Randomized trial comparing protracted infusion of 5-fluorouracil with weekly doxorubicin and cyclophosphamide with a monthly bolus FAC regimen in metastatic breast carcinoma (SPM90).

Infusional 5-fluorouracil in advanced breast cancer has been associated with improved clinical response rates when compared with conventional bolus therapy. As a first line of chemotherapy in proven metastatic breast carcinoma, 258 women were randomly assigned to receive FAC consisting of 5-fluorouracil (F) 600 mg m(-2) intravenously (i.v.) over 1 h on days 1, 2 and 3, doxorubicin (A) 50 mg m(-2) i.v. bolus on day 1 and cyclophosphamide (C), 400 mg m(-2) i.v. bolus on days 1, 2 and 3 or 'FULON' consisting of 5-fluorouracil 250 mg m(-2) day(-1) continuously infused from day 1 to day 22, doxorubicin 15 mg m(-2) i.v. bolus on days 1, 8, 15 and 22 and cyclophosphamide 300 mg m(-2) i.v. bolus on days 1, 8, 15 and 22. Chemotherapy courses were administered 4-weekly for the bolus regimen and 6-weekly for FULON. Pretreatment characteristics were identical between the two groups. Response rates were 54% in the FAC arm and 53% in the FULON arm. Time to progression was 14 months in the FAC arm and 12 months in the FULON arm. Differences were not statistically significant. Median overall survival duration for all patients was 22 months. Haematological toxicity was more severe in the bolus-treated group (P = 0.05), as were nausea and vomiting (P < or = 0.01). We conclude that the two regimens appeared equally effective but have different toxicities.

Phase II trial of doxorubicin, 5-fluorouracil, etoposide, and cisplatin in advanced or recurrent endometrial carcinoma.

We have previously reported an overall response rate of 41% and a median survival duration of 14 months in a series of 49 patients with metastatic or recurrent endometrial carcinoma treated by a combination of etoposide, 5-fluorouracil, and cisplatin. In order to increase response rate and survival duration, doxorubicin was added to this combination. From August 1992 to January 1996, 20 consecutive patients were treated with a monthly combination chemotherapy consisting of doxorubicin 30 mg/m2 i.v. Day 1, 5-fluorouracil 600 mg/m2 i.v. Days 1 to 3, etoposide 80 mg/m2 i.v. Days 1 to 3, and cisplatin 35 mg/m2 i.v. Days 1 to 3 (AFEP). All patients were evaluable for response and toxicity. Median age was 62 years (range 45-72). Two to eight cycles were delivered (median 5). Two of 20 patients had complete response and 7 of 20 had partial response. The objective response rate was 45% (CI 95%: 23-68%). The median survival duration was 17 months. The median progression-free survival was 8 months. Major toxic effect was myelosuppression: 75% of grade 3 and 4 leukopenia and 20% of grade 3 and 4 thrombocytopenia. Seven patients (35%) developed infection and 4 (20%) were hospitalized once or more for toxicity. These results indicate that AFEP is an effective combination therapy in metastatic endometrial carcinoma but its toxicity is unacceptable.

Phase II trial of decapeptyl (D-TRP-6), a potent luteinizing hormone-releasing hormone analogue in untreated advanced breast cancer.

Decapeptyl (D-TRP-6), a potent luteinizing hormone-releasing hormone analogue, was administered to 27 premenopausal women with advanced breast cancer; patients were known to have hormone receptor-positive tumors. An overall response rate of 70% was achieved (complete response = 18%, partial response = 52%), with a median time to progression for the whole patient population of 12 months. Toxicity of the schedule was restricted to hot flushes, and the use of a 4-week initial covering period of tamoxifen prevented any flare-up of disease activity from occurring.

First-line protracted venous infusion fluorouracil with CisDDP or carboplatin in advanced colorectal cancer.

