Capecitabine and oxaliplatin in advanced colorectal cancer: a dose-finding study.

PURPOSE: Capecitabine and oxaliplatin are both active anticancer agents in the treatment of patients with advanced colorectal cancer (ACRC). The aim of this dose-finding trial was to determine the maximum-tolerated dose (MTD), the dose-limiting toxicities (DLTs) and the activity of the combination in patients with advanced colorectal cancer. PATIENTS AND METHODS: Twenty-five chemotherapy-pretreated patients received the combination of capecitabine and oxaliplatin. Capecitabine was administered orally twice a day continuously for 14 days in doses ranging from 1,650 to 2,500 mg/m2/d, and oxaliplatin was administered as a two-hour infusion on day 1 using dose, ranges from 100 to 130 mg/m2 repeated every three weeks. RESULTS: Twenty-five patients were assessable for toxicity, and DLTs were diarrhea (grade > or = 3: 27%) and stomatitis (grade > or = 3: 9%) at dose level VI. Dose level V (capecitabine 2500 mg/m2 and oxaliplatin 120 mg/m2) was found to be the MTD. Hematological toxicity was minimal, overall neurotoxicity (grade 1-4) was 27% with 1% grade 3-4. A global response rate was 17% (95% confidence interval (95% CI): 2%-32%) and the median overall survival was 12 months. CONCLUSION: The recommended dose for further phase II studies is capecitabine 2,500 mg/m2/d with intermittent schedule and oxaliplatin 120 mg/m2 every three weeks. The toxicities were mainly gastrointestinal: diarrhea, stomatitis and vomiting. This combination should be studied in phase II trials in advanced colorectal.

5-fluorouracil plus folinic acid with or without ifosfamide in advanced colorectal cancer: a phase II randomized trial.

AIM: This phase II trial evaluated the biomodulation of 5-fluorouracil (5-FU) plus folinic acid (FA) with or without ifosfamide (IFO) in chemotherapy-naive patients with colorectal cancer. PATIENTS AND METHODS: Forty-eight patients were randomized to receive: FA (25 mg/m2 iv bolus days 1 to 3), followed by 5-FU (750 mg/m2 iv bolus days 1 to 3), arm A; or FA (25 mg/m2 iv bolus days 1 to 3), followed by 5-FU (750 mg/m2 iv bolus days 1 to 3) plus IFO (2,000 mg/m2 in 1000 mL 5% dextrose in a 2-hr infusion, days 1 to 3), arm B. Mesna was added during and after IFO to prevent hemorrhagic cystitis. Treatment was repeated every 21 days in both arms. RESULTS: Forty-five patients were assessable for response: in arm A, 5 patients achieved a partial response (overall response, 25%), and in arm B, 2 patients achieved a complete and 1 a partial response (overall response, 12%). Time to failure was 3.5 months (range, 1-38) in patients treated with 5-FU plus FA, and 3 months (range, 1-21) in patients treated with the IFO combination. The median survival time was 13.5 months (range, 1-49 months) in arm A and 16 months (range, 1-43 months) in arm B. Diarrhea, stomatitis and vomiting were the most common nonhematologic toxicities in both arms. The most notable hematologic toxicity was leukopenia; 15% and 20% of patients experienced grade 4 in arm A and arm B, respectively. CONCLUSIONS: IFO does not increase the activity of the 5-FU plus FA combination in advanced colorectal cancer.

Capecitabine, a new oral fluoropyrimidine for the treatment of colorectal cancer.

