Improved outcomes in metastatic germ cell cancer: results from a large cohort study.

PURPOSE: Treatment of metastatic germ cell cancer (GCC) is based on the International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic classification published in 1997. 5-year survival rates were reported to be 91%, 79%, and 48% for patients with good, intermediate and poor prognosis, respectively. However, treatment results may have improved over time due to cumulative experience, improved supportive care and modern-type chemotherapy. METHODS: Patients with metastatic GCC who received cisplatin-based chemotherapy at two institutions in Munich between 2000 and 2013 were retrospectively studied. Clinical characteristics, treatment and outcomes were analyzed with respect to the IGCCG prognostic classification. RESULTS: Of 225 patients (median age 35 years), 72 (32%) had seminoma (S) and 153 (68%) nonseminoma. 175 (78%), 30 (13%) and 20 patients (9%) had good, intermediate and poor prognosis according to the IGCCCG classification. The 2-year-progression free survival of patients with good, intermediate and poor prognosis was 91%, 83% and 37%, and the 5-year-overall survival (OS) was 98%, 96%, and 66%, respectively. There was no significant difference in the OS between patients in the good and intermediate prognosis group. CONCLUSION: Compared to data from the original IGCCCG classification system, the outcome of patients with metastatic GCC has considerably improved over time. While the prognosis of intermediate-risk patients is excellent, treatment in the poor-prognosis group remains to be improved.

The prognostic impact of different tumor marker levels in nonseminomatous germ cell tumor patients with intermediate prognosis: A registry of the International Global Germ Cell Tumor Collaborative Group (G3).

BACKGROUND: Germ cell tumor patients with intermediate prognosis (IPGCT) according to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification represent a heterogeneous group with different clinical features. This analysis was performed to investigate the prognostic impact of different tumor marker levels prior to first line chemotherapy within IPGCT. METHODS: For this study an international registry for IPGCT was established. Eligibility criteria were intermediate prognosis according to IGCCCG criteria, nonseminomatous histology, male sex, and age ≥ 16 years. Uni- and multivariate analysis were conducted to identify characteristics associated with survival outcomes. Receiver-Operating-Characteristic curve analysis was applied to find cut-off parameters. Five-year overall survival (OS) rate was the primary and 5-year progression-free survival rate the secondary endpoint. RESULTS: This database included 634 IPGCT with a median follow-up of 9.0 years (interquartile range: 14.35). Patients received first line treatment with platinum based chemotherapy, associated with a 5-year OS rate of 87%. The stratification of patients according to AFP levels revealed a correlation between AFP levels and outcome, associated with 5-year OS rates of 88% for AFP levels <1,000 IU/ml (n = 303), 89% for 1,000 to 2,000 IU/ml (n = 82), 87% for >2,000 to 6,000 IU/ml (n = 121), and 82% for >6,000 IU/ml (n = 57) prior first course of chemotherapy, respectively (P= 0.013). LDH levels prior fist course of chemotherapy also correlated with outcome associated with 5-year OS rates of 92% for <2 UNL (n = 271), 89% for ≥2 to 3 UNL (n = 85), 78% for >3 to 4 UNL (n = 34), and 77% for >4 UNL (n = 79), respectively (P= 0.03). Different HCG levels prior chemotherapy were not associated with outcome. In multivariable analysis AFP levels >6,000 IU/ml (P= 0.023; hazard ratio HR 2.263) or >1,982 IU/ml (P= 0.031; HR 1.722), and LDH levels >3 UNL (P< 0.001; HR 2.616) were independent prognosticators for OS. CONCLUSIONS: Prognostication according to LDH and AFP levels prior chemotherapy could offer a new approach to stratify patients within the intermediate prognosis cohort. According to our findings, patients with AFP values above 6,000 IU/ml or/and LDH > 3 UNL represent an independent high risk cohort. Our results need to be confirmed in the upcoming IGCCCG reclassification.

Intermediate prognosis in metastatic germ cell tumours-outcome and prognostic factors.

