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.

Cisplatin (P) versus cyclophosphamide, adriamycin and cisplatin (CAP) for stage III-IV epithelial ovarian carcinoma: a prospective randomized trial.

In 1982 a randomized trial was started to compare a cisplatin-containing polychemotherapy (CAP: cyclophosphamide - CPA 750 mg/m2, adriamycin - ADM 50 mg/m2, cisplatin - P 50 mg/m2 on day 1 every 21 days) with full-dose cisplatin as single agent (P 60 mg/m2/day on days 1 and 2 every 28 days) in 44 patients undergoing exploratory laparotomy or debulking surgery for stage III-IV epithelial ovarian carcinoma with residual disease greater than 5 cm. The response was evaluated at second-look surgery with random biopsies and peritoneal washing. On the basis of the final results the authors underline some data which, although merely indicative (because of the small number of patients) appear to be worth considering since they are in accordance with the latest reports: a) similar response rate (CR + PR = 47%) to first-line treatment in the two groups; b) the CAP treatment may achieve a longer median duration of CRs than the P treatment (20 versus 11 months); c) overall survival seems similar in the two groups of patients (19 versus 18 months), whereas the survival of CRs seems longer in the CAP treated patients (greater than 32 versus 25 months). The authors also discuss some observations on a possible salvage therapy.

Diagnostic aspects and follow-up of 174 cases of hepatocellular carcinoma. Second report.

From June 1981 to June 1989 we diagnosed 174 cases of hepatocellular carcinoma (HCC) at our institution (Piacenza, Northern Italy). Average age was 65.6 years; male to female ratio 3.4. 149 patients were cirrhotic (85.6%); alcohol abuse was present in 88/169 (52.1%); in 53/145 patients all hepatitis B virus markers were negative. Alpha-fetoprotein showed a low diagnostic sensitivity (values above 500 ng only in 49/169 or 29.0%). We used ultrasound (US) examination with a very high identification rate in all cases; pathological diagnosis was achieved by US guided fine-needle aspiration biopsy in 135 patients; in 13, by laparoscopy-histology. Metastases were found in 24/169 cases (14.2%); a second malignancy was diagnosed in 13/169 (7.7%): the most common association was HCC-non-Hodgkin lymphoma. Only 14 patients could be referred to surgery, which significantly improved prognosis.

Antiemetic activity of two different high doses of metoclopramide in cisplatin-treated cancer patients: a randomized double-blind trial of the Italian Oncology Group for Clinical Research.

High-dose metoclopramide has been proposed as an effective antiemetic agent in patients treated with cisplatin. Its optimal dosage schedule, however, has not yet been completely defined. We report the results of a multicenter, double-blind, randomized clinical trial where the efficacy and safety of two fixed high-dose regimens of metoclopramide (60 and 120 mg, respectively) have been tested in 112 patients receiving cisplatin treatment. No statistically significant difference has been found between the two groups. In patients treated with cisplatin at doses greater than 100 mg/m2, the higher dose regimen seems more efficacious, but this result should be confirmed in a larger group of patients. Treatment was generally well-tolerated. However, a consistent percentage of patients (about 60%) still present with vomiting, and this makes further investigation necessary.

Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen.

BACKGROUND: Endocrine factors may affect the clinical course of malignant melanoma and the response to the treatment of this disease. The presence of estrogen receptors in melanomas has been suggested, and occasional responses to antiestrogen therapy have been reported. METHODS AND RESULTS: We randomly assigned 117 patients with metastatic malignant melanoma to treatment with dacarbazine alone or dacarbazine in combination with tamoxifen. The overall rate of response, measured objectively, was higher (28 percent vs. 12 percent, P = 0.03) and survival was longer (median, 48 vs. 29 weeks, P = 0.02) among the patients who received dacarbazine plus tamoxifen than among those who received dacarbazine alone. Among women, both the response rate (38 percent vs. 10 percent, P = 0.04) and the median survival (69 vs. 30 weeks, P = 0.008) were better with dacarbazine plus tamoxifen than with dacarbazine alone, whereas among men the differences were smaller and not statistically significant. Among the patients given dacarbazine alone, there were no significant differences between women and men in response rate (10 percent vs. 13 percent) or survival (30 vs. 27 weeks), whereas among those given dacarbazine plus tamoxifen, women had better outcomes, as indicated by both response rate (38 percent vs. 19 percent, P = 0.15) and survival (69 vs. 31 weeks, P = 0.02). When we analyzed the Quetelet body-mass index (the weight in kilograms divided by the square of the height in meters) as an indirect indicator of the levels of endogenous estrogens in postmenopausal women and in men, survival was not affected by the body-mass index in the group given dacarbazine alone, whereas in the group given dacarbazine plus tamoxifen, survival was longer among patients whose Quetelet index was above the median value than among those with a Quetelet index lower than the median value (60 vs. 26 weeks, P less than 0.001). CONCLUSIONS: In the treatment of metastatic malignant melanoma, dacarbazine plus tamoxifen is more effective than dacarbazine alone, as indicated by both the response rate and the median survival; the difference in efficacy is among women.