Capecitabine (Xeloda)(R) was developed as a tumour-selective fluoropyrimidine carbamate to achieve higher intratumoural 5-FU level and lower toxicity than 5-FU. Capecitabine passes unchanged through the gastrointestinal tract and is metabolised in the liver to 5'-deoxy-5-fluorocytidine (5'-DFCR). Here it is converted to doxifluridine (5'-DFUR) and finally, 5'-DFUR is metabolised by thymidine phosphorilase to 5-FU at the tumour site. Preclinical studies have demonstrated capecitabine's activity in both 5-FU-sensitive and 5-FU-resistant tumours. In a randomised phase II trial in advanced colorectal cancer the recommended dose and schedule of Capecitabine is 2.510 mg/m(2)/day (total dose divided into two equal morning and evening doses) given in an intermittent schedule (2 weeks on/1 week off). Phase III trials in patients with advanced colorectal cancer show a better response rate than the Mayo Clinic schedule, with no differences in terms of DR, PFS. Diarrhoea and hand-foot syndrome were the principal grade 3/4 toxicities noted, occurring in 10% and 16% of patients, respectively. The selectivity of this drug opens an important prospective in the treatment of colorectal cancer in advanced and adjuvant setting.

Modulation of fluorouracil by methotrexate, leucovorin, and cisplatin (M-FLP) in the treatment of advanced pancreatic cancer: a phase II study of the Italian Oncology Group for Clinical Research (GOIRC).

The objective of this trial was to evaluate the activity and tolerability of biomodulation of 5-fluorouracil by leucovorin, methotrexate, and platinum in patients with advanced measurable disease. Thirty-five patients with histologically or cytologically proven adenocarcinoma of the pancreas were treated with methotrexate (100 mg/m2 in 500 ml 5% dextrose in a 2-hour infusion, day 1), 5-fluorouracil (800 mg/m2/day, i.v. in continuous infusion from days 2 to 5) plus 1-leucovorin (7.5 mg/m2 given per os every 6 hours, from days 2 to 5) and platinum (60 mg/m2 i.v., day 2), every 28 days. Four partial responses (12%; exact 95% confidence interval: 1-23%) were obtained in 34 evaluable patients with a median survival time of 49 weeks (range, 20-77 weeks). Ten (29%) of 34 patients had stable disease. Median time to treatment failure from the beginning of therapy was 11 weeks (range, 4-59 weeks) and median survival time was 20 weeks (range, 4-77 weeks). The most common grade III-IV toxicities were diarrhea (15%), stomatitis (41%), and vomiting (17%). Hematologic toxicity was mild. There were no therapy-related deaths. In conclusion, this trial did not report an increase or improvement in response rate and survival rates, and this regimen cannot be recommended as effective therapy for advanced pancreatic cancer.

Dose intensification of mitoxantrone in combination with paclitaxel in advanced breast cancer: a phase II study.

BACKGROUND: Paclitaxel and mitoxantrone are highly active agents in the treatment of advanced breast cancer (ABC). This study evaluated the combination of paclitaxel and mitoxantrone in patients with advanced breast cancer to determine activity and toxicity. PATIENTS AND METHOD: 42 patients with ABC were treated with paclitaxel at a fixed dose of 175 mg/m2 intravenous (IV) by a 3-hour infusion on day 1, while mitoxantrone was given by 2 mg/m2 increments, starting from 10 mg/m2 by bolus IV injection on day 1 after paclitaxel. Cycles were repeated every 3 weeks. Mitoxantrone doses were increased if the maximum tolerated dose (MTD) had not been reached. RESULT: The overall response rate (CR + PR) was 69% (CI 95%: 55-83). Six (14%) patients obtained CR and 23 (55%) PR with a median duration of response of 8 months (range 2-16). There were no differences in response rates (RR) between the three levels of mitoxantrone. Median time to failure and survival were 7 months (range 1-26) and 12 months (range 2-29), respectively. After 12 months 14 (33%) patients had died and 8 (19%) patients were alive after 18 months. MTD was reached at 14 mg/m2 level of mitoxantrone. Leukopenia was evident in 39 (93%) of total patients and was severe in 28 (67%) patients. All non-hematological toxicity observed was mild. CONCLUSION: This trial shows the activity of paclitaxel and mitoxantrone in ABC and finds that a dose of 14 mg/m2 of mitoxantrone is the MTD in combination with a fixed dose of 175 mg/m2 of paclitaxel without granulocyte colony stimulating factor (G-CSF).

