Craig R. Nichols

European Consensus Conference on Diagnosis and Treatment of Germ Cell Cancer: A Report of the Second Meeting of the European Germ Cell Cancer Consensus group (EGCCCG): Part I

OBJECTIVES The first consensus report presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in the year 2004 has found widespread approval by many colleagues throughout the world. In November 2006, the group met a second time under the auspices of the Department of Urology of the Amsterdam Medical Center, Amsterdam, The Netherlands. METHODS Medical oncologists, urological surgeons, radiation oncologists as well as pathologists from several European countries reviewed and discussed the data that had emerged since the 2002 conference, and incorporated the new data into updated and revised guidelines. As for the first meeting, the methodology of evidence-based medicine (EBM) was applied. The results of the discussion were compiled by the writing committee. All participants have agreed to this final update. RESULTS The first part of the consensus paper describes the clinical presentation of the primary tumor, its treatment, the importance and treatment of testicular intraepithelial neoplasia (TIN), histological classification, staging and prognostic factors, and treatment of stage I seminoma and non-seminoma. CONCLUSIONS Whereas the vast majority of the recommendations made in 2004 remain valid 3 yr later, refinements in the treatment of early- and advanced-stage testicular cancer have emerged from clinical trials. Despite technical improvements, expert clinical skills will continue to be one of the major determinants for the prognosis of patients with germ cell cancer. In addition, the particular needs of testicular cancer survivors have been acknowledged.

Dose-intensive chemotherapy in refractory germ cell cancer--a phase I/II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation.

Between September 1986 and March 1988, 33 patients with refractory germ cell cancer were entered on a phase I/II trial of two courses of high-dose carboplatin plus etoposide with autologous bone marrow support. All patients had extensive prior treatment and had either cisplatin-refractory disease (67%) defined as progression within 4 weeks of the last cisplatin dose or failed at least two cisplatin-based regimens (35%) including a cisplatin-ifosfamide salvage regimen. Patients received a fixed total dose of etoposide of 1,200 mg/m2 with each cycle. The carboplatin dose ranged from 900 mg/m2 to 2,000 mg/m2. Twenty of the 33 patients received the second cycle of therapy. Despite extensive prior therapy with cisplatin, neurotoxicity, nephrotoxicity, or hearing impairment with high-dose carboplatin and etoposide was unusual. The most common nonhematologic toxicity was moderate enterocolitis. The hematologic toxicity of this regimen was substantial at each dose level. All 53 courses were accompanied by granulocytopenic fevers. Seven of the 33 patients (21%) died from treatment. All of these deaths occurred during the granulocyte nadir, and five were related to documented sepsis. Overall, 14 of 32 patients (44%) evaluable for response obtained an objective response, including eight complete remissions. Four patients remain in complete remission, with three patients being continuously free of disease in excess of 1 year. Eight responders (including four complete remissions) had progressed while receiving cisplatin. We conclude that carboplatin and etoposide can be administered in combination at high dosages and this regimen may have curative potential for patients with germ cell tumors resistant to conventional-dose cisplatin-based therapies.

Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor.

PURPOSE This study was designed to assess the effectiveness of vinblastine, ifosfamide, and cisplatin (VeIP) as second-line therapy in patients with recurrent germ cell tumors with previous treatment with cisplatin plus etoposide, usually in combination with bleomycin. PATIENTS AND METHODS From July 1984 through December 1989, 135 patients with progressive, disseminated germ cell tumors after cisplatin-etoposide-based combination therapy induction chemotherapy were treated with VeIP. Patients who progressed within 3 weeks of previous cisplatin therapy were not eligible. Progression was documented by biopsy or increasing serum markers. No exclusion was made on the basis of metastatic site or performance status. The dosages were vinblastine 0.11 mg/kg/d (days 1 and 2), ifosfamide 1.2 gm/m2/d (days 1 through 5), and cisplatin 20 mg/m2/d (days 1 through 5), with courses repeated every 21 days for four cycles. RESULTS Sixty-seven (49.6%) patients achieved a disease-free status after chemotherapy with or without surgical resection of residual carcinoma or teratoma. Overall, 42 (32%) patients are alive and 32 (23.7%) are continuously free of disease. None of the 32 patients with nonseminomatous extragonadal tumors are disease-free compared with 30 of 100 patients with gonadal primaries. Two of three extragonadal seminomas are continuously disease-free. CONCLUSION VeIP is capable of producing durable complete remissions in patients with disseminated germ cell cancer who relapse after cisplatin-etoposide-based induction therapy. Long-term disease-free survival is not seen in those patients with extragonadal nonseminomatous germ cell tumors.