A comparison of continuation versus late intensification followed by discontinuation of chemotherapy in advanced breast cancer. A prospective randomized trial of the Italian Oncology Group for Clinical Research (G.O.I.R.C.).

One hundred ninety-eight postmenopausal women with metastatic breast carcinoma were entered in this study. After six induction cycles with cyclophosphamide, methotrexate and 5-fluorouracil (CMF), patients with at least stable disease were randomized to the "continuation arm" (continuation of CMF until progression) (A, 49 evaluable patients) or to the "intensification-discontinuation arm" (addition of adriamycin and vincristine to two of the three drugs of CMF for six more cycles; i.e., CMAV, CFAV, MFAV, twice; discontinuation of chemotherapy; radiotherapy to pre-study sites of disease in patients prospectively considered as candidates to receive this treatment) (B, 46 evaluable patients). After randomization, escalation of response category occurred in five patients on A (10%) and in five on B (11%). Time to progression was transiently delayed in arm B within 6 months after randomization. There were no significant differences in the overall time to progression, duration of response or survival. On arm B, after discontinuation of chemotherapy, median time to relapse was 22 weeks. This time was significantly longer in patients who were candidates for radiation therapy (36 weeks, P = 0.005), or with a disease-free interval greater than 1 year (32 weeks, P = 0.004) or who achieved complete remission (60 weeks, P = 0.0001). On arm B, three patients (7%) are still alive in complete remission in excess of three, five and six years following discontinuation of therapy. This study indicates that late intensification of chemotherapy followed by discontinuation of treatment may maintain palliation, and allow a long treatment-free period in responding patients with advanced breast carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Cisplatin, epirubicin, leucovorin and 5-fluorouracil (PELF) is more active than 5-fluorouracil, doxorubicin and methotrexate (FAMTX) in advanced gastric carcinoma.

BACKGROUND: 5-Fluorouracil (5-FU), doxorubicin and methotrexate (FAMTX) and cisplatin, epirubicin, leucovorin and 5-FU (PELF) have both been reported to be superior to the combination 5-FU, doxorubicin and mitomycin C (FAM) in advanced gastric carcinoma. On the basis of the presence and dose intensity of the included agents, we hypothesised that PELF would be superior to FAMTX. PATIENTS AND METHODS: Two hundred patients with untreated advanced gastric carcinoma were randomised to receive PELF or FAMTX for a maximum of six cycles or until disease progression. RESULTS: The complete response (CR) rates to PELF and FAMTX were, respectively, 13% [95% confidence intervals (CI) 6% to 20%] and 2% (95% CI 0% to 5%; P = 0.003), and the objective response rates [CR plus partial response (PR) rates] 39% (95% CI 29% to 49%) and 22% (95% CI 13% to 30%; P = 0.009), thus significantly favouring the PELF combination. The survival rates after 12 months (30.8% versus 22.4%) and 24 months (15.7% versus 9.5%) were also higher among patients receiving PELF, but these differences were not statistically significant. The toxicities were qualitatively different but quantitatively similar. Both regimens seem to be feasible provided that careful patient monitoring is assured. CONCLUSIONS: PELF is significantly more active than FAMTX and deserves further research in the adjuvant setting.