Phase II trial of lenalidomide in patients with metastatic renal cell carcinoma.

Lenalidomide (CC-5013) is a structural derivative of thalidomide, with antiangiogenic and immunomodulatory effects. Fourteen patients with metastatic renal cell carcinoma (RCC) were enrolled on a phase 2 trial of lenalidomide administered orally at 25 mg daily for 21 days followed by a rest period of 7 days. The best response was stable disease in eight patients (57%) of the 14 evaluable patients. Toxicities included fatigue, hyperglycemia, dyspnea, and myelosuppression with decreased hemoglobin, lymphopenia, and neutropenia. Lenalidomide is tolerable, but no objective responses were observed in this clinical trial.

Phase III randomized trial of conventional-dose chemotherapy with or without high-dose chemotherapy and autologous hematopoietic stem-cell rescue as first-line treatment for patients with poor-prognosis metastatic germ cell tumors.

PURPOSE: To investigate the role of high-dose chemotherapy (HDCT) as first-line treatment in patients with metastatic germ cell tumor (GCT) and poor-prognostic clinical features. Serum tumor marker decline during chemotherapy was assessed prospectively as a predictor of treatment outcome. PATIENTS AND METHODS: In this randomized phase III trial, previously untreated patients with intermediate- or poor-risk GCT received either four cycles of standard bleomycin, etoposide, and cisplatin (BEP alone), or two cycles of BEP followed by two cycles of HDCT containing carboplatin and then by hematopoietic stem-cell rescue (BEP + HDCT). Serum tumor markers alpha-fetoprotein and human chorionic gonadotrophin were correlated with treatment outcome as a secondary end point. RESULTS: Two hundred nineteen patients were randomly assigned: 108 to BEP + HDCT and 111 to BEP alone. The 1-year durable complete response rate was 52% after BEP + HDCT and 48% after BEP alone (P = .53). Patients with slow serum tumor marker decline (alpha-fetoprotein and/or human chorionic gonadotrophin) during the first two cycles of chemotherapy had a shorter progression-free survival and overall survival compared with patients with satisfactory marker decline (P = .02 and P = .03, respectively). Among 67 patients with unsatisfactory marker decline, the 1-year durable complete response proportion was 61% for patients who received HDCT versus 34% for patients receiving BEP alone (P = .03). CONCLUSION: The routine inclusion of HDCT in first-line treatment for GCT patients with metastases and a poor predicted outcome to chemotherapy did not improve treatment outcome. Frequent serum marker determinations to estimate marker decline during the first two cycles of BEP chemotherapy provide a clinically useful estimate of outcome.

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.

Treatment outcome for metastatic papillary renal cell carcinoma patients.

BACKGROUND: Most clinical trial reports in metastatic renal cell carcinoma (RCC) do not distinguish between histologic subtypes, making it difficult to assess specific treatment efficacy. The current retrospective study sought to define clinical features and outcome data for metastatic papillary RCC. METHODS: Clinical features, treatment outcome, and survival were evaluated in 38 patients with metastatic papillary RCC who underwent clinical evaluation at Memorial Sloan-Kettering Cancer Center (MSKCC) between 1985 and 2005. Twenty-three of 513 individuals were identified from a clinical trial database, 14 of 1895 from a surgery database, and 1 of 357 from a pathology database. A literature review of systemic therapy in metastatic papillary RCC was performed. RESULTS: Among the 38 patients, 30 had been treated at MSKCC with various systemic therapies, including cytokines. Twelve therapies resulted in stable disease, 30 in initial progression of disease, and 1 in an unknown response. One patient had a partial response to sunitinib, a novel multitargeted tyrosine kinase inhibitor. The median overall survival time for the entire study group was 8 months (95% confidence interval, 5-12). A literature review on treatment of metastatic papillary RCC produced 4 reports, confirming a lack of efficacy for systemic therapy. CONCLUSIONS: A resistance to systemic therapy characterizes patients with metastatic papillary RCC. Further understanding of the genetics and molecular biology and subtypes involved may provide the basis for more effective agents. Treatment with targeted therapies or other experimental agents is warranted.