Extragonadal germ cell tumors of the mediastinum and retroperitoneum: results from an international analysis.

PURPOSE To characterize the clinical and biologic features of extragonadal germ cell tumor (EGCT) and to determine the overall outcome with currently available treatment strategies. PATIENTS AND METHODS Of an unselected population of 635 consecutive patients treated from 1975 through 1996 at 11 cancer centers, 341 patients (54%) had primary mediastinal EGCT, and 283 patients (45%) had retroperitoneal EGCT. Five hundred twenty-four patients (83%) had a nonseminomatous germ cell tumor (GCT), and 104 patients (16%) had a seminomatous histology. RESULTS After platinum-based induction chemotherapy with or without secondary surgery, 141 patients (49%) with mediastinal nonseminomas (median follow-up, 19 months; range, 1 to 178 months) and 144 patients (63%) with retroperitoneal nonseminoma (median follow-up, 29 months; range, 1 to 203 months) are alive (P =.0006). In contrast, the overall survival rate for patients with a seminomatous EGCT is 88%, with no difference between patients with mediastinal or retroperitoneal tumor location (median follow-up, 49 months; range, 4 to 193 months; respective 70 months; range, 1 to 211 months). A significantly lower progression-free survival rate was found in seminoma patients treated with initial radiotherapy alone compared with chemotherapy. Nonseminomatous histology, presence of nonpulmonary visceral metastases, primary mediastinal GCT location, and elevated beta-human chorionic gonadotropin were independent prognostic factors for shorter survival. Hematologic malignancies (n = 17) occurred without exception in patients with primary mediastinal nonseminoma. Sixteen patients developed a metachronous testicular cancer despite the use of platinum-based chemotherapy. CONCLUSION Whereas patients with pure seminomatous EGCT histology have a long-term chance of cure of almost 90% irrespective of the primary tumor site, 45% of patients with mediastinal nonseminomas are alive at 5 years. This outcome is clearly inferior compared with patients with nonseminomatous retroperitoneal primary tumors.

Randomized study of cisplatin dose intensity in poor-risk germ cell tumors: a Southeastern Cancer Study Group and Southwest Oncology Group protocol.

Between 1984 and 1989, 159 patients presenting with advanced germ cell cancer were entered on a randomized clinical trial comparing the efficacy and toxicity of etoposide and bleomycin and either standard-dose cisplatin (20 mg/m2 daily for 5 days) or high-dose cisplatin (40 mg/m2 daily for 5 days). Of the 159 patients, 153 were assessable for toxicity and response. As expected, patients receiving the high-dose cisplatin regimen experienced significantly more neurotoxicity, ototoxicity, nausea and vomiting, and myelo-suppression. Four patients (3%) died related to therapy. Despite the toxicity encountered, dose intensity was maintained. Overall, 84% of patients in the high-dose arm received 80% or more of the projected dose of cisplatin, etoposide, and bleomycin; and 90% of patients on the standard-dose arm received 80% or more of the projected dose. Of the 76 eligible patients randomized to receive the high-dose cisplatin regimen, 52 (68%) became disease-free with chemotherapy alone or with subsequent resection of residual teratoma or cancer. Of the 77 patients randomized to the standard-dose arm, 56 (73%) became disease-free with chemotherapy alone or with surgery. Median follow-up is now 24 months. Eleven patients (three high-dose and eight standard-dose) relapsed from disease-free status. Overall, 74% of patients receiving the high-dose cisplatin regimen are alive, and 63% are continuously free of disease. Of the patients receiving the standard-dose cisplatin regimen, 74% are alive, and 61% are continuously free of disease. This randomized prospective trial in advanced germ cell cancer achieved dose intensity of the most active single agent in this disease. This dose intensity did not translate into an improved survival or cure. We conclude that dose escalation of cisplatin beyond standard doses results in excess toxicity with no accompanying therapeutic benefit.

