlapping toxicities, gemcitabine and paclitaxel combinations are attractive for testing in clinical trials. Prior weekly gemcitabine and paclitaxel regimens administered on a 28-day cycle have been limited by cumulative hematological toxicity on day 15, thus reducing the planned gemcitabine dose intensity. We therefore conducted a phase I trial of a 21-day schedule of weekly gemcitabine and paclitaxel to determine the tolerability, maximum tolerated dose (MTD), and preliminary estimates of efficacy of this regimen. Patients and Methods. Forty-one patients with advanced malignant solid tumors were accrued. Gemcitabine was given at a fixed dose of 1000 mg/m² while paclitaxel was administered at an initial dose of 60 mg/m², then escalated by 15 mg/m² increments over seven dose levels to a prospectively planned maximum dose of 150 mg/m². Both agents were infused intravenously on days one and eight every 21 days. At least three patients were enrolled per dose level. No intrapatient dose escalation was allowed. Results. All patients were assessable for toxicity and 31 were assessable for response. The regimen was generally well-tolerated. Dose-limiting thrombocytopenia was observed in one patient at a paclitaxel dose of 135 mg/m²/week (dose level 6). After expansion of this dose level by 14 additional patients, no further dose-limiting toxicities were observed although one patient at dose level seven died of neutropenic sepsis after completing three cycles. There were eight partial responders for an overall response proportion of 26% (95% CI: 11, 41). Twelve patients (39%) had stable disease. Conclusion. This 21-day schedule of gemcitabine and paclitaxel is safe, well-tolerated, and active. The recommended phase II dose is gemcitabine 1000 mg/m² and paclitaxel 150 mg/m² on days one and eight every 21 days. The antitumor activity observed with this regimen warrants further investigation.     

5-Fluorouracil and High-Dose Calcium Leucovorin for Hepatocellular Carcinoma: A Phase II Trial

A phase II trial of 5-fluorouracil (5-FU) [250450 mg/m^2/day × 5 days as an intravenous (IV) bolus] combined with calcium leucovorin (500 mg/m²/day × 5 1/2 days by continuous IV infusion) administered on a 28-day schedule was performed in 15 patients with advanced hepatocellular carcinoma. The median age was 58 years; performance status ranged from 50 to 100%. Of 15 evaluable patients, 1 (7%) had a partial response lasting 2.4 months; 8 (53%) had stable disease with a median duration of 5.7 months; and 6 (40%) had progressive disease with a median time to progression of 2.7 months. Median survival was 3.8 months. Treatment with 5-FU and calcium leucovorin was moderately well tolerated; 9% of the treatment courses were complicated by grade 3 or 4 hematological toxicity, and 10% of the courses were complicated by grade 3 or 4 gastrointestinal toxicity. Despite the efficacy of the combination of 5-FU and leucovorin in advanced colorectal cancer, our results document the general resistance of hepatocellular carcinoma to modulated 5-FU.     

A phase I study of gemcitabine and docetaxel for advanced stage solid tumors

Background: We conducted a phase I study to determine the maximum tolerated dose of docetaxel in combination with gemcitabine for patients with refractory solid tumors. Methods: From January 1998 to November 1999, we treated 28 patients on a phase I protocol with gemcitabine given at a constant dose of 800 mg/m² IV over 30 minutes on days 1, 8, and 15. Docetaxel was administered by a phase I schedule over 1 hour on day 1 of a 28-day cycle with a starting dose of 50 mg/m² and increased by increments of 10 mg/m² based on dose-limiting toxicity (DLT) that occurred in the first cycle. Results: Neutropenia and thrombocytopenia were the dose-limiting toxicities. The maximum tolerated dose was 60 mg/m². The most significant nonhematologic toxicities included fatigue, nausea, vomiting, mucositis, and hypersensitivity reactions. There was one partial response at 15 months in a patient with gastric cancer and six patients with stable disease for 4.0 to 15.0 months. Conclusions: The maximum tolerated dose of docetaxel with gemcitabine is 60 mg/m². A phase II study in selected primary sites is planned.     

