G. Varuni Kondagunta

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.

Phase II Trial of Bortezomib for Patients With Advanced Renal Cell Carcinoma

PURPOSE To assess the efficacy and toxicity of bortezomib (Velcade; Milennium Pharmaceuticals Inc, Cambridge, MA; formerly PS-341) in patients with metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS Thirty-seven patients with metastatic RCC were treated with bortezomib. The first 25 patients enrolled onto the trial were treated with a dose of 1.5 mg/m2. The dose was decreased to 1.3 mg/m2 for the subsequent 12 patients, because more than 50% of the patients treated at the higher dose required dose reductions. Bortezomib was given by intravenous administration on a twice-weekly schedule for 2 weeks followed by 1 week without treatment until progression or unacceptable toxicity occurred. Twenty-three patients (62%) previously had undergone nephrectomy, and 19 patients (51%) had previously been treated with cytokine therapy. RESULTS Of the 37 assessable patients, the best response was a partial response in four patients (11%; 95% CI, 3% to 25%) and stable disease in 14 patients (38%; 95% CI, 23% to 55%). The four patients with partial response experienced response durations of 8, 8+, 15+, and 20+ months. Grade 2 or 3 sensory neuropathy was present in 10 patients (53%) overall. One patient in the 1.5 mg/m2 group had grade 3 sensory neuropathy; no grade 3 sensory neuropathy was seen in the 1.3 mg/m2 group. CONCLUSION The results of this trial suggest that bortezomib has an antitumor effect in individual patients with metastatic RCC. The small proportion of patients who achieved a partial response does not support routine use in metastatic RCC. Efforts to identify the molecular profile associated with clinical response or combination therapy with interferon alfa or other novel agents, may be considered.

Paclitaxel Plus Ifosfamide Followed by High-Dose Carboplatin Plus Etoposide in Previously Treated Germ Cell Tumors

PURPOSE To evaluate the optimal dose of carboplatin as well as the efficacy and tolerability of sequential, dose-intense chemotherapy with paclitaxel and ifosfamide followed by carboplatin and etoposide (TICE) plus peripheral-blood stem-cell (PBSC) support in patients with germ cell tumors (GCT) who are likely to experience treatment failure with conventional-dose salvage treatment. This prospective trial followed a similarly designed report of TICE, which used a different means of carboplatin dosing. PATIENTS AND METHODS The 48 patients entered onto this trial had progressive GCT and unfavorable prognostic features after chemotherapy. Two cycles of paclitaxel plus ifosfamide were administered with leukapheresis, followed by three cycles of carboplatin plus etoposide with reinfusion of PBSC. RESULTS Twenty-three (49%) of 47 assessable patients achieved a complete response (CR) to chemotherapy. An additional three patients (6%) achieved a CR to chemotherapy and surgery. The CR rate was 55%. Six patients experienced relapse, but 24 patients (51%) are alive and free of disease at a median follow-up time of 40 months. Four patients who experienced relapse or achieved an incomplete response were rendered disease free by salvage surgical resection. When combined with results of the prior trial of similar design, TICE chemotherapy yielded an overall CR of 56% (n = 84), with 50% of patients alive with no evidence of disease. CONCLUSION TICE is an effective and tolerable dose-intense treatment for patients with previously treated metastatic GCT who have a poor predicted outcome to conventional-dose salvage chemotherapy.

Etoposide and Cisplatin Chemotherapy for Metastatic Good-Risk Germ Cell Tumors

PURPOSE To assess response, overall survival, and relapse-free survival of patients with good-risk metastatic germ cell tumor (GCT) by International Germ Cell Consensus Classification Group (IGCCCG) criteria treated with four cycles of etoposide and cisplatin (EP). PATIENTS AND METHODS Two hundred eighty-nine patients with IGCCCG good-risk GCT were treated with four cycles of EP. EP consisted of four cycles of etoposide 100 mg/m2 and cisplatin 20 mg/m2 on days 1 to 5 every 21 days. RESULTS Two hundred eighty-two of 289 patients (98%) achieved a complete response; 269 (93%) responded to chemotherapy alone and 13 (5%) responded to chemotherapy plus surgical resection of viable disease (GCT other than mature teratoma). Seventeen (6%) experienced relapse, and nine (3%) died as a result of disease at a median follow-up of 7.7 years (range, 0.4 to 21.1 years). Sixty-two of 204 patients (30%) with nonseminoma had findings of teratoma or viable GCT at postchemotherapy surgery. CONCLUSION Four cycles of EP is a highly effective therapy for patients with good-risk GCT, with a high cure rate, low relapse rate, and little evidence of late relapse. Postchemotherapy surgery resection of residual disease remains an important aspect of treatment for these patients. Four cycles of EP is acceptable as a standard regimen for the treatment of good-risk metastatic GCT, and serves as an alternative to three cycles of bleomycin and etoposide before cisplatin.