A total of 55 patients with measurable colorectal metastatic carcinoma were studied to evaluate the impact on toxicity, response, and survival of protracted venous infusion (PVI) 5-FU 200 mg/m2 per day with Cis-DDP 80 mg/m2 or carboplatin 300 mg/m2 every 3 weeks, 1-hour infusion. Patients received continuous uninterrupted therapy until there were signs or symptoms of toxicity. Both 5-FU and cisplatin were withheld when patients experienced grade II stomatitis and diarrhea, severe nausea or vomiting not controlled by standard antiemetic therapy, and clinically significant hand-foot syndrome. The toxicity was neurological (20% grade 2 and 3) hematological (13% grade 2) and dermatological (11% grade 2). The overall response (CR+PR) was 24% with a median survival of 13 months. The results of our study show that there is no improvement in response rate, response duration or survival compared with historical trials. However, this study does confirm the valuable palliative role of the protracted 5-FU infusion treatment. Colorectal carcinoma is one of the most common neoplasms in Western societies, being second only to lung cancer as a cause of death from malignancy. The management of nonmetastatic primary disease in surgical, with adjuvant chemotherapy for those at high risk of relapse. However, for those with metastatic disease at diagnosis or recurrent disease after resection, cytotoxic chemotherapy is the treatment of choice and fluorouracil (5-FU) is the most active cytotoxic agent in this disease, with a response rate of approximately 20%. Efforts to improve the response rate have focused on the use of agents to modulate 5 FU. The Southwestern Oncology Group (SWOG) study reported by Leichman et al. (1) and a study from the United Kingdom by Hill et al. (2) compared conventional FU to modulated FU and found no improvement in response rate or survival. In the SWOG study, two different schedules of bolus FU and LV were compared with bolus FU alone and to continuous infusion FU administered alone or modulated by LV or PALA. In this study, the results obtained with bolus FU were superior to most of the studies in the literature: The response rate was 26%, and the median survival was 14 months. The high- and low-dose LV and FU groups showed response rates and survival similar to bolus FU alone. However, in 12 previously reported randomized studies comparing FU and LV or FU alone, nine reported that the combination of FU and LV produced significant increases in response rates and two reported significant increase in survival (3, 4). Many of these trials used the dose schedules reported in the SWOG trial. Protracted venous infusion (PVI) 5-FU has been shown to have superior efficacy with less toxicity in colorectal cancer when compared to bolus 5-FU and synergy between cisplatin and 5-FU has been demonstrated in vitro. Consequently, we have investigated the efficacy of the combination of bolus cis or carboplatin and PVI 5 FU in 55 patients with advanced colorectal cancer using survival, response rate, symptomatic response, and toxicity as study endpoints.

Protracted continuous infusion of 5-fluorouracil in combination with doxorubicin, vincristine, and oral cyclophosphamide in advanced breast cancer.

Several studies suggest that protracted continuous infusion constitutes an important way to optimize the dose and the efficacy of 5-fluorouracil (5-FU) in metastatic cancer. Eighty-three women aged 27-76 (median age 55) with metastatic breast cancer were treated every 4 weeks with a continuous ambulatory venous infusion of 5-FU 350 mg/m2/day and oral cyclophosphamide 100 mg/m2/day over 15 days. The continuous therapy was associated with a weekly administration of vincristine (0.8 mg/m2) and doxorubicin (15 mg/m2) on day 1, day 8, and day 15. Cycles were repeated every 28 days. Thirty-four patients were treated in first-line metastatic chemotherapy and 49 in second-line. Toxicities included: mucositis (grade > or = 2) 23%, diarrhea (grade > or = 2) 7%, a hand-foot syndrome (grade > or = 2) 9%, alopecia (grade 3) 21%, neurological (grade > or = 2) 4%, grade 3 and 4 leukopenia 29%, and grade 3 and 4 thrombopenia 8%. Heart toxicity was only 3%. Catheter infection was observed in 1 case and 7 patients experienced thrombosis. The overall objective response rate (OR) was 48% and the complete response rate was 23%. The median duration of response was 10 months. The median survival was 16 months. Activity was better in naive than pretreated women (respectively, 55% and 42% of OR, p = 0.21). Analysis of responses according to the metastatic sites shows the pronounced efficacy on soft tissue diseases (skin recurrences 42%, lymph nodes 52%), and also in visceral metastases (hepatic 36%, lung 34%).

