High-dose platinum versus standard dose in advanced ovarian carcinoma: a randomized trial from the Gynecologic Cooperative Group of the French Comprehensive Cancer Centers (FNCLCC).

OBJECTIVE: The aim of this study was to evaluate the impact of platinum dose intensity on pathological response rate and overall survival in patients with advanced ovarian adenocarcinoma. METHODS: Between February 1992 and December 1996, 195 previously untreated patients with FIGO stage IIb-c, IIIb-c, or IV with macroscopic residual disease after suboptimal debulking surgery were randomized to receive CCC (100 mg/m(2) of cisplatin, 300 mg/m(2) of cyclophosphamide, 300 mg/m(2) of carboplatin, n = 96) or CC (100 mg/m(2) of cisplatin, 600 mg/m(2) of cyclophosphamide, n = 99) for six courses at 28-day intervals. A second-look laparotomy was planned at the end of chemotherapy. RESULTS: In the CCC arm, the platinum compound received dose intensity and relative total dose were 85 and 76%; in the CC arm, they were 94 and 85%. Grade 3-4 toxicity was more frequent in the CCC arm than in the CC arm for leukopenia (56% vs 26%, P < 0.001), febrile neutropenia (18% vs 4%, P = 0.002), anemia (31% vs 5%, P < 0.001), thrombopenia (55% vs 4%, P < 0.001), and ototoxicity (8% vs 0%, P < 0.001). The pathologic complete response rate was 22 and 14% in the CCC and CC arms, respectively (P = 0.19). With a median follow-up of 53 months, the median time to failure and the 3-year treatment failure-free survival rate were 17.4 months and 22% vs 13 months and 11% in the two arms, respectively (P = 0.01). The median survival time and the 3-year overall survival rate were, respectively, 30 months and 42% vs 25 months and 33% (P < 0.20). CONCLUSION: The platinum dose intensification (1.6-fold increase) obtained with the CCC association improves the treatment failure-free survival without significant impact on overall survival when compared with the CC regimen in suboptimal debulked ovarian adenocarcinoma. However, because of its high rate of hematologic toxicity and ototoxicity, this association cannot be recommended for routine practice.

[Concomitant radiochemotherapy for cancer of the cervix: critical analysis based on the Standards, Options and Recommendations methodology]. / Radiochimiothérapie concomitante dans les cancers du col de l'utérus: analyse critique des données et mise à jour des Standards, Options et Recommandations.

INTRODUCTION: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the National Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres (CRLCC) and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To update, according to the methodology of SOR, the Standards, Options and Recommendations for the management of patients with cancer of the cervix, and in particular, the place of concomitant radiochemotherapy. METHODS: Data have been identified by a literature search using Medline (to April 1999) and the personal reference lists of experts. Once the guidelines were defined, the document was submitted for review to independent national and international reviewers and to the medical committees of the CRCC. RESULTS: The principle recommendations concerning the place of radiochemotherapy in the treatment of cancer of the cervix are 1/ the available data shows a significant increase in local control (level of evidence A) and of overall survival (level of evidence B1) following concomitant radiochemotherapy as compared to radiotherapy alone or the combination of radiotherapy-hydroxyurea. For stages IB, IIA, proximal IIB with bad prognostic factors (tumour size greater than 4 cm and/or invasion of pelvic nodes and/or microscopic invasion of the parametrium) and without lumbo-aortic nodal invasion, concomitant radiochemotherapy can be considered as standard treatment. This benefit is less clear for stages distal IIB, III and IVA without para-aortic nodal invasion (level of evidence C) and must be confirmed (expert agreement). 2/ the toxicity of radiochemotherapy is essentially haematologic and gastrointestinal (level of evidence B1) and is greater than that of radiotherapy alone (level of evidence B1). 3/ these results have been obtained by the combination of chemotherapy based oncisplatin alone, or in combination with 5-FU. Although of equal benefit, the toxicity of the cisplatin/5-FU/ hydroxyurea combination was greater than that of cisplatin alone in a trial comparing the two protocols. A significantly longer survival have also been obtained by the combination of chemoradiation and adjuvant chemotherapy with epirubicin (level of evidence C). These results must be confirmed. 4/ the exact means of delivering the chemotherapy has not been clearly established. In fact, in these trials, some protocols use cisplatin weekly at a dose of 40 mg/m2 and others every three or four weeks at doses ranging from 50 to 75 mg/m2. Subsequent randomised studies are likely to establish optimal schema for the delivery of chemotherapy when combined with external radiotherapy and brachytherapy.

