Multicenter Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib in Patients With Metastatic or Unresectable Transitional-Cell Carcinoma.

BACKGROUND: Sorafenib, an oral tyrosine kinase inhibitor, may enhance the antitumor activity of platinum-based chemotherapy in transitional-cell carcinoma. This study investigated the safety and clinical outcome of adding sorafenib to gemcitabine and carboplatin for patients with advanced transitional-cell carcinoma. PATIENTS AND METHODS: Subjects with metastatic or unresectable chemotherapy-naive TCC with Eastern Cooperative Oncology Group performance status 0 or 1 received gemcitabine (1000 mg/m2 on days 1 and 8) and carboplatin (area under the curve of 5 on day 1) with sorafenib (400 mg 2 times a day on days 2-19 every 21 days) for 6 cycles. Subjects with stable disease or partial or complete response continued to receive sorafenib until disease progression. The primary end point was progression-free survival (PFS) at 5 months with a secondary end point of response (partial or complete). RESULTS: Seventeen subjects were enrolled. The median number of cycles of gemcitabine and carboplatin with sorafenib provided was 4.4. A total of 15, 5, and 8 subjects required reductions of gemcitabine, carboplatin, and sorafenib, respectively. Thirteen subjects (76%) required multiple dose reductions. Eleven subjects (65%) were free of progression at 5 months. The overall response rate was 54% (95% confidence interval [CI], 0.28-077), with 4 patients experiencing complete response (24%; 95% CI, 0.07-0.50) and 5 partial response (29%; 95% CI, 0.10-0.56); 7 subjects (41%) had stable disease. Median PFS was 9.5 months (95% CI, 0.43-1.26), and median overall survival was 25.2 months (95% CI, 0.96-5.65). One-year PFS was 31%, and 1-year overall survival was 72%. Eleven subjects (65%) discontinued treatment because of toxicity. There were no toxic deaths. CONCLUSION: Gemcitabine and carboplatin with sorafenib showed clinical activity in advanced TCC, with some prolonged progression-free intervals. However, gemcitabine and carboplatin with sorafenib was associated with significant toxicity, causing discontinuation of therapy in most patients.

Combination of paclitaxel, ifosfamide, and cisplatin is an effective second-line therapy for patients with relapsed testicular germ cell tumors.

PURPOSE: The efficacy of paclitaxel was evaluated in combination with ifosfamide and cisplatin as second-line chemotherapy for patients with relapsed testicular germ cell tumors (GCTs). PATIENTS AND METHODS: Forty-six patients with progressive metastatic GCTs were treated with paclitaxel and ifosfamide plus cisplatin (TIP) as second-line therapy. Eligibility required that patients have both a testis primary tumor site and a prior complete response (CR) to a first-line chemotherapy program, which had been identified previously as favorable prognostic factors to conventional-dose salvage chemotherapy. RESULTS: Thirty-two (70%) of 46 patients achieved a CR to treatment. Three patients (7%) who achieved a CR relapsed after TIP chemotherapy. Twenty-nine patients are continuously disease free at a median follow-up time of 69 months, resulting in a 63% durable CR rate and a 2-year progression-free survival rate of 65% (95% CI, 51% to 79%). CONCLUSION: Four cycles of TIP as second-line therapy achieved a durable CR rate in a high proportion of patients with relapsed testicular GCT. The high CR rate emphasizes the importance of patient selection according to prognostic factors to achieve a favorable outcome to conventional-dose salvage therapy.

Chemotherapy for teratoma with malignant transformation.

PURPOSE: Teratoma with malignant transformation (MT) is a well-described entity that refers to the MT of a somatic teratomatous component in a germ cell tumor (GCT) to a histology that is identical to a somatic malignancy (eg, rhabdomyosarcoma [RMS]). Surgical resection has been the mainstay of therapy for localized transformed disease because these tumors are thought to be resistant to standard treatment. We report that chemotherapy has a role in selected patients with MT, determined by cell type. PATIENTS AND METHODS: Chemotherapy was administered to 12 patients with MT of GCT limited to a single cell type (two patients with primitive neuroectodermal tumors, five with undifferentiated RMS, one with anaplastic small-cell tumor, two with adenocarcinoma, and two with leukemia); 10 patients had measurable disease. GCT origin was confirmed by molecular cytogenetics in five patients. Each patient received chemotherapy regimens based on the specific malignant cell observed in the transformed histology. RESULTS: Seven patients with measurable disease achieved a partial response, with the duration of response ranging between 1 month and 7 years. Three of those patients are alive. Three patients did not respond to treatment, and all of those patients died as a result of their disease. CONCLUSION: Chemotherapy for MT limited to a single cell type may result in major responses and long-term survival in selected patients. Local therapy after chemotherapy is an important component of treatment to achieve maximum response.

