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%.

[Adjuvant radio-chemotherapy in cancer of the rectum treated with radical surgery and with high risk of recurrence. Preliminary results of a prospective study]. / Radio-chemioterapia adiuvante nel cancro del retto radicalmente operato e con alto rischio di ricaduta. Risultati preliminari di uno studio prospettico.

UNLABELLED: INTRODUCTION MATERIAL AND METHODS: From January, 1990, to December, 1995, 138 consecutive patients with radically resected stage II and III rectal and rectosigmoid cancers were treated with adjuvant radiochemotherapy. Eighty-one patients with 24 months' follow-up were assessable. Low anterior resection (LAR) was performed in 64 (79%) patients and abdominoperineal resection (APR) in 17 (21%). Twentynine (36%) stage II and 52 (64%) stage III patients entered the study. Within 45-60 days from surgery all patients received 5-Fluorouracil chemotherapy at the dose of 500 mg/m2/iv/d 1-5, every 4 weeks, for six cycles. Chemotherapy cycles 3 and 4 were administered at the same daily dose on radiotherapy days 1-3 and 29-31. Radiotherapy total dose consisted of 45 Gy/1.8 Gy/day administered in 5 weeks with 18 MV photon beam to the pelvis with the four field "box" technique. Perineal scar was encompassed only after APR. A boost dose of 5.4 Gy to the tumor bed was given in 3 fractions of 1.8 Gy. Median follow-up was 37 months (range: 24-74 months). RESULTS AND DISCUSSION: Overall recurrent disease was reported in 28 of 81 patients (34%): local, systemic and both local and systemic relapses in 9 (11%), 14 (17%) and 5 (6%) cases, respectively. According to local extension, recurrence rates were 10% and 48% in stages II and III, respectively. Five-year overall and disease-free actuarial survivals were 64% and 61%, respectively. Median time to relapse was 15 months (range: 7-43 months). Significant prognostic factors for better tumor control were: stage (II vs III), disease site (proximal vs distal rectum), the surgical procedure (LAR vs APR), the number of involved nodes (< or = 4 vs > 4) and no extracapsular node invasion. The recommended dose of combined radiochemotherapy regimen used in this trial was generally well tolerated. The incidence of any grade > or = 3 acute toxicity (according to WHO grading) was 20% diarrhea, 6% tenesmus and 4% myelosuppression. Five (6%) patients had cronic diarrhea and other 3 (4%) radiotherapy-related severe late toxicity which required surgery. CONCLUSIONS: This study seems to provide similar survival and recurrence notes to other radio-chemotherapy regimens published in the literature. However, a more aggressive approach is warranted in stage III patients considering the low 5-year survival recorded.

Long-term results in patients with advanced epithelial ovarian carcinoma treated with a combination of cisplatin, doxorubicin, and cyclophosphamide.

From 1984 to 1988, thirty-nine untreated patients with epithelial ovarian cancer received Cisplatin 50 mg/m2, Doxorubicin 50 mg/m2, and Cyclophosphamide 750 mg/m2 (CAP), at 3 weekly intervals. All patients had FIGO stage III or IV tumors except 2 patients with stage IIb and IIc, respectively. After initial surgery 23 patients had residual disease > 2 cm in diameter. Twenty-five patients (64%) were evaluable for response to chemotherapy. Objective responses were observed in 13 out of 25 patients (52%, 95% confidence intervals (CI), 32.42% to 71.58%), 6 patients had a cCR (24%) and 7 had a cPR (28%). Seventeen out of the 39 patients (44%) had a second-look laparotomy. A pCR was achieved in 5 out of 17 patients (29%); a pPR was obtained in 8 patients (47%). Median duration of survival was 41,5 months (range 2-107+); median duration of time to failure was 21 months (range 2-107+). Median disease-free survival was 86 months (range 3,5-107+). Eleven patients (28%) are alive and 9 patients (23%) are free of recurrence at median follow-up of 86 months. Only 4 of 11 long-term survivors had a pCR. In univariate analysis, histology, clinical response to chemotherapy, and the presence of ascites at the time of diagnosis, achieved a significant correlation with survival and time to failure (TTF); in addition, TTF was significantly affected by pathological response to induction chemotherapy. The only important predictors of disease-free survival (DFS) were tumor grade and stage of disease. In multivariate analysis, the presence of ascites was the only significant prognostic factor with respect to survival and TTF. Our study confirms the effectiveness of CAP in the treatment of epithelial ovarian cancer and the relatively poor long term prognosis.