[Standards, options and recommendations: concomitant radiochemotherapy for cancer of the cervix: a critical analysis of the literature and update of SOR]. / Radiochimiothérapie concomitante dans les cancers du col de l'utérus: analyse critique des données et mise à jour des standards, options, et recommandations. Groupe de travail SOR.

INTRODUCTION: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the National Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres (CRLCC) and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To update, according to the methodology of SOR, the Standards, Options and Recommendations for the management of patients with cancer of the cervix, and in particular, the place of concomitant radiochemotherapy. METHODS: Data have been identified by a literature search using Medline (to April 1999) and the personal reference lists of experts. Once the guidelines were defined, the document was submitted for review to independent national and international reviewers and to the medical committees of the CRLCC. RESULTS: The principle recommendations concerning the place of radiochemotherapy in the treatment of cancer of the cervix are: 1) the available data shows a significant increase in local control (level of evidence A) and of overall survival (level of evidence B1) following concomitant radiochemotherapy as compared to radiotherapy alone or the combination of radiotherapy-hydroxyurea. For stages IB, IIA, proximal IIB with bad prognostic factors (tumour size greater than 4 cm and/or invasion of pelvic nodes and/or microscopic invasion of the parametrium) and without lumbo-aortic nodal invasion, concomitant radiochemotherapy can be considered as standard treatment. This benefit is less clear for stages distal IIB, III et IVA without para-aortic nodal invasion (level of evidence C) and must be confirmed (expert agreement); 2) the toxicity of radiochemotherapy is essentially haematologic and gastrointestinal (level of evidence B1) and is greater than that of radiotherapy alone (level of evidence B1); 3) these results have been obtained by the combination of chemotherapy based on cisplatin alone, or in combination with 5FU. Although of equal benefit, the toxicity of the cisplatin/5FU/hydroxyurea combination was greater than that of cisplatin alone in a trial comparing the two protocols. A significantly longer survival have also been obtained by the combination of chemoradiation and adjuvant chemotherapy with epirubicin (level of evidence C). These results must be confirmed; 4) the exact means of delivering the chemotherapy has not been clearly established. In fact, in these trials, some protocols use cisplatin weekly at a dose of 40 mg/m2 and others every three or four weeks at doses ranging from 50 to 75 mg/m2. Subsequent randomised studies are likely to establish optimal schema for the delivery of chemotherapy when combined with external radiotherapy and brachytherapy.

Results of a European Organization for Research and Treatment of Cancer/Early Clinical Studies Group phase II trial of first-line irinotecan in patients with advanced or recurrent squamous cell carcinoma of the cervix.

PURPOSE: To determine the efficacy and tolerability of irinotecan (CPT-11) in advanced or recurrent cervical carcinoma. PATIENTS AND METHODS: Eligible patients had histologically confirmed, inoperable, progressive, metastatic or recurrent squamous cell cervical carcinoma and had received no radiotherapy in the preceding 3 months and had never received chemotherapy. The initial irinotecan dosage of 350 mg/m(2) every 3 weeks was modifiable according to toxicity. Treatment continued for six cycles after complete response, or until disease progression or excessive toxicity after partial response, or for three additional cycles in the case of stable disease. Patients were stratified into group A (>/= one measurable lesion in a previously unirradiated area, with or without progressive disease in irradiated fields) or group B (measurable new lesion[s] in an irradiated field). RESULTS: Fifty-one of 55 enrolled patients were eligible for inclusion (median age, 47 years; range, 30 to 71 years). The response rate was 15.7% (95% confidence interval [CI], 7.0% to 28.6%) overall, 23.5% (95% CI, 10.7% to 41.2%) for group A (complete response, 2.9%), and zero for group B. The median time to progression and median survival were 4.0 and 8.2 months for group A and 2.5 and 4.2 months for group B, respectively. The major grade 3/4 toxicities for groups A and B were diarrhea (24.3% and 55.5%, respectively) and neutropenia (24.3% and 33.3%, respectively). There were four toxicity-related deaths, three in group B. Patients with no prior external pelvic irradiation experienced fewer grade 3 and 4 adverse events. CONCLUSION: Irinotecan is effective in treating cervical squamous cell carcinoma if disease is located in an unirradiated area. Because of toxicity, a reduced dose is advised for patients previously treated with external pelvic irradiation.