Hematologic Neoplasia Associated with Primary Mediastinal Germ-Cell Tumors

Between September 1983 and December 1988, we observed 16 cases of hematologic neoplasia associated with mediastinal germ-cell tumors. Twenty-eight similar cases have been reported in the literature. A review of the clinical and cytogenetic details in these patients suggests that the hematologic neoplasia is not the result of cisplatin-based chemotherapy of the mediastinal germ-cell cancer. This syndrome was found only in patients with nonseminomatous mediastinal germ-cell tumors, particularly those with serologic or histologic evidence of yolk-sac elements. The two most common hematologic neoplasms seen in this syndrome were acute megakaryoblastic leukemia and malignant histiocytosis. Consistent cytogenetic abnormalities have not yet been identified, but the finding of the marker chromosome isochromosome (12p) in the mediastinal germ-cell tumor and associated leukemic blasts in one patient suggests that these tumors may arise from a common progenitor cell.

Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study.

PURPOSE To compare standard therapy with bleomycin, etoposide, and cisplatin (BEP) to experimental therapy with etoposide, ifosfamide, and cisplatin (VIP) as primary treatment of men with advanced, disseminated germ cell tumors. PATIENTS AND METHODS A total of 304 men with advanced disseminated germ cell tumors were randomly allocated to receive four courses of BEP or VIP. Two hundred ninety-nine patients were assessable for toxicity and 286 were assessable for response. Complete response rates, favorable response (complete remission, surgical free of disease, continuous partial remission for 2+ years), time to treatment failure, and overall survival were assessed. RESULTS Overall complete remission rate (VIP, 37%; BEP, 31%), favorable response rate (VIP, 63%; BEP, 60%), failure-free at 2 years (VIP, 64%; BEP, 60%), and 2-year overall survival (VIP, 74%; BEP, 71%) were not significantly different between the two treatments. Grade 3 or worse toxicity, particularly hematologic and genitourinary toxicity, was significantly more common in patients who received VIP. CONCLUSION BEP and VIP produce comparable favorable response rate and survival in patients with poor-risk germ cell tumors. The substitution of ifosfamide for bleomycin, however, was associated with significantly greater toxicity. Four courses of BEP remain the standard treatment for advanced disseminated germ cell tumors.

Viable Malignant Cells After Primary Chemotherapy for Disseminated Nonseminomatous Germ Cell Tumors: Prognostic Factors and Role of Postsurgery Chemotherapy—Results From an International Study Group

PURPOSE To assess the value of postsurgery chemotherapy in patients with disseminated nonseminomatous germ-cell tumors (NSGCTs) and viable residual disease after first-line cisplatin-based chemotherapy. PATIENTS AND METHODS The outcome of 238 patients was reviewed. Tumor markers had normalized in all patients before resection. A multivariate analysis of survival was performed on 146 patients. RESULTS The 5-year progression-free survival (PFS) rate was 64% and the 5-year overall survival (OS) rate was 73%. Three factors were independently associated with both PFS and OS: complete resection (P <.001), < 10% of viable malignant cells (P =.001), and a good International Germ Cell Consensus Classification (IGCCC) group (P =.01). Patients were assigned to one of three risk groups: those with no risk factors (favorable group), those with one risk factor (intermediate group), and those with two or three risk factors (poor-risk group). The 5-year OS rate was 100%, 83%, and 51%, respectively (P <.001). The 5-year PFS rate was 69% (95% confidence interval [CI], 62% to 76%) and 52% (95% CI, 40% to 64%) in postoperative chemotherapy recipients and nonrecipients, respectively (P <.001). No significant difference was detected in 5-year OS rates. After adjustment on the three prognostic factors, postoperative chemotherapy was associated with a significantly better PFS (P <.001) but not with better OS. Patients in the favorable risk group had a 100% 5-year OS, with or without postoperative chemotherapy. Postoperative chemotherapy appeared beneficial in both PFS (P <.001) and OS (P =.02) in the intermediate-risk group but was not statistically beneficial in the poor-risk group. CONCLUSION A complete resection may be more critical than recourse to postoperative chemotherapy in the setting of postchemotherapy viable malignant NSGCT. Immediate postoperative chemotherapy or surveillance alone with chemotherapy at relapse may be reasonable options depending on the completeness of resection, IGCCC group, and percent of viable cells. Validation is necessary.