Treatment of advanced or recurrent endometrial carcinoma with combination of etoposide, cisplatin, and 5-fluorouracil: a phase II study.

Forty-nine consecutive patients with metastatic or recurrent endometrial carcinoma were treated with a monthly combination chemotherapy consisting of VP 16-213 80 mg/m2 i.v. Days 1-3, 5-fluorouracil (5-FU) 600 mg/m2 i.v. Days 1-3, and cisplatin 35 mg/m2 i.v. Days 1-3. The objective response rate was 41% (95% CI, 27-54%) with 14.3% complete responses. The median survival duration was 14 months. The median response duration was 12 months. The estimated median survival for responders was 20 months. Three patients are still free of disease 5 years after treatment. The major toxic effects were myelosuppression (less than 25% of grade III and IV leucopenia, and 14% grade III and IV thrombocytopenia). Grade III peripheral neuropathy was observed in five patients. Cisplatin administration had to be stopped due to renal toxicity in six patients. No treatment-related deaths occurred. The combination of etoposide, 5 fluorouracil, and cisplatin is an effective regimen with an acceptable toxicity in patients with recurrent or metastatic endometrial carcinoma.

Ifosfamide seven-day infusion for recurrent and cisplatin refractory ovarian cancer.

BACKGROUND: The prognosis of advanced ovarian cancer is very poor, with about 15% of patients surviving at five years. Since most of these patients will relapse and/or progress while on therapy, effective salvage treatments are needed. A phase II trial was designed to evaluate the feasibility, toxicity, and response of a seven-day ambulatory continuous infusion of ifosfamide in patients with recurrent or chemoresistant advanced ovarian cancer. PATIENTS AND METHODS: Nineteen patients with progressive ovarian cancer following a cisplatin-based induction chemotherapy were treated with continuous infusion ifosfamide with mesna at 1 g/m2/d and 400 mg/m2/d, respectively, for seven days every 28 days. RESULTS: The overall response rate was 37%. Responses were observed both in patients who relapsed after induction chemotherapy (4/6) and in those who were resistant to cisplatin (3/13). Toxicity was mild and tolerable in these heavily pretreated patients. CONCLUSION: Ifosfamide, when administered as a protracted continuous infusion is an active drug in ovarian cancer and can be safely administered in an out-patient setting. Toxicity is minor even in heavily pretreated patients. Responses are observed in cisplatin refractory ovarian cancer.

Breast tumour response to primary chemotherapy predicts local and distant control as well as survival.

The purpose of the present paper was to evaluate correlations between clinical response to chemotherapy and outcome in a subgroup analysis of premenopausal patients with tumours considered too large for breast conserving surgery, treated with primary chemotherapy (n = 200) from a previously published trial (Scholl S.M., Fourquet A., Asselain B, et al. Eur J Cancer 1994, 30A, 645-652). Objective response rates amounted to 65% following four courses. In a multivariate Cox regression analysis, comparing seven parameters, the following variables were associated with poor survival: clinically involved nodes [N1b:RR: 2.7 (95% CI 1.3-5.3)], the failure to respond to chemotherapy [D:RR: 2.62 (95% CI 1.3-5)] and a raised S phase fraction [SPF > 5%: RR: 2.4 (95% CI 1.2-5)]. Parameters associated with increased metastatic recurrence rates, by order of entry in the model, were: young age [< 35: RR: 2.46 (95% CI 1.2-5)], large clinical tumour size [T3: RR: 2.02 (95% CI 1.2-3.4)], poor histological grade (SBR III: RR: 1.93 (95% CI 1.1-3.3)] and the failure to respond to chemotherapy [D: RR: 1.91 (95% CI 1-3.4)]. The assessment of both tumour cell proliferation rates as well as possibly drug resistance markers (although not available in the present study) should be helpful in selecting patients likely to benefit from intensified chemotherapy regimens. The most accurate predictor of response in the present study appeared to be the response to chemotherapy treatment itself.