A multicenter phase II study with triptorelin (sustained-release LHRH agonist) in advanced or recurrent endometrial carcinoma: a French anticancer federation study.

The objective of this phase II multicenter study was to assess the efficacy and tolerance of triptorelin (a sustained-release LHRH agonist) in advanced or recurrent endometrial cancer. A total of 101 monthly intramuscular injections were administered to 24 eligible patients (median number/patient = 3; range 1-12). Mainly due to progression, only 16 patients received 3 or more injections. Among the 23 evaluable patients, 1 complete and 1 partial response (response rate of 8.7%) and 5 disease stabilizations were observed, often of long duration, but never in an irradiated area or after progestogens treatment failure. Median survival for eligible patients was 7.2 months (range: 1-36 months). Only grade 1 toxicities possibly related to the treatment were observed in 4 patients. In conclusion, triptorelin was safe, well tolerated, and easily manageable, and the very low toxicity did not impair the quality of life in these patients with a very poor prognosis. Although the response rate was disappointing, several patients showed early evidence of efficacy which may be of long duration. Response rates range between 0 and 45% in different published studies. Additional studies with stricter inclusion criteria and a larger sample size are necessary to better evaluate the role of LHRH agonists in endometrial adenocarcinomas.

An EORTC-ECSG phase II study of vinorelbine in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: Vinorelbine is an active drug in the treatment of lung and breast cancers and has a favorable toxicity profile. Many clinical trials have demonstrated its antitumor activity in other tumor types including squamous cell carcinoma of the head and neck (SCCHN). We investigated the efficacy and tolerability of vinorelbine in patients with recurrent and/or metastatic SCCHN, previously untreated by chemotherapy. PATIENTS AND METHODS: Seventy-one patients with locoregional recurrent and/or metastatic SCCHN were treated with vinorelbine at a dose of 30 mg/m2/week i.v. by short-duration infusion on an out-patient basis. Doses were adjusted according to tolerance. RESULTS: Two complete and seven partial responses were observed among 56 evaluable patients, yielding a response rate of 16% (95% confidence interval (CI): 8%-28%). The overall response rate of all eligible patients (63) was 14%. The responses were seen in recurrent tumors, lymph nodes and in lung metastases, and their median duration was 19 weeks (12-63). The main toxicity, severe and reversible neutropenia (grade 3-4) occurred in 53% of the 69 evaluable (for toxicity) patients. Twelve patients developed severe bronchopulmonary infections, which caused two early deaths. Constipation was observed in 31 patients (45%). Other gastrointestinal toxicities, asthenia, acute pain syndrome and peripheral sensory neuropathy, were mild to moderate. The median number of treatments was seven cycles and the median relative dose intensity of vinorelbine was 85% (25.5 mg/m2/week). CONCLUSIONS: Vinorelbine is an active drug, with acceptable toxicity, in recurrent and/or metastatic SCCHN, at the dose and schedule administered in the present study. Further evaluation in association with other agents and/or radiotherapy is warranted.

[Predictive value of the hemogram for myelotoxicity induced by the association of carboplatin-fluorouracil on the 4th day of the therapeutic regimen]. / Valeur prédictive de l'hémogramme du 4e jour pour la myélotoxicité induite par l'association carboplatine-5-fluorouracile.

The aim of this study was to determine the value of haematological counts at the 4th day of a chemotherapy cycle, in order to foresee neutro and/or thrombocytopenia during the same chemotherapy cycle. One hundred and ten cycles of chemotherapeutic regimens with carboplatin (400 mg/m2, dl) and 5-fluorouracile (1 g/m2/d, by iv continuous infusion for 96 hours) every 3 weeks, were analyzed for 42 patients with locally advanced but non metastatic squamous cell carcinoma of head and neck, without prior chemotherapy. Lymphocyte counts were significantly decreased at the 4th day but normalized at the 8th day (P < 10(-6)). Decreases of lymphocyte and neutrophil counts at the 4th day were significantly correlated to grade > 2 neutropenia. The positive predictive value of lymphocyte or neutrophil counts is about 50% for some cut-off values but not high enough, with the schedule of chemotherapy in our study, to justify the systematic prophylactic therapy with haematopoietic growth factors.