Cisplatin and VP16 in metastatic breast carcinoma as a third-line chemotherapy: a randomized study comparing low versus high doses of cisplatin.

AIMS AND BACKGROUND: The study was designed to define the activity of the combination of cisplatin and etoposide as third-line chemotherapy for advanced breast cancer and to investigate the role of the dosage of cisplatin on the effectiveness of the combination. METHODS: Ninety-five eligible patients with advanced breast cancer who had failed or relapsed on two previous lines of chemotherapy were randomized to receive cisplatin at a high dose (100 mg/m2 i.v. day 1, arm A) or a low dose (60 mg/m2 day 1, arm B), combined with etoposide (100 mg/m2 i.v. days 4, 6 and 8). Cycles were repeated every 3 weeks. RESULTS: Of the 78 patients evaluable for response (39 in arm A and 39 in arm B), 9 (12%) showed complete or partial response, 5 (13%) in the high-dose arm and 4 (10%) in the low-dose arm. One complete response was seen in the high-dose arm and none in the low-dose arm. The only 2 patients with brain involvement showed an objective response (one CR in arm A and one PR in arm B). Median time to progression was 14 weeks in arm A and 10 weeks in arm B, median duration of remission 28 and 34 weeks, and survival 36 and 35 weeks, respectively. The differences were not significant. As expected, the patients in the high-dose arm experienced more severe toxicity. One toxic death was observed in each arm due to sepsis in agranulocytosis. The difference was statistically significant regarding nausea and vomiting. Neurotoxicity and ototoxicity were not relevant problems in this patient setting. CONCLUSIONS: Considering the very poor prognostic factors presented by these patients, the combination showed a certain activity, and further evaluation in earlier stages of disease is warranted. A particular responsiveness on brain metastases is suggested. The dose of cisplatin was not proven to be of significant importance.

Fluorouracil-alone versus high-dose folinic acid and fluorouracil in advanced colorectal cancer: a randomized trial of the Italian Oncology Group for Clinical Research (GOIRC).

One hundred eighty-one patients with measurable recurrent or metastatic colorectal cancer, who had not received prior chemotherapy, were randomized in a prospective controlled trial to receive 5-fluorouracil (5FU), 13.5 mg/kg, for five days (arm A) or high-dose folinic acid [Cyanamid-Lederle, Italy] (FA), 200 mg/m2, for five days and 5FU, 400 mg/m2 for five days (arm B). The treatments were repeated every four weeks. One hundred fifty-five patients were evaluable for response. The two arms were balanced for all potential prognostic factors studied. The response rate (CR+PR) was 18% in the 5FU arm and 16% in the 5FU plus FA arm. Median duration of response was 56 weeks for 5FU alone and 42 weeks for the combination (p = 0.48). Median time to failure (TTF) was 20 weeks for arm A and 21 for arm B (p = 0.62). Median survival was 62 weeks on the 5FU arm and 53 weeks on the FA plus 5FU arm (p = 0.14). Dose intensity (DI) delivered was the same in both arms. Diarrhea and mucositis were the most frequent adverse reactions in arm B; 20% of the patients in arm A and 38% of those in arm B experienced diarrhea (p = 0.008). Mucositis occurred in 34% of patients in arm A and 42% in arm B (p = 0.04). In general nausea and vomiting were moderate. Hematological toxicity was more severe in patients treated with 5FU alone: 31% in arm A and 14% in arm B developed leukopenia (p = 0.015). In the combination arm one patient died due to gastrointestinal and hematological toxicity after the seventh cycle. This study indicates that, in advanced colorectal cancer, the combination of high-dose FA and 5FU is not superior to 5FU alone when utilized at standard high-dose intensity.

Combination therapy with platinum and etoposide of brain metastases from breast carcinoma.