A brief symptom index for advanced renal cell carcinoma.

BACKGROUND: Our objective was to test a brief, symptom index for advanced renal cell carcinoma, a disease affecting over 38,000 Americans each year and often diagnosed in late stages. METHODS: We conducted secondary data analyses on patient-reported outcomes of 209 metastatic renal cell carcinoma patients participating in a Phase III clinical trial. Patient-reported outcomes, obtained from the FACT-Biological Response Modifier (FACT-BRM) scale, were available at baseline, 2, and 8 weeks. We analyzed data from eight FACT-BRM items previously identified by clinical experts to represent the most important symptoms of advanced renal cell carcinoma. Items comprising this index assess nausea, pain, appetite, perceived sickness, fatigue and weakness, with higher scores indicating fewer symptoms. We determined reliability and validity of the index and estimated a minimally important difference. RESULTS: The index had excellent internal reliability at all three time points (alphas > or = 0.83). Baseline scores were able to discriminate patients across Karnofsky performance status, number of metastatic sites, and risk group categories (ps < .01). Mean index scores declined over time likely indicative of the toxic nature of the administered treatments. Distribution- and anchor-based methods converged on a minimally important difference estimate of 2 to 3 points. CONCLUSION: The 8-item index of patient-reported symptoms of renal cell carcinoma appears to be a psychometrically sound measure. It is a brief, reliable, and valid measure that can easily be adapted for use in clinical trials and observational studies.

A phase II trial of 17-(Allylamino)-17-demethoxygeldanamycin in patients with papillary and clear cell renal cell carcinoma.

The aim of this study was to determine the antitumor activity of 17-(Allylamino)-17-demethoxyge-ldanamycin (17-AAG), a heat shock protein 90(hsp90) inhibitor in patients with metastatic papillary renal cell carcinoma (RCC) or metastatic clear cell RCC. Eligible patients were divided into 2 cohorts based on histological subtype: papillary or clear cell RCC. All patients had advanced RCC with measurable disease, a Karnofsky performance status of at least 70, and no evidence of brain metastases. Twelve patients with clear cell RCC and 8 patients with papillary RCC were treated with 17-AAG on this phase II trial. 17-AAG was given intravenously at 220 mg/m(2) twice weekly for 2 weeks followed by a week of rest. Cycle length was 21 days. No patient in either cohort achieved a complete or partial response. Toxicities included elevated liver function tests, optic neuritis, dyspnea, fatigue, and gastrointestinal side effects. Six of the 20 patients required dose reduction. At the dose and schedule used in this trial, 17-AAG did not achieve objective response in the treatment of clear cell or papillary renal cell carcinoma patients.

Sunitinib in patients with metastatic renal cell carcinoma.

CONTEXT: Current treatment options for metastatic renal cell carcinoma (RCC) are limited and there is a need to identify novel and effective therapies. Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor, which has shown activity in an initial study of cytokine-refractory metastatic RCC patients. OBJECTIVE: To confirm the antitumor efficacy of sunitinib as second-line treatment in patients with metastatic clear-cell RCC, the predominant cell type of this malignancy. DESIGN, SETTING, AND PATIENTS: Open-label, single-arm, multicenter clinical trial. Patients were enrolled between February and November 2004, with follow-up continuing until disease progression, unacceptable toxicity, or withdrawal of consent. The reported data apply through August 2005. Patients (N = 106) had metastatic clear-cell RCC, which had progressed despite previous cytokine therapy. INTERVENTION: Repeated 6-week cycles of sunitinib, 50 mg per day given orally for 4 consecutive weeks followed by 2 weeks off per treatment cycle. MAIN OUTCOME MEASURES: Assessment of clinical response, degree of tumor regression on imaging studies using the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Primary end point was overall objective response rate (complete plus partial). Secondary end points were progression-free survival and safety. Response was evaluated by independent third-party core imaging laboratory and by treating physicians (investigator assessment). RESULTS: All 106 patients received sunitinib and were included in the intent-to-treat population for safety analyses. Of these, 105 patients were evaluable for efficacy analyses. The objective response rate according to an independent third-party assessment resulted in 36 patients with partial response (34%; 95% confidence interval, 25%-44%), and a median progression-free survival of 8.3 months (95% confidence interval, 7.8-14.5 months). The most common adverse events experienced by patients were fatigue in 30 (28%) and diarrhea 21 (20%). Neutropenia, elevation of lipase, and anemia were the most common laboratory abnormalities observed in 45 (42%), 30 (28%), and 27 (26%) patients, respectively. CONCLUSION: The results of this trial demonstrate the efficacy and manageable adverse-event profile of sunitinib as a single agent in second-line therapy for patients with cytokine-refractory metastatic clear-cell RCC. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00077974.

