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.

Phase II study of pirarubicin (THP) in patients with cervical, endometrial and ovarian cancer: study of the Clinical Screening Group of the European Organization for Research and Treatment of Cancer (EORTC).

From 1986 to 1990, a multicentric phase II study was conducted with pirarubicin, a new semi-synthetic anthracyclin[4'-O-tetrahydropyranyl-adriamycin (THP)]. 87 patients with advanced gynaecological cancers were treated: epidermoid cervical carcinoma (n = 31), adenocarcinoma of the endometrium (n = 28) and ovarian adenocarcinoma (n = 28). THP was administered by short intravenous infusion, for 3 consecutive days, every 3 weeks. The initial dose of THP was 25 mg/m2 day (25% of patients) which was then reduced to 20 mg/m2 day. The average number of courses was 3.7 (range 1-10). The cumulative THP dose was 180 mg/m2 (range 56-594) in cervix and endometrial tumours and 121 mg/m2 (range 58-425) in ovarian tumours. Myelosuppression was the major observed toxicity with grade 3-4 leukopenia and thrombocytopenia in 62 and 19% of the patients, respectively. Severe general complications occurred in 6% of the patients with three fatalities due to infections. Gastro-intestinal side-effects were frequent and usually mild (7% of grade 3 vomiting). 48% of the patients showed alopecia, which was complete in 9 cases (10%). 3 patients experienced cardiac events. No significant antitumoral activity was observed in patients who had failed to respond to previous chemotherapy. Promising antitumoral activity was noticed in untreated cervico-uterine carcinomas with 19% partial responses and 12% complete responses (CR). THP activity was lower in endometrial carcinomas (9.5% CR). Results were found to be negligible in ovarian cancer patients, most of them being refractory to previous chemotherapy containing an anthracyclin compound. On the basis of these results, the definite role of THP in gynaecological cancers deserves to be studied in more favourable programmes (e.g. in combined protocols as first-line chemotherapy).

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.

Analysis of a series of sixty soft tissue sarcomas in adults treated with a cyclophosphamide-vincristine-adriamycin-dacarbazine (CYVADIC) combination.

From 1976 to 1983, a group of 60 adult patients presenting with metastatic and/or locally advanced soft tissue sarcomas was treated with combination chemotherapy consisting in cyclophosphamide, vincristine, adriamycin, and DTIC (CYVADIC). A tumor response was obtained for 29 patients (48.3%), with 4 (6.7%) cases of complete regression. The median duration of the response was 10 months. Responses were noted in 14/22 patients receiving induction chemotherapy for advanced, and previously nonirradiated, primary tumors; among the patients with metastatic disease tumor regression was recorded in 17/32 patients with pulmonary metastases, but in none of the patients with metastases at other sites. Moreover, the attainment of a response was found to correlated with the patient's general condition, while response duration depended on the histoprognostic grade of the tumors.

The strategy of treatment of Hodgkin's disease.

The treatment of Hodgkin's disease necessitates, in most cases, an association of radiotherapy for the macroscopic tumoral masses and chemotherapy for the cells generalized in the organism. Whenever a systematic chemotherapy is associated with radiotherapy, a precise staging topography with laparotomy is useless. The current therapeutic trials should seek methods to lighten these treatments by determining the best equilibrium between the two principal methods and by specifying the ventual place of immunotherapy. The present possibility of curing more than three-fourths of Hodgkin's patients incites us to look for means of reducing the treatment and its inconveniences for the curable forms, and search for more active or tolerable treatments for the uncurable forms.

BCG in the immunotherapy of non-Hodgkin's malignant lymphomas: preliminary results of a controlled trial.

Thirty-three patients exhibiting non-Hodgkin's malignant lymphoma with one or more criteria of poor prognosis and in whom complete remission had been induced by an association of chemo + radio + chemotherapy were randomized to either receive BCG or no further treatment. The present results indicate that BCG may be useful to maintain remission in about one-third of the patients, but these results are not yet significant.

Cisplatinumdiamminodichloride (CPDD) in chemotherapy of cancers: a phase II therapeutic trial.

We have conducted a phase II trial of cisplatinumdiamminodichloride (CPDD) which not only demonstrated its remarkable activity in embryonic carcinoma of the testes, but also in ovarian carcinoma, in melanoma, and in epidermoid carcinoma, especially of the head and of the uterus cervix. Its toxicity, manifested mainly in the digestive and renal tracts, confines its administration to hospitalized patients only. This compound is now indicated in combination therapy for the above-mentioned tumors.

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.

Malignant lymphoplasmacytoid lymphomas. Clinical and evolutive data.