Twenty-two consecutive patients with brain metastases from breast carcinoma were treated with a combination of platinum (100 mg/m2 day 1) and etoposide (100 mg/m2 days 4, 6, 8) every three weeks. Five (23%) achieved a complete response (CR) while 7 (32%) obtained a partial response (PR) for an overall response rate of 55%. The 95% confidence interval for combined CR and PR was 34-76%. Five patients received brain irradiation after reaching the maximum degree of objective remission by chemotherapy. Median duration of combined CR plus PR was 40 weeks (12+; 152). Median duration of survival was 58 weeks (2; 208+). Fifty-five percent of the patients were alive at one year. Our study demonstrates that this combination treatment is highly effective in the management of brain metastases from breast carcinoma.

Chemotherapy with cis-platin, doxorubicin, and cyclophosphamide (CAP) in patients with metastatic breast cancer.

Thirty-three evaluable patients with metastatic breast cancer (12 previously treated with adjuvant chemotherapy) were treated with a combination of cis-platin, doxorubicin, and cyclophosphamide (CAP). cis-Platin was given intravenously, 20 mg/m2, on days 1-3, doxorubicin, 40 mg/m2 i.v., on day 1, and cyclophosphamide, 200 mg/m2 i.v., on days 1-3. Cycles were repeated every 3 weeks. A complete response (CR) was obtained in 3 patients (9%) and a partial response (PR) in 18 (54%). The highest response rate was observed in soft tissue and in liver metastases. Median response duration was 48 weeks and median survival 93 weeks. Toxicity was moderate and consisted of alopecia (100%), gastrointestinal toxicity (86%), and myelosuppression (60%). We conclude that this regimen is active in the treatment of advanced breast carcinoma, with a generally acceptable tolerance, but further evaluations in Phase III studies are required.

5-Fluorouracil and isoprinosine in the treatment of advanced colorectal cancer. A limited phase I, II evaluation.

We studied the effects of 5-fluorouracil (5-FU) and isoprinosine (ISO) on 15 patients with previously untreated metastatic colorectal carcinoma. The patients were treated in a limited Phase I, II protocol. All patients received a fixed ISO dose of 4 g orally on days 1 through 5 of each cycle. Each cycle was repeated every 35 days. The first seven patients were treated with an initial 5-FU dose of 7.5 mg/kg intravenously (IV) on days 1 through 5, which was escalated to 11.5 mg/kg IV after the first course and to 13 mg/kg IV after the second course. The next eight patients were treated with an initial 5-FU dose of 11.5 mg/kg IV on days 1 through 5, which was escalated to 13 mg/kg IV on days 1 through 5. No major responses (complete or partial) were documented. Median survival for all evaluable patients was 33 weeks. Toxicity was predominantly gastrointestinal and hematologic and was considered moderate. Our data suggest that 5-FU and ISO, at the doses used, were ineffectual in the treatment of metastatic colorectal carcinoma.

Platinum and etoposide in chemotherapy refractory metastatic breast cancer. A phase II trial of the Italian Oncology Group for Clinical Research (G.O.I.R.C.).

Twenty-four evaluable extensively pretreated advanced breast cancer patients received a combination of platinum and etoposide. Platinum was given i.v. at the dose of 80 mg/mq at day 1. Etoposide was given at the dose of 120 mg/mq i.v. at day 1, and p.o. at the dose of 200 mg/mq at day 3 and 5. Treatment was repeated every 3 weeks. CR was never obtained. PR was observed in four patients (17%), MR in two, NC in seven and PD in 11 patients. PR plus MR occurred in six patients (25%). Considering the extensive pretreatment of patients, the results seem to indicate that this combination is active and can be included among the possible options in treating chemotherapy refractory advanced breast cancer. Moreover, it deserves further evaluation in an earlier phase of the disease.

Early detection of breast cancer recurrences through periodic follow-up--is it useless?

The authors report on a multicentric consecutive series of 1120 breast cancer first recurrences. Cases detected as subjectively asymptomatic thanks to periodic follow-up examinations are compared to cases detected as symptomatic. The relapse-free interval from primary treatment was shorter for asymptomatic recurrences, confirming that an earlier diagnosis was achieved in these cases. In spite of this diagnostic anticipation, median and actuarial survival from primary treatment did not differ when asymptomatic recurrences were compared to symptomatic recurrences. The study results did not show any prognostic impact of periodic follow-up in breast cancer and urge for prospective controlled studies on this diffuse and expensive practice.