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.

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.

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.

Presentation and subsequent publication rates of phase I oncology clinical trials.

BACKGROUND: Many trials submitted to scientific meetings are not reported in peer-reviewed journals. Results may vary substantially and the lack of final publication constitutes a form of reporting bias. The authors sought to determine the presentation and publication rates of Phase I trials submitted to a major oncology meeting and the factors impeding their subsequent publication. METHODS: The authors identified all Phase I studies submitted to the annual meeting of the American Society of Clinical Oncology in 1997, categorizing them as novel (agents not approved by the Food and Drug Administration at the time of submission) or nonnovel (at least one agent approved), and as industry sponsored or not. MEDLINE searches and an E-mailed questionnaire confirmed publication in peer-reviewed literature and the reasons for nonpublication. RESULTS: Approximately 54% of the 275 Phase I studies were selected for presentation. Abstracts reporting novel agents were more likely selected for presentation than those reporting nonnovel compounds (68% vs. 38%; P < 0.0001). Seventy-two percent of the presented abstracts were subsequently published, compared with 62% of those not presented (P = 0.08). The overall publication rate was 67% at 7.5 years. Presentation status was associated with time to publication (P = 0.01), with abstracts chosen for presentation being published sooner. The median time from presentation to publication was found to be 3.4 years. Lack of time and author relocation were the major obstacles to publication. CONCLUSIONS: The underreporting of final results of Phase I oncology trials remains a serious problem. In the future, investigators must commit to the publication of final results in a timely manner. Journals should provide mechanisms for rapid reporting of Phase I trials.

The development of a validated instrument to evaluate bowel function after sphincter-preserving surgery for rectal cancer.

PURPOSE: Sphincter-preserving surgery is technically feasible for many rectal cancers, but functional results are not well understood. Therefore, the purpose of this study was to develop an instrument to evaluate bowel function after sphincter-preserving surgery. METHODS: A 41-item bowel function survey was developed from a literature review, expert opinions, and 59 patient interviews. An additional 184 patients who underwent sphincter-preserving surgery between 1997 and 2001 were asked to complete the survey and quality-of-life instruments (Fecal Incontinence Quality of Life, European Organization for Research and Treatment of Cancer QLQ 30/Colorectal Cancer 38). A factor analysis of variance was performed. Test-retest reliability was evaluated, with 20 patients completing two surveys within a mean of 11 days. Validity testing was done with clinical variables (gender, age, radiation, length of time from surgery), surgical variables (procedure: local excision, low anterior resection, coloanal anastomosis), reconstruction (J-pouch, straight), anastomosis (handsewn, stapled), and quality-of-life instruments. RESULTS: The survey response rate was 70.1 percent (129/184). Among the 127 patients with usable data, 67 percent were male, the median age was 64 (range, 38-87) years, and the mean time for restoration of bowel continuity after sphincter-preserving surgery was 22.9 months. Patients had a median of 3.5 stools/day (range, 0-30), and 37 percent were dissatisfied with their bowel function. Patients experienced a median of 22 symptoms (range, 7-32), with 27 percent reported as severe, 37 percent as moderate, and 36 percent as mild. The five most common symptoms were incomplete evacuation (96.8 percent), clustering (94.4 percent), food affecting frequency (93.2 percent), unformed stool (92.8 percent), and gas incontinence (91.8 percent). The factor analysis identified 14 items that collapsed into three subscales: FREQUENCY (alpha = 0.75), DIETARY (alpha = 0.78), and SOILAGE (alpha = 0.79), with acceptable test-retest reliability for the three subscales and total score (0.62-0.87). The instrument detected differences between patients with preoperative radiation (n = 67) vs. postoperative radiation (n = 15) vs. no radiation (n = 45) (P = 0.02); local excision (n = 10) vs. low anterior resection (n = 55) vs. coloanal anastomosis (n = 62) (P = 0.002); and handsewn (n = 18) vs. stapled anastomosis (n = 99) (P = 0.006). The total score correlated with 4 of 4 Fecal Incontinence Quality of Life (P < 0.01) and 9 of 17 European Organization for Research and Treatment of Cancer subscales (all P < 0.01). CONCLUSIONS: Patients undergoing sphincter-preserving surgery for rectal cancer have impaired bowel function, and those treated with radiation, coloanal anastomoses, or handsewn anastomoses have significantly worse function. This reliable and valid instrument should be used to prospectively evaluate bowel function after sphincter-preserving surgery in patients undergoing rectal cancer 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.