A series of 31 cases of malignant lymphoplasmacytoid lymphomas (excluding Waldenström disease) is analyzed. Two-thirds of the patients initially had localizations elsewhere than in the lymph nodes and presented clinical stage I or II. The median survival is around 4 years and is particularly favorable for stage I and II patients who have received an association of radiotherapy and systematic chemotherapy; the estimated "cure rate" for these patients is around 80%.

[Permanent survey in the cancerology. Evaluation of the first three years of application of an automated system for recording and analysis of cancer data. Information Unit of the National Federation of French Cancer Control Centers]. / Enquête permanente en cancérologie. Bilan des trois premières années d'application d'un système automatisé de recueil et de traitement des informations (SARTIC). Unité d'informatique de la Fédération Nationale des Centres de Lutte contre le Cancer de France (F.N.C.L.C.C.F.).

A general oncological file system has been perfected and used since 1975 for the recording and analysis of data from twenty French centres. By virtue of the use of common basic language, the structures for the collection of information which have been developed (basic card containing clinical and therapeutic data as well as information concerning the course of the disease) represent a normalised medical record which has proved to be a useful tool in establishing regular statistical reviews (more than 265,000 records have been analysed in 3 years). This automatized system for the collection and exploitation of data offers a method which is suitable for studies aimed at improving knowledge of many aspects of malignant disease and the conditions of treatment. It makes possible the rapid collection of large numbers (more than 65,000 carcinomas in 2 years, including almost 40,000 not yet treated). Thorough analysis aids in revealing valuable facts, carrying out epidemiological studies and in perfecting therapeutic orientations.

[Rationalization of adjuvant chemotherapy by induction chemotherapy]. / Rationalisation de la chimiothérapie adjuvante par une chimiothérapie d'induction.

An induction chemotherapy, before any local treatment, allows to precise the chemosensitivity of the primary tumor. These data may help to improve indication and type of a further adjuvant chemotherapy. However there are many biological differences between different sites of the same tumor and along the time, without or after treatment. It is thus impossible to be sure that a chemotherapeutic regimen effective as first treatment on the primary will be equally active on micro-metastases some months later. Many questions in this field will be answered only by controlled studies and careful observations.

[10-year experience in the chemotherapy of epidermoid carcinomas of the upper aerodigestive system (5 protocols - 458 patients)]. / Dix ans d'expérience de la chimiothérapie des carcinomes épidermoïdes des voies aéro-digestives supérieures (5 protocoles - 458 malades).

The authors report protocols and results observed with various palliative chemotherapy, used successively against epidermoid carcinomas of head and neck area. This study was followed up during the last ten years by a group of physicians working in 8 specialized oncological centers. The poor prognosis and efficiency of antimitotic drugs in head and neck carcinomas require analyse of a great number of patients files. The cooperative work of several teams allows for more rapidly significant results. Each protocol was closed after a two year period. The protocols were dropped one after another, in order to provide a greater efficiency and a lower toxicity. It was possible to confirm the limited efficiency of "heavy" protocols and the most useful association. The members of this group now pursue a randomised study comparing the results obtained with cis-platyl used alone or in addition to three other drugs. The aim of this study is to assess which is more efficient and less toxic.

[Ovarian cancer: role of medical treatment]. / Cancers de l'ovaire: place des traitements médicaux.

The objective of medical treatment is to define the most active regimen and to combine them with optimal efficiency in the overall management of ovarian cancer patients, according to the results of surgical examination and the radiotherapeutic possibilities. The chemotherapy of common epithelial tumours is basically composed of alkylating agent, adriamycin, cis-platinum and hexamethylmelamine. The combination of these drugs leads to a high rate of surgically controlled tumor regressions and more complete responses, the only treatment which significantly increases survival. Results are less efficient for relapses or after failure of first line chemotherapy. The adjuvant chemotherapy of malignant germ cell tumours is used more and more often. The present indications of hormonotherapy are limited. Immunostimulant agents are being studied by several assays and preliminary results are interesting.

[Hormonotherapy of metastatic breast cancer with tamoxifen and medroxyprogesterone acetate. Randomized trial comparing alternating sequences with successive applications]. / Hormonothérapie du cancer du sein métastatique par tamoxifène et acétate de médroxyprogestérone. Essai randomisé comparant des séquences alternées à des applications successives.