Familial cluster of ovarian small cell carcinoma: a new mendelian entity?

We report a pedigree in which three sisters had a particular type of ovarian cancer, small cell carcinoma of the hypercalcaemic type. This rare type of ovarian carcinoma is now well characterised by clinical and pathological findings and is well distinguished from other ovarian epithelial tumours and ovarian germ cell tumours. The occurrence of this rare type of cancer in several members of the same family and the existence of four other similar published observations raises the question of the genetic determination of this kind of tumour.

[Carboplatin and etoposide combination for the treatment of recurrent epithelial ovarian cancer]. / Association de carboplatine et étoposide dans le traitement des rechutes des cancers épithéliaux de l'ovaire.

UNLABELLED: The objective of this phase II study was to determine the efficacy and toxicity of a combination of carboplatin and etoposide as salvage treatment, in previously treated patients with persistent or recurrent ovarian cancer following first-line cisplatin-based chemotherapy. PATIENTS AND METHODS: From July 1990 to August 1994, 58 patients were treated with 3-week cycles of chemotherapy consisting of carboplatin (200 mg/m2, D1) and etoposide (120 mg/m2, D1, D2). Criteria for evaluating previous response to cisplatin were strictly defined. RESULTS: The overall response rate was 36%, with five complete responses (CR, 9%), 16 partial responses (PR, 27%) and the median duration of response was 10 months (range: 4 to 38). In the group of patients who progressed during the first year following the diagnosis, the response was 1 CR and 2 PR (12%) and in the group of patients who progressed from the second year after diagnosis, 4 CR and 14 PR (56%), with a median survival of 8.5 and 21 months respectively (p = 0.0013). The response rate was 59% in the potentially platinum sensitive group versus 8.7% in the primary resistant group (0.02 < p < 0.05). Myelotoxicity was the main side-effect but did not appear to be cumulative. Grade 3 and grade 4 anemia were observed in 26% and 3% of the patients respectively, neutropenia in 14% and 2% and thrombocytopenia in 14% and 8.5%. One patient died of sepsis associated with neutropenia. CONCLUSION: Treatment was easily manageable and well tolerated. The advantage of carboplatin and etoposide combination in potentially responsive patients is represented by the reduced nephrotoxicity, neurotoxicity and ototoxicity as compared with cisplatin containing regimen, with durable feasibility in outpatients. This second-line chemotherapy for ovarian cancer is effective as salvage treatment in potentially responsive patients with late recurrent tumors, while paclitaxel is the drug of choice for patients who have developped primary or secondary resistance to platin therapy.

[Functional outcome of laparoscopically transposed ovaries in the multidisciplinary treatment of cervical cancers. Analysis of risk factors]. / Avenir fonctionnel des ovaires transposés par coelioscopie dans le traitement multidisciplinaire des cancers du col utérin. Analyse des facteurs de risque.

OBJECTIVES: To evaluate the place of ovarian transposition by laparoscopy in the treatment of cervical cancers. METHODS: From March 1992 to November 1994 at Institut Bergonié, 11 patients (mean age: 40 years; 36-44 years) with invasive squamous cell carcinoma of the uterine cervix stages Ib (4 cases) and IIb (7 cases) underwent lateral high ovarian transposition by laparoscopy performed during a staging inter-iliacal lymphadenectomy. There was no complication during surgery but one phlebitis occurred postoperatively. The treatment for the cervical cancer included: brachytherapy (11 cases), external beam radiotherapy (EBRT) (9 cases), surgery (6 cases), chemotherapy (2 cases). Ovarian radiation dosis was calculated and hormonal status assessed. RESULTS: Ovarian preservation was achieved in 30% of the cases. The mean lowest cumulative dosis to the ovaries was 1.78 Gy. Age was the most predictive factor for ovarian preservation. CONCLUSION: With ovarian laparoscopic transposition, ovarian function can be preserved in selected patients requiring first line radiotherapy for cancer of the cervix. After the age of 40 years, transposition should be restricted to small T1 tumors treated by brachytherapy. When EBRT is required for larger lesions, transposition should be reserved to younger patients.