Phase II trial of a 24-hour infusion of gemcitabine in previously untreated patients with advanced pancreatic adenocarcinoma

The antitumor effect of gemcitabine is not dose-response related but schedule dependent. Here we report a phase II trial of a weekly 24-hour infusion of gemcitabine in previously untreated patients with advanced pancreatic cancer. Patients with histologically proven, measurable, and irresectable pancreatic adenocarcinoma were treated with gemcitabine at a dose of 100 mg/m² infused over 24 hr on days 1, 8, and 15. Treatment was repeated every 28 days until progression of disease or limiting toxicity. All 18 patients enrolled were evaluable for response. Neutropenia and thrombocytopenia grade 3 occurred in 1 patient each. One partial response and two minor responses were observed. Median time to progression of disease was 4.4 months. Improvement of the European Organization for Research and Treatment of Cancer C30 scores was observed in 6 patients (pain and overall symptom score, respectively) and in 3 patients (overall functioning score and global quality of life, respectively). Weekly 24-hr gemcitabine was well tolerated in previously untreated patients with advanced pancreatic cancer. It shows marginal antitumor activity in terms of response rate. However, the 24-hr infusion at a dose of 100 mg/m² seems to be as active as the standard 30-min gemcitabine at a dose of 1000 mg/m². Relatively long median time to progression of disease and improvement of symptom and quality-of-life scores suggest, that patients may benefit from 24-hr gemcitabine.     

A phase II study of oxaliplatin with low dose leucovorin and bolus and continuous infusion 5-fluorouracil (modified FOLFOX-4) as first line therapy for patients with advanced gastric cancer

To determine the activity and toxicities of a low dose leucovorin (ldLV) plus fluorouracil (5-FU) regimen, combined with oxaliplatin administered fortnightly (modified FOLFOX-4), as a first-line therapy for patients with advanced gastric cancer. Patients were treated with cycles of oxaliplatin 85 mg/m² on day 1 plus LV 20 mg/m², followed by 5-FU a 400 mg/m² bolus and a 22 hour continuous infusion of 600 mg/m² 5-FU on days 1 - 2 every two week intervals. Forty-five patients were enrolled in this study. Forty-two patients were assessable for response. One of the 42 patients demonstrated complete response, and 20 partial responses, and overall response rate of 50%. The median time to progression and overall survival time were 7.7 months (95% CI: 3.6 - 11.9 months) and 11.2 months (95% CI: 9.1 - 13.3 months), respectively. Major hematologic toxicities included grade 1 - 2 anemia (39.7%), neutropenia (30.4%) and grade 3 - 4 neutropenia (10.9%). Twelve cycles were associated with neutropenic fever. The most common non-hematological toxicities were grade 2 nausea/vomiting (20%). There was no treatment related death. The modified FOLFOX-4 regimen was found to be a safe and effective first line therapy in advanced gastric cancer.     

Toxicity of a 24-hour infusion of gemcitabine in biliary tract and pancreatic cancer: a pilot study

The antitumor activity of gemcitabine is not dose-response related but schedule-dependent. Based on the results of a published phase I study in patients with non-small-cell lung cancer we started a pilot study of a 24-hr infusion of gemcitabine in patients with adenocarcinoma of the pancreas and biliary tract cancer. Twenty-five patients were enrolled and received a 24-hr infusion of gemcitabine once weekly on three consecutive out of 4 weeks. Dose levels of gemcitabine ranged from 100 to 150 mg/m². One of 13 chemotherapy-naive patients had a partial response. Dose-limiting toxicity (DLT) was thrombocytopenia in pretreated patients and neutropenia in chemotherapy-naive patients. Other toxicities were oral mucositis, fever, flu-like symptoms, and asthenia. Maximum tolerated dose (MTD), especially in pretreated patients, was 100 mg/m².     

Metastatic or Locally Advanced Colorectal Cancer Treated with 5-Fluorouracil and Low Dose Leucovorin

Eighty-one patients with metastatic or locally advanced colorectal cancer were treated at four oncological centers in Denmark with a regimen consisting of 5-fluorouracil 400 mg/m² and leucovorin 20 mg/m² for 5 consecutive days every 4 weeks. The response rate was 21% among all 81 patients (CR 3, PR 14). The median survival was 10 months regardless of measurability, sex and location of disease. Toxicity was mild, 6 (7%) patients were excluded from the study due to gastrointestinal side-effects and 15 (19%) patients had the 5-FU dose reduced due to side-effects. The results are comparable to those of other studies using different doses of leucovorin.     

A phase I and pharmacokinetic study of lapatinib in combination with infusional 5-fluorouracil, leucovorin and irinotecan.

BACKGROUND: This study determined the optimally tolerated regimen (OTR) of oral lapatinib administered in combination with infusional 5-fluorouracil (5-FU), leucovorin and irinotecan (FOLFIRI) and assessed the safety, tolerability and pharmacokinetics of the combination. PATIENTS AND METHODS: Twenty-five patients were enrolled; 12 patients were treated at three dose levels to determine OTR; then 13 patients were treated at OTR to evaluate the pharmacokinetics of the combination. RESULTS: The 2-weekly OTR comprised lapatinib 1250 mg/day with irinotecan 108 mg/m(2) (day 1) and leucovorin 200 mg/m(2), 5-FU bolus 240 mg/m(2) and 5-FU infusion 360 mg/m(2) (days 1 and 2); doses of 5-FU and irinotecan represent a 40% reduction in dose compared to conventional FOLFIRI. Dose-limiting toxicities were grade 3 diarrhoea and grade 4 neutropenia. Co-administration of lapatinib increased the area under the plasma concentration-time curve of SN-38, the active metabolite of irinotecan, by an average of 41%; no other pharmacokinetic interactions were observed. Of 19 patients evaluable for disease response assessment, four patients had partial response and nine patients had stable disease. CONCLUSION: The combination of lapatinib and FOLFIRI is safe and demonstrates clinical activity; the documented PK interaction can effectively be compensated by lowering the doses of 5-FU and irinotecan. This regime may be further tested in a phase II trial.     

