[The use of GnRH analogues in early and advanced breast carcinomas]. / Analogues de la LHRH: leur utilisation dans le traitement du cancer du sein en situation métastatique et adjuvante.

Breast cancer is often an estrogen-dependent disease. The primary goals of the treatment of breast carcinomas are multiple, depending on the situation in which the patients are treated. In adjuvant setting, the aims are to delete the time of relapse, to increase the overall survival, and to offer to the patients the best quality of life they may expect. Tamoxifen is the standard hormonal agent for premenopausal women with receptor-positive breast cancer. Recent data show an increasing role for aromatase inhibitors in postmenopausal women. In metastatic setting, the primary goals are improved quality of life and prolonged survival; effective therapies with minimal toxicity, such as endocrine therapy, are highly desirable and should be considered a primary option over chemotherapy for selected estrogen-receptor positive patients. Ovarian ablation has been worldwide used. Methods of irreversible ovarian ablation include surgical oophorectomy and ovarian irradiation. Potentially reversible castration can be medically accomplished using luteinizing hormone releasing hormone analogues (LHRH agonists). In the metastatic setting, ovarian ablation (induced by the use of LHRH agonists or by surgical ovarian ablation) and tamoxifen monotherapies produce comparable outcomes, and may be more effective when used together (combined estrogen blockade). In advanced breast cancer, the combination prolongs the progression-free survival and increases response rates and duration of response rate relative to the use of LHRH agonist alone. In the adjuvant setting, data suggest that ovarian ablation followed by tamoxifen produces similar results to those obtained with adjuvant chemotherapy in hormone-receptor positive breast cancer women. The value of combining these modalities remains unclear, but the addition of the LHRH analogue goserelin to standard treatment results in a significant benefit in terms of relapse-free and overall survival, especially for estrogen-receptor positive patients. Finally, considering the efficacy of the new aromatase inhibitors, the interest of combining these drugs with the LHRH analogues has yet to be defined, both for pre- and post-menopausal patients.

[Therapeutic intensification and autotransplantation of hematopoietic stem cells in metastatic breast cancers]. / Intensification thérapeutique et autogreffe de cellules souches hématopoïétiques dans les cancers du sein métastatiques.

The first studies on intensive chemotherapy for metastatic breast cancer conducted in the 80s were disappointing. Despite good response rates, the duration of remission was short and long-term survivals exceptional. Nevertheless, these phase I and II trials helped to develop a better understanding of the potential indications of this new therapeutic approach and apprehend its technical aspects. Over the last 5 years, considerable progress has been made in grafting techniques and hematopoietic support greatly improving the safety of the method. Notwithstanding the financial considerations involved, it must be noted that the efficacy autologous stem cell support, in terms of recurrence-free overall survival, has not yet been demonstrated although the (controversial) results of two randomized controlled trials have recently been published. In France, the PEGASE programs for the study of autologous stem cell support in breast cancer have been developed in an attempt to elucidate the question.

[High-dose therapy and hematopoietic cell autotransplantation in the treatment of adult gynecologic tumors]. / Intensification thérapeutique et autotransplantation de cellules souches hématopoïétiques dans le traitement des tumeurs gynécologiques de l'adulte.

Autologous bone marrow transplantation for the treatment of gynecologic tumors in adults remains an uncommon therapeutic approach. The feasibility of such high-dose therapies is clearly proved, especially with the advent of hematopoietic growth factors and the rescue by the peripheral stem cells to reduce the duration of the chemotherapy-induced myeloid aplasia. The question is to exactly define the place of high-dose therapy in the land of solid tumors. In the treatment of poor prognosis breast cancer, high-dose therapy with autologous bone marrow transplantation or with peripheral stem cells support is able to convert some patients with partial response into complete responders. However, the consequences on overall survival and disease-free survival are not convincing. For metastatic breast cancer and for poor-prognosis tumors (inflammatory breast cancer, axillary metastatic nodes > or = 8), the interest of high-dose therapy has to be determined by randomized studies. These studies are ongoing in USA and in France. For the treatment of poor-prognosis ovarian cancer, the situation is more difficult to appraise. Randomized studies have to be done to precisely define the interest of high-dose therapy in terms of response and disease-free survival for the treatment of ovarian carcinomas.

Phase II trial of 5-fluorouracil, leucovorin and cisplatin for treatment of advanced pancreatic adenocarcinoma.

BACKGROUND: Advanced pancreatic adenocarcinoma is a rapidly fatal disease for which an active chemotherapy regimen is sought. Here we report the outcome of a phase II trial to assess the toxicity and efficacy of a combination of 5-fluorouracil (5-FU), leucovorin and cisplatin (CDDP). METHODS: A regimen combining leucovorin (200 mg/m2/d x 5d), 5-FU (375 mg/m2/d x 5d in a 2-hour infusion) and CDDP (15 mg/m2/d x 5d) was given to 52 patients with histologically-proven, previously untreated, locally advanced (n = 13) and/or metastatic (n = 39) pancreatic adenocarcinoma. RESULTS: Of 48 patients evaluable for response, 10 achieved partial responses, for an overall response rate of 21% (95% CI 9.5%-32.5%), and a palliative effect was observed in 52%. The median survival was 9.5 months (18 months for locally-advanced and 5 months for metastatic disease) with a 1-year survival of 34.6% and a median progression-free survival of 4.5 months. Chemotherapy was well tolerated with grades 3 or 4 nausea/vomiting in 12%, diarrhea in 6%, anaemia in 17%, neutropenia in 12%, and thrombocytopenia in 10%. Eleven patients (21%) had Grade 2 peripheral neuropathy. CONCLUSION: The combination of leucovorin, 5-FU and CDDP seems to be an effective palliative treatment, with moderate toxic effects, in advanced pancreatic adenocarcinoma.

