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Ovarian germ cell malignancies pose a therapeutic challenge especially amongst young patients. This is a retrospective review of 49 patients treated for such malignancies at KK Women's and Children's Hospital over a 13-year period. The relative proportion of such tumors was 6.2%. Age at presentation ranged from 14 to 51 years (mean 25.4 years). Forty-nine percent of tumors were immature teratomas and 81.6% had stage I disease. All patients had surgery initially and 67.3% required postoperative adjuvant chemotherapy. The patients were followed-up for one to 145 months (mean 51.6 months). All the 87.8% of patients on follow-up are alive and disease-free. There was one recurrence. Five patients had eight successful pregnancies, with no congenital anomalies. Mean duration when menstruation was resumed and regular was 2.5 and 3.5 months, respectively. With combination chemotherapy and conservative surgery, the outlook for patients is excellent, with emphasis on preservation of ovarian function and fertility.

Background: The prognosis of patients with germ cell tumours of the testis has Improved over the past two decades following cisplatinum-based chemotherapy. Currently, staging and risk assessment of the disease is crucial in order to provide curative therapy for patients with poor risk features and not over-treat good risk patients., Methods: We reviewed the case records of 71 men diagnosed to have germ cell tumours between January 1993 and October 1999. Their clinical characteristics, staging, treatment outcome and prognostic factors for response and survival were analysed., Results: The median age of the patients was 30 years (range: 3-65 years); 69% were in the third and fourth decades. Sixty-one patients (86%) had a primary testicular tumour while in 10 (14%) the tumour was extragonadal. Histopathologically, 53 patients (75%) had non-seminomatous germ cell tumours and 15 (21%) had a seminoma. Twenty-seven patients (62%) had evidence of metastatic disease at the time of diagnosis. On prognostication, non-seminomatous germ cell tumour patients could be divded into good, intemediate and poor prognostic groups comprising 41%, 17% and 40% of patients, respectively. All patients with a seminoma were in the good prognostic subgroup. Fifty-eight patients were evaluable for response. Overall, 91% of patients responded: complete response 71% and partial response 20%. Complete response rates were signiflcantly higher for the good risk (95%) compared to the intermediate (49%) and poor risk (47%) categories (p< 0.003). At a median follow up of 26 months, the 2-year overall and progression-free survival for all patients was 70% and 57%, respectively. The predictors for decreased overall and progression-free survival were age >35 years, presence of poor risk features and mediastinal primary disease., Conclusion: The outcome for germ cell tumours in men with good risk is excellent. A protocol consisting of bleomycin, etoposide and cisplatin is effective. Tailoring of chemotherapy In good risk patients to minimize toxicity and Improving results in poor risk patients are areas that need further work.

Background and Objectives: Germ cell tumors (GCTs) are very chemosensitive cancers, in which high-dose chemotherapy (HDCT) has been investigated as salvage therapy or as first-line treatment in poor prognosis patients. This paper presents an update of available information in order to define the status of HDCT in GCT patients., Information Sources: The authors have been working in this field, contributing to international clinical trials and to peer-reviewed journals with original papers. The material examined in this review includes articles published in journals covered by MedLine, reviews from journals with high impact factor, and unpublished data from the European Group for Blood and Marrow Transplantation (EBMT) registry., State of the Art and Perspectives: The delineation of prognostic factors associated with a poor probability of survival after HDCT contributed to the selection of patients who are likely to get an advantage from HDCT and those who should be spared from dose-intensive treatment. HDCT as first-line therapy for poor prognosis GCT (IGCCCG classification), and in a salvage setting in good risk GCT (prognostic index from Beyer et al.77), has been associated with a very high rate of complete remissions and long-term disease-free survivors. However, it is important to wait for the results of ongoing randomized trials for the validation of these findings. Other strategies are required for patients with refractory GCTs. Several new treatment options are currently emerging for this subset of patients.

Among intracranial germ cell tumors, nongerminomatous tumors have proved refractory to conventional treatment with surgery and irradiation. The median survival is less than 2 years. Since 1983, chemotherapy has been delivered in Japan as an adjuvant therapy in patients with intracranial nongerminomatous germ cell tumors. Based on our clinical experience, we undertook a multi-institutional phase II study to establish post-surgical combined chemotherapy and radiation therapy for primary germ cell tumors in the brain. We adopted carboplatin-etoposide (CARB-VP) or cisplatin-etoposide (PE) combination chemotherapy for patients with germinomas and those with tumors that placed them in the intermediate prognosis group, and ifosphamide-cisplatin-etoposide (ICE) for patients with tumors that placed them in the poor prognosis group. One hundred and twelve patients were evaluated. Among patients with germinoma (n = 75), the rate or complete remission after combination therapy was 92.0%; it was 67.8% for patients in the intermediate prognosis group (n = 28). Tumor recurrence was noted in 9 patients with germinoma and 2 patients in the intermediate prognosis group. Of 9 patients with a poor prognosis, 4 experienced disease progression during treatment and died within 10 months. There were no serious complications attributable to the combination therapy. Our treatment protocols are effective for patients with germinomas and those with an intermediate prognosis.