Sixty-eight women with metastatic breast cancer occurring less than five years positives after the treatment of the primary tumour, with estrogens and/or progesterone receptors (EPR), were randomized. Sixty-four patients were available for evaluation of efficacy and toxicity. Thirty patients received treatment A: tamoxifen 30 mg per day alternating every two weeks with medroxyprogesterone acetate (MPA) 1 000 mg per day orally. Thirty-four received treatment B: tamoxifen 30 mg per day and after relapse, high dosage of MPA alone. The distribution of the evaluable metastasis and the value of the ER are the same in the two groups. The total responses or the responses by metastatic site were as follows: complete response, one case in each treatment group, partial response, 6 and 10 cases, no change, 14 and 17 cases and progressive disease, 9 and 6 cases respectively. The duration of the response was the same in the two groups with a median of 6 months (extremes of 30 and 19 months). Among the patients under protocol B, 19 received MPA after failure of tamoxifen: eight responded (3 partial responses and 5 no change). Toxicity was slight but 2 treatments in group A were discontinued. Alternated sequential hormonal treatment is theoretically attractive for these patients with known and positive EPR but it is not more efficient than the two hormonotherapies applied successively.

[Palliative chemotherapy of adult soft tissue sarcomas with an association of cyclophosphamide-vincristine-adriamycine-dacarbazine (CYVADIC) (author's transl)]. / Chimiothérapie palliative des sarcomes des tissus mous de l'adulte par une association cyclophosphamide-vincristine-adriamycine-dacarbazine (CYVADIC).

From January 1976 to December 1979, 23 adults with advanced soft tissue sarcomas were treated with palliative chemotherapy associating cyclophosphamide, vincristine, adriamycin and dacarbazine (CYVADIC) according to two different schema administered successively. A higher than 50 per cent rate of tumoral response was observed in 52 per cent of cases with 13 per cent complete remissions. Median survival was 14 months in patients who responded to treatment, and 4 months in non-responders (p less than 0,01). Side effects were severe however, and it was necessary to discontinue treatment in 5 patients, and modify dosage in 9 other patients. The CYVADIC protocol is effective but requires some modifications to improve tolerance.

[Chemotherapy of malignant melanoma. Results of a controlled clinical trial comparing vincristine + dacarbazin (DTIC) with and without duborimycin (author's transl)]. / Chimiothérapie des mélanomes malins. Résultats d'un essai contrôlé comparant vincristine et dacarbazine (DTIC) avec ou sans duborimycine.

Adding duborimycin to the association of vincristine + DTIC in the treatment of malignant melanoma produces therapeutic results interesting but not statistically significant and not counter-balancing the toxic side effects. This study confirms the lack of positive results of polychemotherapy in melanoma as compared to treatment by an efficacious single drug therapy (DTIC); it also emphasizes the necessity of randomized studies so that valuable comparisons may be done.

[Anticancerous chemotherapy and the general practitioner]. / Chimiothérapie anticancéreuse et omnipraticiens

The evolution of anti-cancer chemotherapy has led to long duration treatments, which preferentially are given at home, with the participation of the general practitionner (G.P.). The indications and general supervision of these belong to the oncologist, so thus necessitates a coordinated effort between the many physicians. A postal inquiry has permitted the collection of the opinions of 169 G.P. (more than half of the consulted physicians) from the southwest of France, in the region depending on the Fondation Bergonié. Thus it was possible to establish the importance of this type of treatment for the majority of the G.P., the details of problems of practical application, and the value attached to the relationships with the oncologist, which need further development.

[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.

[Cancers of the breast at metastatic high-risk: prediction of survival by steroidal receptors]. / Les cancers du sein à haut risque métastatique: prédiction de la survie par les récepteurs stéroïdiens.

From 1982 to 1985, 279 patients with locally advanced breast cancer have been treated with induction chemotherapy, adjusted loco-regional treatment (surgery and/or radiotherapy) and adjuvant chemotherapy with or without immunostimulation. Overall and relapse free survivals are better for tumors with estrogen and progesterone receptors (EPR). For these patients, we may hope that tumoral reduction with hormonotherapy would get the same overall and relapse-free survivals as induction chemotherapy.

[Ovarian cancer in France. Epidemiological, clinical and histological status]. / Le cancer de l'ovaire en France. Bilan épidémiologique, clinique et histologique.

With 2 436 deaths in 1979, ovarian cancer is relatively infrequent in France comprising but 5 per cent of female mortality from malignant disease. However, the rate of increase in mortality is considerable, 70 per cent between 1955 and 1979 or 2,9 per cent per year, greater than that for female bladder and breast cancer. The estimated morbidity and mortality rates (age-adjusted to the world standard population) were 7,5 and 5,4 per 100,000 per annum respectively for 1979, figures in the mid range of international data. This is situated below the rates observed in Scandinavia and North America which occupied the first ranks. The high proportion of metastatic dissemination (55%) at the time of diagnosis and the variety of morphological types (80% being epithelial cancers) emerges from clinical data relating to a series of 2,937 ovarian cancers diagnosed by the "Enquête Permanente Cancer". The 5-year survival rate was 13 per cent with only 50 per cent being alive at the end of the first year. To improve these poor results it is necessary to identify new risk factors in a future French epidemiological study using case control and prospective approaches.