High dose chemotherapy with ifosfamide, carboplatin, and etoposide combined with autologous bone marrow transplantation for the treatment of poor-prognosis germ cell tumors and metastatic trophoblastic disease in adults.

BACKGROUND: A Phase I-II trial to assess the toxicity and efficacy of a tandem high dose chemotherapy combining ifosfamide, carboplatin, and etoposide in germ cell tumors and metastatic trophoblastic disease was performed. METHODS: Thirty-nine patients, with a total of 22 testicular tumors, 9 extragonadal germ cell tumors, 3 ovarian germ cell tumors, and 5 cases of metastatic trophoblastic disease, received tandem high dose therapy combining ifosfamide (7500-12,500 mg/m2), carboplatin (875-1225 mg/m2), and etoposide (1000-1250 mg/m2), followed by bone marrow reinfusion. Among the 39 patients, 33 were refractory to cisplatin- or carboplatin-based regimen and the response of 37 could be evaluated; 69 cycles of this tandem high dose therapy were administered. RESULTS: The overall response rate was 46%, including a complete response (CR) rate of 35%. Of 21 patients with testicular tumors who could be evaluated, 10 (47%) achieved a CR. No CRs were obtained in patients with refractory extragonadal germ cell tumors. Nine partial responders after the first cycle became complete responders after the second. Nine (23%) of the patients were long term survivors (> 18 months), 7 of them in continuous CR. Side effects primarily were renal toxicity and enterocolitis. Seven patients (18%) died of therapy-related be explored and the maximum tolerated doses of this three-drug regimen remain to be determined. CONCLUSION: This tandem therapeutic regimen is able to overcome resistance to a platinum-based regimen in highly refractory germ cell tumors and gestational trophoblastic disease and to cure a number of patients.

[Therapeutic intensification and hematopoietic stem cell autotransplantation in the treatment of solid tumors in adults: principles, realization and application to the treatment of germ cell, trophoblastic, breast, ovarian and small-cell bronchial tumors. 1]. / Intensification thérapeutique et autotransplantation de cellules-souches hématopoïétiques dans le traitement des tumeurs solides de l'adulte: principes, réalisation et application au traitement des tumeurs germinales, trophoblastiques, mammaires, ovariennes et bronchiques à petites cellules. Première partie.

Autologous bone marrow transplantation for the treatment of solid tumors in adults remains an uncommon therapeutic approach. The feasibility of such high-dose therapies is clearly proved, especially with the advent of hematopoietic growth factors and the rescue by the peripheral stem cells to reduce the duration of the chemotherapy-induced myeloid aplasia. The question is to exactly define the place of high-dose therapy in the land of solid tumors. For the treatment of primary chemoresistant gonadal germ-cell tumors, the possibility to cure the patients and the interest of high-dose therapy with autologous bone marrow transplantation are clearly demonstrated. As consolidation for the treatment of poor prognosis tumors, the place of high-dose therapies remains moot. For the treatment of chemoresistant extragonadal germ-cell tumors, especially for primary mediastinal tumors, the level of resistance to cisplatin-based chemotherapy regimens is generally too high to be overcome by intensive therapies given as single course or as tandem courses. However in association with debulking surgery, this therapeutic approach has to be considered for some patients. In the treatment of poor prognosis breast cancer, high-dose therapy with autologous bone marrow transplantation or with peripheral stem cells support is able to convert some patients with partial response into complete responders. However, the consequences on overall survival and on disease-free survival are not evident. For metastatic breast cancer and for poor-prognosis tumors (inflammatory breast cancer, axillary metastatic nodes > or = 8), the interest of high-dose therapy has to be determined by randomized studies. These studies are ongoing in USA and in Europe. For the treatment of poor-prognosis ovarian cancer, the situation is more difficult to appraise. Once again, randomized studies have to be done to precisely define the place of high-dose therapy. In the land of small-cell lung carcinomas, high-dose therapy is actually forsaken by most of authors, even for limited diseases. The results of previous studies are disappointing. Moreover, occult medullary micrometastases involvement is frequent, once again even in limited diseases. However new therapeutic associations, as the ICE regimen (IFM, Carboplatin, VP-16) delivered as single or tandem therapy, have to be studied, especially as early consolidation therapy for the treatment of limited small-cell lung carcinomas.

Treatment of unresectable hepatocellular carcinoma with a combination of human recombinant alpha-2b interferon and doxorubicin: results of a pilot study.

Based on the in vitro and in vivo potentiation of the cytotoxic activity of chemotherapeutic agents by the interferons, a pilot study combining human recombinant alpha-2b interferon (IFN) and doxorubicin was conducted for the treatment of unresectable, histologically proven hepatocellular carcinoma. Between March 1988 and May 1990, 21 patients (median age: 60 years, range: 29-76) entered the study. The dose of doxorubicin was fixed at 35 mg/m2, every 3 weeks. The dose of alpha-2b IFN was 6 million U/m2 per day, 5 days a week. 3 patients (14%) obtained a partial response lasting 11, 16 and 30 months, and 1 had a stable disease during 8 months. The other 17 patients died within a median survival time of 4 months. All patients experienced flu-like symptoms. 7 patients experienced WHO grade III-IV haematological toxicity. We conclude that the association of alpha-2b IFN and doxorubicin is feasible, with respect to the use of doxorubicin at an inferior dose level than the same agent used without IFN. The response rate is comparable to that observed with doxorubicin used alone. Further phase I studies and randomised trials are required to confirm the role of this regimen in the treatment of unresectable hepatocellular carcinoma.