Relapse-Free and Overall Survival in Patients With Pathologic Stage II Nonseminomatous Germ Cell Cancer Treated With Etoposide and Cisplatin Adjuvant Chemotherapy

PURPOSE To assess the long-term relapse-free survival and overall survival of patients with stage II nonseminomatous germ cell tumor (NSGCT) who received two cycles of adjuvant etoposide and cisplatin (EP) after primary retroperitoneal lymph node dissection. PATIENTS AND METHODS Eighty-seven patients with completely resected pathologic stage II NSGCT were treated with adjuvant EP chemotherapy. Adjuvant EP consisted of two cycles of etoposide (100 mg/m(2)) plus cisplatin (20 mg/m(2)) per day, administered days 1 to 5 at a 21-day interval. RESULTS Ten patients (11%) had pN1 disease, 73 (84%) had pN2 disease, and four (5%) had pN3 disease. Eighty-six patients received two cycles of EP, and one patient received an additional two cycles of EP after a transient marker increase after his first cycle. Eighty-seven patients are alive, and 86 patients (99%) remain relapse-free at a median follow-up of 8 years (range, 0.9 to 13.5 years). CONCLUSION Two cycles of adjuvant EP is highly effective in preventing relapse in patients with pathologic stage II pN1 and pN2 NSGCT. An alternative treatment strategy is surveillance with full-course chemotherapy at relapse. Because there is a higher risk of relapse for patients with pN2 disease, these patients are offered adjuvant chemotherapy.

Incidence of late-relapse germ cell tumor and outcome to salvage chemotherapy

PURPOSE To define the incidence, clinical features, and outcome to salvage chemotherapy in patients with late-relapse germ cell tumor (GCT) after a complete response to first-line chemotherapy. PATIENTS AND METHODS Two patient populations were examined. First, retrospective analysis of 246 patients treated on a clinical trial with salvage chemotherapy was performed; 29 patients with late-relapse GCT were identified and evaluated for treatment outcome and survival. Salvage regimens included paclitaxel, ifosfamide, and cisplatin, single agents, or a high-dose chemotherapy program. Second, the incidence of late relapse was assessed by retrospective analysis of 551 patients after a complete response (CR) to first-line chemotherapy. RESULTS Twenty-nine patients received salvage chemotherapy on a clinical trial for late relapse GCT. The median survival was 23.9 months. At a median follow-up of 50.6 months, there were nine survivors. The chemotherapy regimens varied, but the only CRs were observed in patients treated with paclitaxel, ifosfamide, and cisplatin. Seven (50%) of 14 patients treated with paclitaxel, ifosfamide, and cisplatin achieved a continuous CR. Among the second population of 551 patients who had previously achieved a CR to a first-line chemotherapy trial, 17 were identified as having a late relapse (3%). The median time to relapse for these 17 patients was 7.8 years. CONCLUSION Late-relapse GCT is uncommon and is associated with a poor prognosis resulting from a high degree of resistance to chemotherapy. Chemotherapy with paclitaxel, ifosfamide, and cisplatin followed by surgery may be effective in patients with late-relapse GCT who are not considered candidates for primary surgery.

Clinical Outcome and Predictors of Survival in Late Relapse of Germ Cell Tumor

PURPOSE Late relapse (LR) of germ cell tumor (GCT) is a well recognized entity associated with poor survival. We report on our experience with LR and determine predictors of survival. PATIENTS AND METHODS From 1990 to 2004, 75 patients were managed for LR of GCT at our institution. Clinical and pathologic parameters were reviewed. Estimates of cancer-specific survival were generated using the Kaplan-Meier method, and a Cox proportional hazards model was used to assess potential predictors of outcome. RESULTS The median time to LR was 6.9 years (range, 2.1 to 37.7 years). Overall, 56 patients (75%) had LR in the retroperitoneum, including 25 (93%) of 27 patients initially managed without retroperitoneal lymph node dissection. The 5-year cancer-specific survival (CSS) was 60% (95% CI, 46% to 71%). Patients who underwent complete surgical resection at time of LR (n = 45) had a 5-year CSS of 79% versus 36% for patients without complete resection (n = 30; P < .0001). The 5-year CSS for chemotherapy-naive patients was significantly greater than patients with a prior history of chemotherapy as part of their initial management (5-year CSS, 93% v 49%, respectively). In multivariable analysis of pretreatment parameters available at the time of LR, the presence of symptoms (hazard ratio [HR] = 4.9) and multifocal disease (HR = 3.0) were associated with an inferior CSS. CONCLUSION The data suggest that meticulous control of the retroperitoneum is critical to prevent LR in the retroperitoneum. In multivariable analysis, patients with a symptomatic presentation and those with multifocal disease have a significantly decreased survival. Survival is greatly improved if complete surgical excision of disease is attained.

