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.