Randomized trial comparing two different modalities of administration of the same cytotoxic drugs in metastatic breast cancer.

This protocol compare the efficacy of continuous infusion fluorouracil (5-FU) with weekly doxorubicin (DOX) and cyclophosphamide (CPM) to a "classical" monthly regimen of the same drugs, as a first line of treatment in metastatic breast carcinoma. The first arm of this protocol consisted of FAC: 5-FU 600 mg/m2 i.v. over 1 hour, day(d) 1, 2, 3, DOX 50 mg/m2 i.v. bolus, d1, and CPM, 400 mg/m2 i.v. bolus, d 1, 2, 3. The second arm consisted of FULON: 5-FU 250 mg/m2 per day continuously infused from d1 to d22, CPM 300 mg/m2 i.v. bolus, d1, 8, 15, 22, and DOX 15 mg/m2 i.v. bolus, day 1, 8, 15, 22. Between January 1990 and June 1993, 258 women with proven metastatic breast carcinoma were randomly assigned either to receive FAC or FULON chemotherapy regimen. Chemotherapy courses were administrated every 4 weeks for FAC regimen and every 6 weeks for FULON. Response rate (54 versus 53%), response duration (14 versus 12 months) and overall survival duration (23 versus 21 months) were not significantly different in the two regimens (FAC versus FULON). Preorative prognostic value of liver metastasis or high LDH level was slightly attenuated in patients treated by FULON. Efficacy of infusional 5-FU in metastatic breast cancer could have been lowered by weekly infusion of doxorubicin in the FULON regimen compared to monthly infusion. According to the modalities of delivery of the drugs, the two regimens seem equally effective.

[2d and 3d line hormonal therapy in postmenopausal metastatic breast tumor. Comparison of medroxyprogesterone acetate and aminoglutethimide in tamoxifen-resistant patients]. / Terapia ormonale di seconda e terza linea nel tumore mammario metastatico in post-menopausa. Confronto tra il medrossiprogesterone acetato e l'aminoglutetimide in pazienti divenute resistenti al tamoxifen.

In order to evaluate the effectiveness of second and third line hormone therapy for postmenopausal (spontaneous or surgical) women with metastatic tamoxifen-resistant breast cancer, 293 women aged 36 to 91 (mean 63.6) were divided into two groups submitted to a multicenter study of two treatment schedules: a) Aminoglutethimide (AG; 500 mg daily plus hydrocortisone 40 mg daily); b) Medroxyprogesterone (MPA; 1,000 mg daily per os). Of the 293 patients receiving second line hormone therapy, only 161 were available for third line treatment. In phase 1, 153 patients were treated with AG: 36% had objective responses (complete or partial); of 140 patient receiving MPA, 33% had objective responses (p = 0.045, significant). In the AG-treated group, duration of response was 11.3 +/- 8.4 months as against 8.3 +/- 5.6 months in the MPA group (p = 0.07, significant). In phase 2, 87 women previously treated with MPA received AG, and 74 previously AG-treated patients were given MPA. There were no significant differences in the results obtained. In conclusion, there were no significant differences in the results obtained by AG and MPA treatment as far as toxicity and survival was concerned but there was a statistically significant advantage for AG as second and third line management both as to objective responses and mean time until renewed progression of the disease.