[Randomized placebo trial of myeloprotection with goralatide in patients with squamous cell carcinoma of the upper respiratory and digestive tracts or esophagus, treated with a carboplatin-fluorouracil combination]. / Essai randomisé avec placebo de myéloprotection par le goralatide des patients présentant un carcinome épidermoïde des voies aérodigestives supérieures ou de l'oesophage, traités par l'association carboplatine-5 fluorouracile.

Eighty-four patients with locally advanced, non metastatic squamous cell carcinoma of head and neck or esophagus, were included in a multicentric double-blind randomized trial, comparing goralatide (12.5 or 62.5 micrograms/kg/day, d1-d4) to placebo, associated with carboplatin (400 mg/m2, d1) and 5-fluorouracile (1 g/m2/d continuous IV over 96 hours). Haematological toxicity was analysed on 221 cycles of chemotherapy. All but one patient were evaluable because of early death without haematological toxicity. No significant difference was observed for mean nadir of leukocytes, granulocytes, platelets counts and hemoglobin level. Duration of haematological toxicity was no significantly different for the two groups of patients. Anemia and lymphopenia were more frequent in the goralatide treated patients. Clinical and biological tolerability of goralatide was excellent.

Evaluation of whole abdominal irradiation in ovarian carcinoma with a four orthogonal fields technique.

PURPOSE: The purpose of this study is to evaluate the toxicity and the results of abdominopelvic irradiation with a four orthogonal field's technique in patients with ovarian carcinoma. METHODS AND MATERIALS: Between May 1981 and December 1990, 167 patients with ovarian carcinoma have been treated with whole abdominal irradiation: 62 patients with no or minimal residual disease < 2 cm after initial surgery (group 1) and 105 patients with no residual disease or macroscopic residual disease < 2 cm assessed by second-look surgery after incomplete debulking surgery and cisplatin-based polychemotherapy (group 2). Irradiation was performed by a four orthogonal field's technique. Thirty grays were given with a 25 MV photon beam (1.5 Gy/fraction/day, 20 fractions over 30 days). Boosts were performed in 50 cases (median dose of 15 Gy). RESULTS: With a median follow-up of 68 months, the 5-year actuarial survival rate was 50% in the entire group, 67% in group 1, 40% in group 2, and 84% in T1, 61.5% in T2, 38% in T3. Five-year actuarial survival was analyzed according to the residuum: (a) after initial surgery (no residual disease: 70%, residual disease: 36.5%), (b) after second-look surgery: 76% in patients with a negative second look, 66% in patients with microscopic residual disease, 22% in patients with macroscopic residual disease and secondary surgical reduction, and 10% in patients with small unresectable nodules. Nine percent of the patients failed to complete irradiation acute side effects related. Five percent required surgery for bowel obstruction. CONCLUSION: The abdominopelvic irradiation with this four orthogonal field's technique was associated with tolerable acute toxicity and a low risk of serious late complications. Similar late results to have been reported whole abdominal irradiation with chemotherapy in patients with negative or microscopic residual disease after surgery. Randomized trials comparing these two adjuvant treatments are warranted.

Acute antiemetic efficacy and safety of dolasetron mesylate, a 5-HT3 antagonist, in cancer patients treated with cisplatin. European Dolasetron Study Group.

Dolasetron mesylate (MDL 73,147EF), a new serotonin receptor (5-HT3) antagonist was administered to 164 cancer patients naive or non-naive to chemotherapy, in single, rising doses of 10, 20, 30, 40, or 50 mg i.v. 15 minutes prior to an infusion of cisplatin. The severity of nausea and number of episodes of emesis were recorded during the 24-hour period following cisplatin administration. There were significant differences between the dose groups, sex, and naive and non-naive patients. There were also significant dolasetron dose-dependent differences for no emesis (p = .01), less than 3 emetic episodes (p = .01), time-to-onset of nausea (p = .04), and time-to-onset of emesis (p = .003). The severity of symptoms was greater for females, for patients with previous chemotherapy, and with shorter duration of cisplatin infusion. Adjustment for these variables and the study center reduced the associations between the dose of dolasetron mesylate and the outcome variables. The principal adverse events were headache (11%) and diarrhea (6%). Dolasetron mesylate was well tolerated; a single dose of 40 or 50 mg controlled acute nausea and vomiting induced by highly emetogenic chemotherapy in the majority, in particular in chemotherapy-naive and male patients. In conclusion, 50 mg and a larger dose merit study in controlled trials with stratification for sex and previous chemotherapy.