Intensive chemotherapy as salvage treatment for solid tumors: focus on germ cell cancer

Germ cell tumors present contrasting biological and molecular features compared to many solid tumors, which may partially explain their unusual sensitivity to chemotherapy. Reduced DNA repair capacity and enhanced induction of apoptosis appear to be key factors in the sensitivity of germ cell tumors to cisplatin. Despite substantial cure rates, some patients relapse and subsequently die of their disease. Intensive doses of chemotherapy are used to counter mechanisms of drug resistance. So far, high-dose chemotherapy with hematopoietic stem cell support for solid tumors is used only in the setting of testicular germ cell tumors. In that indication, high-dose chemotherapy is given as the first or late salvage treatment for patients with either relapsed or progressive tumors after initial conventional salvage chemotherapy. High-dose chemotherapy is usually given as two or three sequential cycles using carboplatin and etoposide with or without ifosfamide. The administration of intensive therapy carries significant side effects and can only be efficiently and safely conducted in specialized referral centers to assure optimum patient care outcomes. In breast and ovarian cancer, most studies have demonstrated improvement in progression-free survival (PFS), but overall survival remained unchanged. Therefore, most of these approaches have been dropped. In germ cell tumors, clinical trials are currently investigating novel therapeutic combinations and active treatments. In particular, the integration of targeted therapies constitutes an important area of research for patients with a poor prognosis.

Intensive chemotherapy as salvage treatment for solid tumors: focus on germ cell cancer.

Germ cell tumors present contrasting biological and molecular features compared to many solid tumors, which may partially explain their unusual sensitivity to chemotherapy. Reduced DNA repair capacity and enhanced induction of apoptosis appear to be key factors in the sensitivity of germ cell tumors to cisplatin. Despite substantial cure rates, some patients relapse and subsequently die of their disease. Intensive doses of chemotherapy are used to counter mechanisms of drug resistance. So far, high-dose chemotherapy with hematopoietic stem cell support for solid tumors is used only in the setting of testicular germ cell tumors. In that indication, high-dose chemotherapy is given as the first or late salvage treatment for patients with either relapsed or progressive tumors after initial conventional salvage chemotherapy. High-dose chemotherapy is usually given as two or three sequential cycles using carboplatin and etoposide with or without ifosfamide. The administration of intensive therapy carries significant side effects and can only be efficiently and safely conducted in specialized referral centers to assure optimum patient care outcomes. In breast and ovarian cancer, most studies have demonstrated improvement in progression-free survival (PFS), but overall survival remained unchanged. Therefore, most of these approaches have been dropped. In germ cell tumors, clinical trials are currently investigating novel therapeutic combinations and active treatments. In particular, the integration of targeted therapies constitutes an important area of research for patients with a poor prognosis.

Effect of ABCB1 C3435T polymorphism on docetaxel pharmacokinetics according to menopausal status in breast cancer patients.

BACKGROUND: It can be hypothesised that inherited polymorphisms in the drug-transporter ABCB1 gene may interfere with interindividual variations in drug response in breast cancer patients. Docetaxel is a substrate for ABCB1 whose function has been shown to be modulated by oestrogen and progesterone. METHODS: Whether ABCB1 polymorphisms including T-129C, A61G, C1236T, G2677T/A and C3435T polymorphisms could account for variations in the disposition of docetaxel and whether menopausal status at the time of diagnosis might interact with this effect were analysed in women receiving neoadjuvant chemotherapy for breast cancer (n=86). RESULTS: A highly significant association was observed, but restricted to premenopausal women (n=53), between the pharmacokinetics of docetaxel and C3435T polymorphism, as patients with CC genotype had lower mean values of the area under the plasma concentration-time curve (AUC) of docetaxel than patients with CT and TT genotypes (P<0.0001). Comparison between pre- and postmenopausal women with the same C3435T genotype yielded a significant difference in docetaxel AUC only for CC genotype (P<0.0001). CONCLUSION: These results suggest that C3435T polymorphism genotyping and menopausal status at the time of diagnosis might be useful when considering chemotherapy regimens including docetaxel in breast cancer patients.

[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.

Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study.

BACKGROUND: Since gemcitabine-oxaliplatin (GEMOX) has been used in pancreatic adenocarcinoma, we studied its activity and tolerability in advanced biliary tract adenocarcinoma (ABTA). PATIENTS AND METHODS: Consecutive adult patients with confirmed ABTA were recruited from four centers. Those in group A had performance status (PS) 0-2, bilirubin <2.5x normal and received GEMOX as first-line chemotherapy. Those in group B had PS >2 and/or bilirubin >2.5x normal and/or prior chemotherapy. All received gemcitabine 1000 mg/m2 as a 10 mg/m2/min infusion on day 1, followed by oxaliplatin 100 mg/m2 as a 2-h infusion on day 2, every 2 weeks. RESULTS: Tumor sites were gallbladder (19), extrahepatic bile ducts (5), ampulla of vater (3) and intrahepatic bile ducts (29). Results for group A (n = 3) were: objective response 36% [95% confidence interval (CI) 18.7% to 52.3%], stable disease 26%, progressive disease 39%, median progression-free survival (PFS) 5.7 months and overall survival (OS) 15.4 months. Results for group B (n = 23) were: objective response 22% (95% CI 6.5% to 37.4%), stable disease 30%, progressive disease 48%, PFS 3.9 months and OS 7.6 months. National Cancer Institute Common Toxicity Criteria grade 3-4 toxicities were neutropenia 14% of patients, thrombocytopenia 9%, nausea/vomiting 5% and peripheral neuropathy 7%. CONCLUSION: The GEMOX combination is active and well tolerated in ABTA.

[Adenocarcinoma of the pancreas. Diagnosis and evaluation]. / Adénocarcinome du pancréas. Diagnostic et bilan.

SYMPTOMS: Pain, jaundice, or weight loss are the presenting features of 90% of the cases. Patients with tumors of the body or the tail of the pancreas do not rapidly develop jaundice. Therefore, their diagnosis is delayed and metastasis are more frequently detected at diagnosis. RADIOLOGIC DIAGNOSIS: The diagnosis may be established by ultrasonography, endoscopic ultrasonography and most importantly by CT scan with helicoidal continuous acquisition and contrast injection. However, these methods do not efficiently detect tumors smaller than 2 cm or with only superficial peritoneal involvement. Laparoscopy and angiography are used less and less frequently to evaluate resectability. The diagnostic work-up with CT scanning is able to anticipate resectability in 50 to 90% of the cases. PATHOLOGY: Histopathology must be obtained since 10% of the pancreatic carcinoma are not of the ductal type and not all pancreatic tumors are malignant. When a pathological specimen cannot be obtained during surgery, a cytology specimen may be obtained with a fine needle guided by CT scan. PROGNOSIS: Survival depends on the possibility of a complete resection of the tumor. If complete resection is obtained, the prognostic factors are in decreasing importance: tumor size, lymphatic and vascular involvement, and invasion of peri-pancreatic tissues.

[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.

[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.