[Continuous infusion of doxorubicin for 10 days as third-line chemotherapy in metastasized breast tumors. Initial observations]. / L'infusione continua di doxorubicina per 10 giorni come chemioterapia di terza linea nel tumore mammario metastatizzato. Osservazioni iniziali.

The authors undertook a study to test the feasibility and efficacy of doxorubicin (Dox) administered as continuous infusion (c.i.) in the treatment of advanced breast cancer patients. All patients were previously treated as first line chemiotherapy with bolus-administered Dox; then they received a second line treatment without Dox. Patients were eligible if they had advanced measurable breast cancer, resistant to first and second line chemotherapy regimens, and if previous Dox treatment had been performed more than one year before, and after ECG and cardiac echographic controls were performed. A dose of 4.5 mg/m2/day of Dox was planned for 10 consecutive days in c.i. through a central venous catheter, repeated at 28 day intervals, for a maximum of 10 cycles. Among the 71 patients, 56 received 3 or more treatment courses; 10 patients refused further therapy after the first cycle. Objective responses were achieved in 25 patients (35%), 3 complete and 22 partial remissions. Stabilization was obtained in 11 patients (16%). The median time to progression was 9.3 months. Obviously, haematological toxicity was the major problem; in the 71 patients, 376 courses were administered (mean number of courses per patient: 5.3): grade 4 neutropenia (WHO system) occurred in 2 patients, and grade 3 in 9 patients; while one patient died of gastric haemorrhage. Severe cardiac toxicity occurred in only one patient who died 24 hours after the beginning of therapy, with ECG lateral ischemia. Grade 4 stomatitis was observed in only one patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic factors in inflammatory breast cancer and therapeutic implications.

223 inflammatory breast cancer patients were diagnosed at the Institut Curie between 1977 and 1987. Patients received chemotherapy and radiation treatment according to three consecutive randomised trials. Five- and 10- year survival rates were 41 and 32%, respectively. Disease-free interval rates were 25.5% at 5 years and 19% at 10 years. Parameters significantly linked with a pejorative prognosis in a multivariate analysis were: diffuse erythema, lymph node involvement, chest wall adherence, and age above 50 years. When therapeutic response parameters were included in the multivariate analysis, the five most important prognostic factors in order of significance were complete tumour regression after completion of induction treatment (at 8 months), complete regression of inflammatory symptoms after 3 months of neoadjuvant chemotherapy, limited erythema at presentation and, less significantly, complete regression of inflammatory symptoms at 8 months and tumour regression at 3 months. In conclusion, patients who achieved a rapid and complete remission had a better prognosis than patients who had an incomplete response to chemotherapy. High-dose chemotherapy and reversal or prevention of drug resistance will be evaluated in future trials. Detailed information on the biology of this disease should allow the design of new strategies aiming to improve patient management.

Phase II trial of weekly intravenous vinorelbine in first-line advanced breast cancer chemotherapy.

PURPOSE: This study investigated the therapeutic effects of single-agent intravenous (IV) weekly Navelbine (vinorelbine or 5'-nor-anhydro-vinblastine; Pierre Fabre Médicament, Boulogne, France), a semisynthetic vinca alkaloid, in women who had received no prior chemotherapy for locally advanced or metastatic breast cancer. PATIENTS AND METHODS: One hundred fifty-seven patients with assessable advanced or metastatic breast cancer who had received no prior chemotherapy were entered onto the study. They were stratified into five groups according to the main assessable tumor target: lung, liver, lymph nodes, skin, and others. One hundred forty-five patients were assessable for toxicity and response using World Health Organization (WHO) criteria; the 12 patients who were not evaluated were excluded because they were found not to meet the eligibility criteria. Navelbine was administered as a weekly 30-mg/m2 short IV infusion, and treatment was continued until disease progression. RESULTS: The overall response rate (WHO criteria) was 41% (complete response [CR], 7%; partial response [PR], 34%; 95% confidence interval [CI], 33% to 49%). In addition, 30% of the patients had stable disease. The response rate according to target was lymph nodes (28 of 42), 67%; liver (nine of 39), 23%; lung (10 of 30), 33%; skin (21 of 30), 70%; primary tumor (10 of 16), 56%; and bone (three of 10), 30%. The median time to treatment failure was 6 months and the median survival was 18 months. A total of 1,673 cycles were given to 145 eligible patients. At least one episode of WHO grade 3 or 4 granulocytopenia was seen in 72% of the patients. Nausea and/or vomiting, anemia, and/or thrombocytopenia were seen in less than 1% of cycles. Other side effects were rare, and additional toxicities were documented in the following proportions of patients: grade 2 to 3 alopecia, 8%; infectious episodes, 6%; and peripheral neuropathy, 3%. CONCLUSION: Our data confirm that Navelbine has major single-agent antitumor activity as front-line therapy in advanced breast cancer. Given its excellent tolerance profile and low toxicity, it should be considered for inclusion in first-line combination chemotherapy regimens.