Cluster analysis of p53 and Ki67 expression, apoptosis, alpha-fetoprotein, and human chorionic gonadotrophin indicates a favorable prognostic subgroup within the embryonal carcinoma germ cell tumor.

PURPOSE: The prognostic information provided by alpha-fetoprotein and human chorionic gonadotrophin in the management of germ cell tumor (GCT) patients is a biochemical reflection of tumor differentiation. Ki67, p53, and apoptosis have been found to be related to proliferation (Ki67), cell death (p53, apoptosis), and possibly differentiation chemoresistance (p53). We sought to determine whether simultaneous expression of one or more of these markers could identify clinically relevant subgroups of patients with nonseminomatous GCT (NSGCT). PATIENTS AND METHODS: These five marker values were obtained for 95 previously untreated patients with embryonal carcinoma with or without other germ cell components. A multivariate cluster analysis was performed to identify patients with similar marker patterns. RESULTS: One prominent cluster (n = 37; 36 testis retroperitoneum), consisting of 26 (70%) good-risk (GR), nine (24%) intermediate-risk (IR), and two (6%) poor-risk (PR) patients, as defined by the International Germ Cell Consensus Cancer Group (IGCCCG), was observed. The 5-year survival of the prominent cluster (with 30% IR/PR patients) was 94% (95% confidence interval [CI], 86% to 100%), which is comparable to the 91% (95% CI, 89% to 93%) 5-year survival of the IGCCCG GR patients. IGCCCG risk status (P =.005) and cluster affiliation (P =.04) were independent predictors of outcome with hazard ratios of 5.0 (95% CI, 1.6 to 15.4) and 4.6 (95% CI, 1.04 to 20.1), respectively. CONCLUSION: These results suggest that there is a subgroup of NSGCT patients with embryonal carcinoma (with or without other histologies) with a specific tumor biology profile (high Ki67, low apoptosis, and low p53) whose survival is better than that of the overall patient group. The unexpectedly good outcome for the prominent cluster and independent-risk status suggest that subgroups of GCT reflecting different abilities to respond to treatment exist within IGCCCG prognostic categories.

Characteristic promoter hypermethylation signatures in male germ cell tumors.

BACKGROUND: Human male germ cell tumors (GCTs) arise from undifferentiated primordial germ cells (PGCs), a stage in which extensive methylation reprogramming occurs. GCTs exhibit pluripotentiality and are highly sensitive to cisplatin therapy. The molecular basis of germ cell (GC) transformation, differentiation, and exquisite treatment response is poorly understood. RESULTS: To assess the role and mechanism of promoter hypermethylation, we analyzed CpG islands of 21 gene promoters by methylation-specific PCR in seminomatous (SGCT) and nonseminomatous (NSGCT) GCTs. We found 60% of the NSGCTs demonstrating methylation in one or more gene promoters whereas SGCTs showed a near-absence of methylation, therefore identifying distinct methylation patterns in the two major histologies of GCT. DNA repair genes MGMT, RASSF1A, and BRCA1, and a transcriptional repressor gene HIC1, were frequently methylated in the NSGCTs. The promoter hypermethylation was associated with gene silencing in most methylated genes, and reactivation of gene expression occurred upon treatment with 5-Aza-2' deoxycytidine in GCT cell lines. CONCLUSIONS: Our results, therefore, suggest a potential role for epigenetic modification of critical tumor suppressor genes in pathways relevant to GC transformation, differentiation, and treatment response.

The future of therapy for nonseminomatous germ cell tumors.

This article has reviewed recent advances in understanding the molecular mechanisms of germ cell transformation, germ cell tumor differentiation, and germ cell tumor chemotherapy sensitivity and resistance. Future developments should include the following: The use of high-throughput techniques to assess tumor biology and evaluate new markers will allow more sophisticated assessment of prognosis. Future therapy will use oligonucleotide chips, perhaps specific to germ cell tumors or gene products associated with drug resistance, to assign treatment (radiation, RPLND, chemotherapy). The pathways associated with metastases and resistance will either replace or amplify the current risk algorithms and the clinician's ability to select therapy. The same high-throughput techniques will identify critical molecules and pathways, providing new specific treatment targets. Cell cycle-specific targets are an ideal focus of study, because genes abrogating normal cell cycle control and promoting germ cell tumorigenesis are increasingly identified. In germ cell tumors, CCND2 and KIT are open to study. Molecular and genetic markers of differentiation are additional resistance markers and should be a focus of study. In this context, the treatment of malignant transformation and the prediction of teratoma at metastatic sites will take on a greater importance. Over the past 2 decades, the treatment of germ cell tumors has become well-defined. Further improvement requires that investigators find new markers corresponding to tumor phenotype. This achievement will prevent unnecessary treatment in patients destined to have a favorable outcome, and will target biologically unfavorable or resistant disease for new therapy developed specifically to target the molecular or genetic defects that disrupt normal cell cycle control.