Prognostic factors for survival of patients with stage IV renal cell carcinoma: memorial sloan-kettering cancer center experience.

Prospective identification of patients with stage IV renal cell carcinoma more likely to benefit from cytokine therapy could be used as a stratification factor in Phase III trials and in risk-directed therapy. The relationship between pretreatment clinical features and survival was evaluated in patients treated in Phase II and III clinical trials for metastatic renal cell carcinoma at the Memorial Sloan-Kettering Cancer Center. The first analysis was performed in 670 patients treated with cytokines or chemotherapy, and a multivariate model was created to predict survival. Studies that followed addressed four topics: (1) the survival of patients given interferon alpha as first-line therapy, (2) a comparison of survival for patients treated with chemotherapy versus cytokine therapy, (3) survival of patients with nonclear cell histologic features, and (4) survival of patients treated with a second-line therapy. Prognostic models based on pretreatment clinical and laboratory variables can help identify patients more likely to benefit from standard therapies, as well as assist in the interpretation of drug effectiveness in Phase II clinical trials. Investigations into new prognostic factors based on tumor biology are needed and of high priority.

Role of promoter hypermethylation in Cisplatin treatment response of male germ cell tumors.

BACKGROUND: Male germ cell tumor (GCT) is a highly curable malignancy, which exhibits exquisite sensitivity to cisplatin treatment. The genetic pathway(s) that determine the chemotherapy sensitivity in GCT remain largely unknown. RESULTS: We studied epigenetic changes in relation to cisplatin response by examining promoter hypermethylation in a cohort of resistant and sensitive GCTs. Here, we show that promoter hypermethylation of RASSF1A and HIC1 genes is associated with resistance. The promoter hypermethylation and/or the down-regulated expression of MGMT is seen in the majority of tumors. We hypothesize that these epigenetic alterations affecting MGMT play a major role in the exquisite sensitivity to cisplatin, characteristic of GCTs. We also demonstrate that cisplatin treatment induce de novo promoter hypermethylation in vivo. In addition, we show that the acquired cisplatin resistance in vitro alters the expression of specific genes and the highly resistant cells fail to reactivate gene expression after treatment to demethylating and histone deacetylase inhibiting agents. CONCLUSIONS: Our findings suggest that promoter hypermethylation of RASSF1A and HIC1 genes play a role in resistance of GCT, while the transcriptional inactivation of MGMT by epigenetic alterations confer exquisite sensitivity to cisplatin. These results also implicate defects in epigenetic pathways that regulate gene transcription in cisplatin resistant GCT.

Phase II trial of temozolomide in patients with cisplatin-refractory germ cell tumors.

Fourteen patients with cisplatin-refractory germ cell tumors (GCT) were treated with temozolomide on a phase II trial. Temozolomide was given orally at 150 mg/m2/day on days 1-5. The cycle length was 28 days. No patient experienced a grade 3 or 4 toxicity, and none of the 14 evaluable patients achieved a complete or partial response. Temozolomide is not efficacious in the treatment of cisplatin-refractory GCT patients.

Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma.