BACKGROUND: For metastatic germ cell tumour patients with intermediate prognosis (IPGCT) according to the IGCCCG classification 5-year overall survival (OS) rates of 79% were described, but recent data suggest significant changes. PATIENTS AND METHODS: To compare the outcome of current IPGCT with former patients and to find new prognosticators a retrospective observational study was performed. Eligibility criteria were: age ≥16 years, diagnosed between 1979 and 2014. Primary end-point was the 5-year OS rate. RESULTS: This database includes 707 IPGCT: group 1 was diagnosed 1979-1996 (n = 237), and group 2 1997-2014 (n = 470). Median follow-up was 8.6 years (IQR: 14.4). Group 1 and 2 received first-line treatment with BEP (median 4 cycles; range 1-6) in 99% (group 1) and 95% (group 2), respectively. The proportion of first-line chemotherapy responders (CR and marker negative PR) was similar: 94% (group 1) and 96% (group 2), respectively (P = 0.290), but OS was superior in group 2 with a 5-year OS rate of 89% compared with 83% in group 1 (P = 0.035). In refractory disease, high-dose chemotherapy and treatment beyond second line was performed more often in group 2. A lactate dehydrogenase (LDH) cut-off value of 2 ULN (P = 0.002; HR 2.121) and alpha-fetoprotein (AFP) levels of 6200 IU/ml (P = 0.032; HR 2.155) pre-chemotherapy were independent prognosticators for OS in a multivariate analysis. CONCLUSION: Outcome of IPGCT has improved and is now closer to the good prognosis category. LDH and AFP levels represent potential markers to stratify IPGCT before treatment initiation.

Smoking cessation in long-term survivors of germ cell tumour.

PURPOSE: Long-term survivors of germ cell tumours (GCT) are at increased risk of cardiovascular morbidity. We investigated the use of tobacco in patients after therapy for GCT. METHODS: Four hundred and seventy-four patients treated between 1979 and 2000 at the University of Munich were asked to complete a self-report questionnaire on psychosocial dimensions which included items on tobacco smoking before and after treatment of GCT. RESULTS: Three hundred and forty-one patients (72%) returned a completed questionnaire. The median follow-up period was 9.6 years. 160 of 341 patients (47%) reported to smoke at the time of GCT diagnosis. Of those, 134 (84%) had changed their smoking behavior with 32 patients (20%) having reduced, 56 (35%) having intermittently quitted and 46 (29%) having definitively quitted smoking. Patients reduced or stopped smoking irrespective of tumour histology, tumour stage, whether they had received chemotherapy or not, and irrespective of the number of chemotherapy courses applied. CONCLUSION: Most patients changed their habit of tobacco smoking after diagnosis and treatment of GCT but only a minority of patients are sustained quitters. Patients with GCT should be strongly encouraged to stop smoking or to participate in smoking cessation programs.

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.

Extragonadal germ cell tumors: relation to testicular neoplasia and management options.

An unselected population of 635 consecutive extragonadal GCT patients (EGCT) treated between 1975 through 1996 at 11 cancer centers was retrospectively evaluated for clinical prognosis and biological features of this disease. Five hundred twenty-four patients (83%) had a nonseminomatous GCT, and 104 patients (16%) a seminomatous histology; 341 (54%) patients had a primary mediastinal EGCT, and 283 patients (45%) a retroperitoneal EGCT. Following platinum based induction chemotherapy+/-secondary surgery, 141 patients (49%) with mediastinal nonseminomas (median follow up period: 19 months) and 144 patients (63%) with retroperitoneal nonseminoma (median follow up period: 29 months) are alive [p=0.0006]. In contrast, the overall survival rate for patients with seminomatous EGCT is 88% with no difference between patients with mediastinal or retroperitoneal tumor location (median follow up period: 49 months). Multivariate analysis revealed nonseminomatous histology, the presence of non-pulmonary visceral metastases, primary mediastinal GCT location, and elevated beta-HCG as independent prognostic factors for shorter survival. Sixteen patients (4.1%) developed a metachronous testicular cancer despite the use of platinum based chemotherapy. The cumulative risk of developing a MTC 10-years after a diagnosis of EGCT was 10.3% (95% CI=4.9 to 15.6%), but higher among patients with nonseminomatous EGCT (14.3%; 95% CI=6.7 to 21.9%) or retroperitoneal EGCT location (14.2%; 95% CI=5.6 to 22.8%) than among patients with seminomatous EGCT (1.4%; 95% CI=0.0 to 4.2) or mediastinal EGCT location (6.2%; 95% CI=0.1 to 12.2). After a median follow-up of 51 months (range=1 to 154 months), all 16 MTC patients were alive without disease. Patients with pure seminomatous EGCT histology have a long term chance of cure of almost 90% irrespective of the primary tumor site. Patients with mediastinal nonseminomas have a five-years survival rate of 45%. This outcome is clearly inferior compared to patients with nonseminomatous retroperitoneal primaries who have a five-year survival rate of 62%.

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 II.

OBJECTIVES: The first consensus report that had been presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in 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, The Netherlands. METHODS: Medical oncologists, urologic 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 second part of the consensus paper includes the treatment of metastasised disease, residual tumour resection, salvage therapy, follow-up, and late toxicities. CONCLUSIONS: Whereas the vast majority of the recommendations made in 2004 remain valid 3 yr later, refinements in the treatment of early-stage as well as of 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.