[Possibilities of palliation in pancreatic cancer]. / Possibilità di palliazione nel carcinoma pancreatico.

Adenocarcinoma of the pancreas is the cause of 3-4% of cancer related deaths in Italy and over 80% of all patients exhibit advanced disease. Treatment with surgery and chemio-radiotherapy may have meaningful results in resectable and locoregional tumours respectively. Chemotherapy is the treatment of choice in metastatic disease as palliative intent, although pancreatic tumour is considered resistant to treatment with conventional cytotoxicity drugs. Assessment of response of primary tumor is extremely difficult because of its anatomical location and fibrotic reaction around the tumor. Furthermore, medical problems associated with the age of patients, reduced performance status (PS), mainourished conditions, jaundice and pain, limit patients' tolerance and response to chemotherapy. 5-fluorouracil (5-FU) is the most frequently used drug in the treatment of pancreatic cancer with a RR of 28% in the trials performed in mid 1980, while more recently studies have reported a RR of 5-15%. Biochemical modulation of 5-FU by leucovorin, PALA and interferon does not appear to produce better results than 5-FU alone. 5-FU-based combination chemotherapy (FAM, SMF, etc) have shown interesting results in phase II (30-40%), but in a randomized trial the results of combination were similar to 5-FU alone (< 15%). Also, regimens containing platinum gave disappointing results just as the other combinations and cannot be recommended outside prospective clinical trials. When chemotherapy was compared to best supportive care (BSC), the results demonstrated a survival gain. Six studies, comparing chemotherapy versus BSC and 3 trials showed statistically significant difference in survival for patients treated with chemotherapy. Recently, new drugs have been introduced in the treatment of gastrointestinal tumour (gemcitabine, CPT11, raltitrexed, taxanes, etc.). Gemcitabine is a novel nucleoside analogue that has shown a very favourable toxicity profile and RR of 10-15% in advanced pancreatic cancer. Data from a phase II and randomized comparative trials suggest that gemcitabine offers an advantage over 5-FU in terms of improvement of PS and general clinical symptoms. Given the difficulty of accurate tumor measurement in this disease, some authors introduced a novel new end-point to evaluate the response: clinical benefit (CB). In a randomized trial of gemcitabine vs. 5-FU, RR using CB was 23.8 with gemcitabine and 4.8 with 5-FU, this difference was statistically significant with a median survival of 5.6 and 4.4 months, respectively. In conclusion, future studies should focus on phase III trials with gemcitabine, alone or in combination and phase II with new promising drugs. Quality of life, pharmaco-economic studies, CB should be the principal end-point of these studies. All patients with advanced pancreatic cancer should be included in clinical cooperative trials.

High-dose folinic acid and 5-fluorouracil alone or combined with hydroxyurea in advanced colorectal cancer: a randomized trial of the Italian Oncology Group for Clinical Research.

Patients with histologically confirmed advanced colorectal cancer were randomized to receive folinic acid (FA; 500 mg/mq in 2-hour intravenous infusion) and 5-fluorouracil (5FU; 600 mg/mq given as an intravenous bolus 1 hour after FA), beginning every week for 6 weeks, followed by a 2-week rest period, either without hydroxyurea (HU, arm A) or with HU (35 mg/kg per day) given orally in three administrations (every 8 hours) starting 6 hours after 5FU administration (arm B). Six weekly doses were considered one course. One hundred eighty-two patients were randomized in this trial and 162 (89%) were evaluable for response: 81 patients in arm A and 81 patients in arm B. Objective response was observed in 18 (one complete response and 17 partial responses) of 81 evaluable patients (22%; 95% confidence interval, 13-31%) in arm A, and 24 (nine complete responses and 15 partial responses) of 81 patients (30%; 95% confidence interval, 20-40%) in arm B. There was no difference in terms of median time to progression and median survival. Gastrointestinal toxicity was the most frequently observed toxicity in both arms. The double modulation of 5FU, FA plus HU does not appear to be better than the classic 5FU plus FA schedule. This trial confirms that 5FU and FA reached a plateau of 20% to 30%.