Phase I Study of Sequential Administration of Topotecan and 5-Fluorouracil in Patients with Advanced Malignancies

Topotecan is a topoisomerase-I inhibitor, a drug that stabilizes a covalent complex of enzymes and causes strand cleavage of DNA. 5-Fluorouracil (5FU) is an antimetabolite that interferes with DNA synthesis. Preclinical studies using human cancer cell line models have shown potential therapeutic synergy between these two drugs by showing the maximum cytolytic effect using sequential 5FU followed by topotecan. In the current study, 5FU was used at a fixed dose of 375 mg/m² given intravenously for five consecutive days on a 28 day cycle. Topotecan was dose-escalated in cohorts of patients from 0.5 to 1.0 mg/m² given intravenously for 5 days after the 5FU dose. Eleven patients were entered at different dose levels. Both hematological and gastrointestinal toxicity were dose limiting. Diarrhea was the dose-limiting toxicity at the dose of 0.75 mg/m² of topotecan. Two cases of grade 4 neutropenia were also observed at this dose level. One patient with small cell lung cancer had a complete response, while one patient with metastatic colorectal cancer had a partial remission. Three other patients had stable disease, lasting between 6 and 8 months. Overall, the regimen was well tolerated. A phase II study using a dose of 5FU at 375 mg/m² followed by topotecan at 0.75 mg/m² intravenously over 5 days every 28 days is recommended.     

Phase II study of irinotecan plus leucovorin and bolus 5-fluorouracil as first- or second-line chemotherapy in patients with advanced gastric or esophageal-gastric junction adenocarcinoma

The aim of this study was to evaluate the activity and safety of 5-fluorouracil (5-FU)/leucovorin (LV) and irinotecan as first- or second-line treatment in patients with advanced gastric adenocarcinoma. Treatment consisted of irinotecan 80 mg/m(2) intravenously (i.v.), followed by LV 200 mg/m(2) (i.v.) and 5-FU 450 mg/m(2) as an i.v. bolus, administered weekly for 6 weeks, followed by a 2-week rest period. Thirty-one patients (23 chemo-na?ve, 8 chemo-exposed) were enrolled. The overall response rate was 22.6% and the disease control rate was 38.7%. Among the patients who received the regimen as first-line treatment, objective response rate was 30.4% and the disease control rate was 52.1%. However, progression of the disease was recorded in all the patients receiving the combination as second-line chemotherapy. The median time to disease progression (TTP) was 4 months and the median duration of survival was 7 months. The median TTP was 6 months for patients treated with first-line chemotherapy and 2.5 for those who received study treatment as second line. Furthermore, the median survival duration was 8 months and 6 months, respectively. The most frequent grade 3 toxicity was febrile neutropenia. Grade 3 non-hematological toxicities were rare. There were no treatment-related deaths. The combination of 5-FU/LV and irinotecan as first-line treatment was found to be well tolerated and effective in patients with advanced gastric cancer. Further investigation would be worthwhile, particularly in elderly or debilitated patients who cannot tolerate aggressive chemotherapy.     

Treatment of acute myeloid leukemia patients aged more than 75 years: results of the E-AML-01 trial of the Japanese Elderly Leukemia and Lymphoma Study Group (JELLSG)

The feasibility and effects of combination chemotherapy for very elderly patients with acute myeloid leukemia was examined in 65 patients (including previous myelodysplastic syndrome) aged 76 years or morewith a performance status of 0 - 3. Induction chemotherapy was performed with 30 mg/m² daunorubicin on days 1 - 3, 150 mg/m² behenoyl cytosine arabinoside on days 1 - 7, and 70 mg/m² 6-mercaptopurine with 300 mg allopurinol taken orally on days 1 - 7 (BHAC-DM). The complete remission (CR) rate was 38.5%, whereas overall survival at 2 and 5 years was 22.0% and 4.7%, respectively. Two- and 5-year survival of CR patients was 41.8% and 11.2%, respectively. The relapse rate of the 25 CR patients was 64.0% and disease-free survival at 2 and 5 years was 21.0% and 11.2%, respectively. The therapy-related mortality rate at induction was 13.8%. BHAC-DM is feasible and effective for selected very elderly acute myeloid leukemia patients.     