[Treatment of cancers of the ovary. Phase II trial of increase of the dose of cisplatin]. / Traitement des cancers de l'ovaire. Essai phase II d'une augmentation de la dose de cisplatine.

Between March 1985 and December 1987, 34 women who had advanced adenocarcinoma of the ovary with macroscopic residual disease entered in a phase II trial of chemotherapy. Treatment consisted of a 3-month induction with monthly ifosfamide combined with 5-fluorouracil and high-dose cisplatin, and a maintenance treatment with ifosfamide, 5-fluorouracil, cisplatin and hexamethylmelamine in monthly cycles. At the end of the treatment patients with complete remission were evaluated by surgery. Neurotoxicity was a limiting factor, and treatment had to be prematurely withdrawn in 10 patients. The above treatment was found to be effective with a 94 percent objective response rate, a 54-month median survival and a 51-month median relapse-free survival. Because of the neurotoxicity, a shorter therapy and the use of neuroprotective agents may be envisaged.

[Malignant epidermoid degeneration of dermoid cysts of the ovary. Apropos of 2 cases]. / Dégénérescence maligne épidermoïde des kystes dermoïdes de l'ovaire. A propos de deux observations.

Malignant transformation of benign ovarian cystic teratomas has been reported in 0.5 to 2% of cases. Many different types of cancer can develop, including squamous cell carcinoma, which is by far the most frequent (75%). The mean age of diagnosis is over 50 years. Minimal surgical techniques have been increasingly popular and laparoscopic removal of benign ovarian cysts has become common practice. Malignant transformation is rare but needs to be recognized in order to avoid dissemination of malignant cells during surgery. Direct invasion of the adjacent pelvic structures and small intestine represents the most common mode of spread. Survival is not improved by post-operative radiotherapy or adjuvant chemotherapy in patients with extracapsular disease. We report two cases, one of which presented with spontaneous ovarian abscess and paraneoplastic hypercalcemia.

Second and third line hormonotherapy in advanced post-menopausal breast cancer: a multicenter randomized trial comparing medroxyprogesterone acetate with aminoglutethimide in patients who have become resistant to tamoxifen.

In order to evaluate the efficacy of two different sequences of second and third line hormonotherapy in advanced post-menopausal breast cancer, 257 women aged 36-91 years (mean age: 63.6 years) who had become resistant to tamoxifen (TAM), entered into a multicenter randomized trial comparing two different regimens: 1) Aminoglutethimide (Ag) 500 mg/day with hydrocortisone supplementation from 30 to 60 mg/day; and 2) oral medroxyprogesterone acetate (MPA) 500 mg twice a day. 250 patients were evaluated following second line hormone therapy and, after cross-over, 128 following third line hormonotherapy. No significant difference was observed, during either second or third line therapies, for toxicity, survival, or response rate; however, in both second and third line therapies the median time to progression was significantly longer with Ag therapy.