Testicular Cancer Survivorship: Research Strategies and Recommendations

Testicular cancer represents the most curable solid tumor, with a 10-year survival rate of more than 95%. Given the young average age at diagnosis, it is estimated that effective treatment approaches, in particular, platinum-based chemotherapy, have resulted in an average gain of several decades of life. This success, however, is offset by the emergence of considerable long-term morbidity, including second malignant neoplasms, cardiovascular disease, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, decreased fertility, and psychosocial problems. Data on underlying genetic or molecular factors that might identify those patients at highest risk for late sequelae are sparse. Genome-wide association studies and other translational molecular approaches now provide opportunities to identify testicular cancer survivors at greatest risk for therapy-related complications to develop evidence-based long-term follow-up guidelines and interventional strategies. We review research priorities identified during an international workshop devoted to testicular cancer survivors. Recommendations include 1) institution of lifelong follow-up of testicular cancer survivors within a large cohort setting to ascertain risks of emerging toxicities and the evolution of known late sequelae, 2) development of comprehensive risk prediction models that include treatment factors and genetic modifiers of late sequelae, 3) elucidation of the effect(s) of decades-long exposure to low serum levels of platinum, 4) assessment of the overall burden of medical and psychosocial morbidity, and 5) the eventual formulation of evidence-based long-term follow-up guidelines and interventions. Just as testicular cancer once served as the paradigm of a curable malignancy, comprehensive follow-up studies of testicular cancer survivors can pioneer new methodologies in survivorship research for all adult-onset cancer.

Long-Term Outcome of Patients with Relapsed and Refractory Germ Cell Tumors Treated with High-Dose Chemotherapy and Autologous Bone Marrow Rescue

OBJECTIVE To review the long-term outcome of patients with recurrent and refractory germ cell tumors treated with high-dose chemotherapy and autologous bone marrow rescue. DESIGN Cohort study. SETTING A university hospital. PATIENTS Forty consecutive patients with recurrent or refractory germ cell tumors treated at Indiana University between September 1986 and June 1989. INTERVENTIONS Patients were treated with high-dose carboplatin (900 to 2000 mg/m2 body surface area) and etoposide (1200 mg/m2). Three patients also received ifosfamide (10 g/m2). All patients had autologous bone marrow rescue. Of the 40 study patients, 26 received two full courses of therapy. MEASUREMENTS Patient charts were reviewed to determine the rate and duration of complete and partial remission and the number of long-term, disease-free survivors. The influence of cisplatin-refractory disease and the site of the primary tumor on the incidence of remission and survival were also investigated. RESULTS Of the 40 study patients, 26 (65%) responded to treatment; 12 (30%) achieved a complete response, and 14 (35%) achieved a partial response. Of the 12 complete responders, 5 relapsed, and 1 died of treatment-related acute leukemia 27.5 months after treatment without evidence of germ cell cancer. Six (15%) of the original 40 patients, of whom 3 were refractory to cisplatin, remained in complete remission after at least 24 months of follow-up. Eight of 40 patients had primary mediastinal germ cell tumors with no complete remissions and a median survival of 2 months (range, 0.5 to 9.0 months). CONCLUSIONS Treatment with high-dose carboplatin and etoposide in conjunction with autologous bone marrow rescue in patients with relapsed or refractory germ cell tumors is a potentially curative therapeutic option, even for heavily pretreated or cisplatin-refractory patients. Some degree of disease resistance to cisplatin can be overcome with dose escalation of platinum compounds. Patients with multiple recurrences of relapsed or refractory primary mediastinal germ cell tumors were not helped by this approach.