PURPOSE: To describe survival in previously treated patients with metastatic renal cell carcinoma (RCC) who are candidates for clinical trials of new agents as second-line therapy. PATIENTS AND METHODS: The relationship between pretreatment clinical features and survival was studied in 251 patients with advanced RCC treated during 29 consecutive clinical trials between 1975 and 2002. Clinical features were first examined in univariate analyses, and then a stepwise modeling approach based on Cox regression was used to form a multivariate model. RESULTS: Median survival for the 251 patients was 10.2 months and differed according to year of treatment, with patients treated after 1990 showing longer survival. In this group, the median overall survival time was 12.7 months. Because the purpose of this analysis was to establish prognostic factors for present-day clinical trial design, prognostic factor analysis was performed on these patients. Pretreatment features associated with a shorter survival in the multivariate analysis were low Karnofsky performance status, low hemoglobin level, and high corrected serum calcium. These were used as risk factors to categorize patients into three different groups. The median time to death in patients with zero risk factors was 22 months. The median survival in patients with one of these prognostic factors was 11.9 months. Patients with two or three risk factors had a median survival of 5.4 months. CONCLUSION: Treatment with novel agents during a clinical trial is indicated for patients with metastatic RCC after progression to cytokine treatment. Three prognostic factors for predicting survival were used to categorize patients into risk groups. These risk categories can be used in clinical trial design and interpretation.

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.

Reoperative retroperitoneal surgery for nonseminomatous germ cell tumor: clinical presentation, patterns of recurrence, and outcome.

OBJECTIVES: To describe the clinical characteristics and outcome of patients with metastatic nonseminomatous germ cell tumor requiring reoperative retroperitoneal surgery at the Memorial Sloan-Kettering Cancer Center, because such patients are poorly characterized. METHODS: The Memorial Sloan-Kettering Cancer Center germ cell tumor surgical database was reviewed from January 1989 through April 2001, and the clinical characteristics of patients undergoing reoperative retroperitoneal surgery for nonseminomatous germ cell tumor were identified. The initial presentation, histologic findings, morbidity, and survival were analyzed. Disease-specific survival was calculated using the Kaplan-Meier method. RESULTS: A total of 56 patients underwent 61 repeat operations: 22 after primary retroperitoneal lymph node dissection (RPLND) and 34 after postchemotherapy RPLND. Left testicular primary tumors were more common than right (33 versus 23), and the most common sites of disease prompting reoperation were the para-aortic and left hilar regions. Teratoma was the most common histologic finding at the time of reoperation. Of 56 patients, 37 (66%) required chemotherapy between the initial operation and reoperation. The overall perioperative complication rate was 27%, and median length of hospital stay was 8 days. Sixty-nine percent of patients required adjunctive procedures at the time of reoperation, the most common of which was thoracotomy. The 5-year disease-specific survival rate was 67% for the entire group (86% following reoperation after primary RPLND and 56% following reoperation after postchemotherapy RPLND). CONCLUSIONS: Reoperative retroperitoneal surgery for nonseminomatous germ cell tumor can be performed with acceptable morbidity in select referral centers. Teratoma is highly prevalent in the retroperitoneum at the time of reoperation. A significant subset of these high-risk patients can be salvaged with complete resection.

Phase II trial of ZD1839 (IRESSA) in patients with advanced renal cell carcinoma.

Eighteen patients with advanced renal cell carcinoma (RCC) were treated on a phase II trial with ZD1839 (IRESSA). Treatment efficacy was determined using the endpoint of improvement in time to progression (TTP) compared to TTP in patients who received interferon-alpha therapy. The Memorial Sloan Kettering Cancer Center database of renal cell patients shows that patients receiving therapy with interferon-alpha had a median TTP of 4.7 months, with 40% of patients having disease progression at 4 months. To show efficacy in this trial, 60% of evaluable patients would have to remain progression free at 4 months. Treatment with ZD1839 did not result in any complete or partial responses, and 13 patients (81%) had progression of disease within 4 months of start of therapy. At the dose and schedule used in this trial, the lack of antitumor activity associated with ZD1839 does not support further study in patients with metastatic RCC.