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.

Predicting retroperitoneal histology in postchemotherapy testicular germ cell cancer: a model update and multicentre validation with more than 1000 patients.

OBJECTIVES: Surgical resection of postchemotherapy retroperitoneal lymph nodes is often performed in patients with advanced nonseminomatous testicular germ cell cancer. We previously developed a model to predict the probability that the lymph nodes contain only necrotic or fibrotic (benign) tissue versus mature teratoma and viable cancer (tumour) to identify patients who actually need resection. The present study used an updated model with new patient data and studied the validity of the updated model across various settings. METHODS: We combined data of 544 patients from the original model with data of 550 new patients and performed a new logistic regression analysis, which included the same six predictors: histology of the primary tumour, prechemotherapy serum levels of alpha-fetoprotein, human chorionic gonadotropin, lactate dehydrogenase, residual mass size measured on computed tomography, and change in mass size. The validity of the updated model was studied in individual centres. Calibration of the predicted probabilities was assessed graphically and with the Hosmer-Lemeshow test. Discrimination was studied with the concordance (c)-statistic. RESULTS: The updated model had slightly different, although more precise, regression coefficients. Statistically nonsignificant Hosmer-Lemeshow tests confirmed good calibration in most centres. The c-statistic for all centres except one exceeded 0.80. The updated model was valid over the complete range of predicted probabilities across a broad spectrum of centres. CONCLUSIONS: This finding gives confidence in the applicability of the model to select patients for resection, particularly patients with small residual masses and low predicted probabilities of benign tissue (i.e., substantial predicted risks of residual tumour).

Phase I/II study of sequential dose-intensified ifosfamide, cisplatin, and etoposide plus paclitaxel as induction chemotherapy for poor prognosis germ cell tumors by the German Testicular Cancer Study Group.

PURPOSE: To evaluate the feasibility and the toxicity of sequential, dose-intensified chemotherapy combined with paclitaxel plus peripheral blood-derived hematopoietic stem-cell support (PBSC) for patients with untreated metastatic germ cell tumors (GCTs) who have poor International Germ Cell Consensus Cancer Group prognostic features. PATIENTS AND METHODS: Paclitaxel was added to high-dose (HD) etoposide, ifosfamide, and cisplatin (VIP; etoposide 1,500 mg/m2, ifosfamide 10,000 mg/m2, and cisplatin 100 mg/m2; cumulative dose; days -6 through -2 per cycle) at three dose levels (135, 175, and 225 mg/m2) applied on day -6. Cycles were supported by PBSC and granulocyte colony-stimulating factor. One cycle of standard VIP was administered before start of HD-VIP plus paclitaxel cycles to collect autologous PBSC. RESULTS: Fifty-two of 53 patients receiving 152 cycles were assessable. As expected, myelosuppression was the major adverse effect. Median durations of leukocytes less than 1,000/microL and thrombocytes less than 25,000/microL were 6 and 4 days, respectively, independently of the dose of paclitaxel applied. WHO grade 2 neurotoxicity and grade 3 encephalopathy were observed in 5% of patients each. Other main adverse effects observed were stomatitis, diarrhea, and obstipation. Seventy-nine percent of patients achieved a favorable response to chemotherapy plus secondary surgery. After a median follow-up time of 41 months in surviving patients, the calculated 2- and 5-year survival rates were 77.6% (95% CI, 65.4% to 89.9%) and 75.2% (95% CI, 62.5% to 87.8%), respectively. CONCLUSION: Dose-intensive, sequential HD-VIP plus paclitaxel up to a dose of 225 mg/m2 in patients with poor prognosis GCT is a feasible approach. The regimen warrants investigation for its therapeutic potential in an expanded cohort of poor prognosis GCT patients.

Management and outcome of bilateral testicular germ cell tumors: Twenty-five year experience in Munich.

We analyzed characteristics, therapy and outcome of patients with bilateral testicular germ cell tumor (TGCT) at our institutions. Among 1,180 TGCT patients diagnosed and/or treated between 1979 and 2003, 47 (4.0%) developed a second TGCT. Nine of 14 patients (64%) with synchronous TGCT are alive with no evidence of disease (NED) at a median follow-up of 37 months. Thirty-three patients had a metachronous bilateral TGCT. Median time to the 2(nd) TGCT was 71 months. At diagnosis of 2(nd) TGCT 30 patients had stage I, 1 had stage II and 2 had stage III disease. Thirty-two of 33 patients are alive with NED at a median follow up of 41 months. No patient died from second TGCT. As a review of the literature confirms our data we do not recommend a routine biopsy of the contralateral testicle for early detection of testicular intraepithelial neoplasia (TIN).