Pathologic findings and clinical outcome of patients undergoing retroperitoneal lymph node dissection after multiple chemotherapy regimens for metastatic testicular germ cell tumors

Postchemotherapy surgery is an essential component in the management of patients with metastatic germ cell tumors (GCT). The authors assessed their institutional experience of retroperitoneal lymph node dissection (RPLND) after multiple chemotherapy regimens for advanced GCT.

Chemotherapy for Advanced Germ Cell Tumors

PURPOSE Germ cell tumors constitute the most curable of all cancers. Standard treatment of previously untreated and treated patients has evolved on the basis of prospective clinical trials and prognostic factors. This review summarizes the prognostic criteria on which treatment decisions may be based, and outlines the current treatment approaches. PATIENTS AND METHODS Randomized and nonrandomized trials of first-line, salvage, and palliative therapy and the role of surgery after chemotherapy were reviewed. In the treatment of previously untreated patients, emphasis was placed on interpretation of data of trials according to the International Germ Cell Cancer Collaborative Group model, which has evolved into a universally accepted classification algorithm for determining appropriate risk-directed chemotherapy. This system permits treatment choices based on the balance between benefit and toxicity and allows comparison of results across multiple clinical trials. RESULTS Standard therapy for good-risk patients is four cycles of etoposide plus cisplatin or three cycles of cisplatin, etoposide plus bleomycin (BEP x 3); both approaches cure approximately 90% of patients. After chemotherapy and normalization of markers, patients should generally undergo resection of residual masses. Approximately 75% of intermediate-risk and 45% of poor-risk patients group achieve a durable complete response with BEP x 4. Potentially curative options in the salvage setting include ifosfamide plus cisplatin-containing standard dose therapy and high-dose carboplatin plus stem-cell rescue. Surgery remains an essential component of care. CONCLUSION Curative therapy exists even in patients with resistant disease, and treatment choices can be based on established clinical criteria. Serum tumor markers and surgery after chemotherapy have essential roles in patient management

Medullary Renal Cell Carcinoma and Response to Therapy With Bortezomib

TO THE EDITOR: Metastatic non–clear cell renal carcinoma comprises several histologic subtypes, including medullary and collecting duct carcinoma. Medullary renal carcinoma is difficult to separate from collecting duct carcinoma morphologically, but has been diagnosed in patients with sickle cell disease or sickle cell trait. We previously reported a retrospective review of 64 patients with non–clear cell histology and found that patients had a median overall survival time of 9.4 months. Twenty-six (41%) of the 64 patients were identified with collecting duct or medullary pathology. These patients were treated with cytokine therapy or systemic chemotherapy. There were no responses to cytokine therapy. One of the patients with collecting duct/medullary carcinoma had a 5-month-long partial response to systemic chemotherapy. Median survival for the patients of the collecting duct subset was 11 months. Partial responses to systemic chemotherapy have been reported elsewhere, but are rare and of short duration. In the September 15, 2004, issue of the Journal of Clinical Oncology, we reported a phase II study evaluating bortezomib, a proteasome inhibitor, in patients with advanced renal cell carcinoma. Of 37 assessable patients, four patients achieved a partial response to therapy; three patients had clear cell histology and one patient had medullary carcinoma. We now report the updated follow-up of the medullary carcinoma patient. The patient received 7 months of bortezomib and achieved a complete response. He remains without evidence of disease after more than 27 months of follow-up. Metastatic non–clear cell renal carcinoma is a rare entity with a poor outcome. Given the small numbers, patients with non–clear cell renal carcinoma have not been well represented in clinical trials. Better molecular characterization will help to more accurately identify appropriate agents for this subset of patients. Further study of bortezomib in medullary renal carcinoma is indicated.