Phase II Study of Irinotecan plus Leucovorin and Bolus 5-Fluorouracil as First- or Second-Line Chemotherapy in Patients with Advanced Gastric or Esophageal-Gastric Junction Adenocarcinoma

Abstract

The aim of this study was to evaluate the activity and safety of 5-fluorouracil (5-FU) / leucovorin (LV) and irinotecan as first- or second-line treatment in patients with advanced gastric adenocarcinoma. Treatment consisted of irinotecan 80 mg/m² intravenously (i.v.), followed by LV 200 mg/m² (i.v.) and 5-FU 450 mg/m² as an i.v. bolus, administered weekly for 6 weeks, followed by a 2-week rest period. Thirty-one patients (23 chemo-naïve, 8 chemo-exposed) were enrolled. The overall response rate was 22.6% and the disease control rate was 38.7%. Among the patients who received the regimen as first-line treatment, objective response rate was 30.4% and the disease control rate was 52.1%. However, progression of the disease was recorded in all the patients receiving the combination as second-line chemotherapy. The median time to disease progression (TTP) was 4 months and the median duration of survival was 7 months. The median TTP was 6 months for patients treated with first-line chemotherapy and 2.5 for those who received study treatment as second line. Furthermore, the median survival duration was 8 months and 6 months, respectively. The most frequent grade 3 toxicity was febrile neutropenia. Grade 3 non-hematological toxicities were rare. There were no treatmentrelated deaths.

The combination of 5-FU/LV and irinotecan as first-line treatment was found to be well tolerated and effective in patients with advanced gastric cancer. Further investigation would be worthwhile, particularly in elderly or debilitated patients who cannot tolerate aggressive chemotherapy.     

Nordic 5-fluorouracil/leucovorin bolus schedule combined with oxaliplatin (Nordic FLOX) as first-line treatment of metastatic colorectal cancer

This study combined oxaliplatin with the Nordic bolus schedule of 5-fluorouracil (5-FU) and folinic acid (FA) as first-line treatment in metastatic colorectal cancer. Twenty-seven patients were treated every second week with oxaliplatin 85 mg/m² as a 2-h infusion on day 1, followed by a 3-min bolus injection with 5-FU 500 mg/m² and 30 min later a bolus injection with FA 60 mg/m² given on days 1 and 2. Seventeen patients achieved a complete (n=2) or partial (n=15) response, leading to a confirmed response rate of 63% (95% CI 45-81%). The estimated median times to progression and survival were 8.9 and 18.7 months, respectively. Neutropenia grade 3-4 toxicity was seen in 63% of patients, neuropathy grade 3 in one patient and grade 2 in 12 patients. Oxaliplatin combined with the bolus Nordic schedule of 5-FU/FA (Nordic FLOX) appears to be well tolerated, effective and feasible as first-line treatment of metastatic colorectal cancer yielding results comparable with those obtained by more complex schedules.     

First-line ifosfamide, methotrexate, etoposide and prednisolone chemotherapy +/- radiotherapy is active in stage I/II extranodal NK/T-cell lymphoma

Although most patients diagnosed with extranodal NK/T-cell lymphoma (NTCL) have localized disease, radiotherapy alone is unsatisfactory because of frequent systemic failure and conventional doxorubicin-based chemotherapy has low efficacy. Twenty-six patients with NTCL received ifosfamide, methotrexate, etoposide and prednisolone (IMEP) chemotherapy as first-line treatment [ifosfamide 1.5 g/m² (days 1 - 3), methotrexate 30 mg/m² (days 3 and 10), etoposide 100 mg/m² (days 1 - 3) and prednisolone 120 mg (days 1 - 5)]. Radiotherapy was administered only to patients with Ann Arbor stage I/II that had not achieved complete remission (CR) or to those that developed local failure after completing chemotherapy. Sixteen patients (group A) had nasal or upper aerodigestive tract localization (stage I/II) and 10 (group B) had extranasal or disseminated disease. Of the 14 evaluable patients in group A, 11 (79%) achieved CR after IMEP alone and 13 (93%) after chemotherapy ± additional radiotherapy. Although, out of the 11 patients who achieved CR with chemotherapy alone, seven developed recurrence, all recurrences were local failure and successfully treated by additional curative radiotherapy. However, patients in group B responded poorly (CR 13%). IMEP regimen was active in NTCL patients with nasal or upper aerodigestive tract localization. Considering local failure rate after IMEP alone, initial IMEP chemotherapy followed by radiotherapy may be a promising treatment strategy in this subset of NTCL.     

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.