Background: The chances for cure in medulloblastoma, supratentorial primitive neuroectodermal tumors (stPNET) and intracranial germ cell tumors have decisively improved within the last decades. Today long-term survival in the range between 60% and 80% and more than 90%, respectively, can be achieved. The low incidence of brain tumors in childhood and the necessity for optimal patient care has led to the fact that more than 90% of children are treated within national and international controlled studies today in order to assure a constant improvement of therapeutic outcome. Recent developments in neurosurgery achieved complete tumor resections in the majority of children at a low risk for morbidity and mortality., Methods: Systemic irradiation of neuroaxis is an essential part in the management of medulloblastoma, stPNET and intracranial germ cell tumors. The introduction of quality assurance programs in radiooncology assures a precise radiotherapy of target volumes and is a prerequisite to improve survival., Results: Hyperfractionated radiotherapy has the potential of increasing dose to tumor more safely without increasing the risk for late adverse effects. Pilot studies revealed excellent tumor control in medulloblastoma with acceptable acute toxicity and a long-term survival of up to 96%. In medulloblastoma stereotactic radiation techniques reveal an acceptable toxicity and promising results in tumor control in recurrent disease or as primary treatment. They are now part of future treatment protocols in case of persisting residual tumor. Radiotherapy alone in pure germinoma is continuously yielding high cure rates. In secreting germ cell tumors cisplatin containing chemotherapies in conjunction with radiotherapy achieve a long-term survival rate of 80% today. Especially in high risk medulloblastoma and secreting germ cell tumors chemotherapies are playing an increasingly important role in the interdisciplinary management. It can be expected that future developments of chemotherapeutic protocols and the introduction of new cytostatic substances will further improve the therapeutic outcome., Conclusions: The therapeutic endeavors of all those caring for children are aiming to study modifications of the therapeutic components in the interdisciplinary approach in order to optimize the therapeutic strategies. In future the affected children and young adolescents should be accrued for the forthcoming cooperative, prospective trial HIT 2000 and ongoing trial SIOP CNS GCT 96, respectively, in order to provide the body of data supporting the selection of novel and optimized approaches for future treatment strategies.

For patients with a clinical stage 1 non-seminomatous germ cell tumour of the testis cure rates should be close to 100%, whether surveillance, primary surgery, primary chemotherapy or a combination is chosen. The identification of patients with microscopic metastases is difficult. Even with the best predictive factors currently available (vascular invasion and percentage embryonal cell carcinoma in the primary tumour), the identification of micro-metastases is no better than the flip of a coin. Several additional prognostic factors have been studied, but none is yet applicable in daily practice.

Background: The presence of liver metastases represents an independent poor risk prognostic factor for survival in patients with germ cell tumors., Methods: The clinical files of 37 patients who had undergone liver resection for the treatment of disseminated germ cell tumors were reviewed to define the indications for resection of residual liver metastases after chemotherapy in patients with germ cell tumors. The histologic patterns of primary tumor and residual disease were compared. The prognostic factors for survival were studied by univariate analysis., Results: All but 2 of 37 patients underwent complete resection. One patient died of postoperative complications. Thirteen complications occurred in 10 patients. Twelve patients had active residual tumor, 7 patients had mature teratoma, and 18 patients had only necrosis on histologic examination. Twenty-three of 37 patients (62%) were alive with no evidence of disease after a median follow-up of 66 months (range, 31-134 months). Three prognostic factors were found to be significant in the univariate analysis for unfavorable outcome: the presence of pure embryonal carcinoma in the primary tumor, liver metastases measuring > 30 mm in greatest dimension at the time of surgery, and the presence of viable, active residual disease., Conclusions: Because it is impossible to determine the histologic pattern of residual liver masses after chemotherapy with current imaging tools and percutaneous biopsy, patient selection for liver surgery may be undertaken according to the size of residual liver masses. Patients with masses that measure < or = 10 mm in greatest dimension should be considered for close follow-up, because they have a high probability of necrosis and are at low risk for malignant disease. Male patients with masses that measure > or = 30 mm in greatest dimension represent a high-risk group of patients who are not likely to benefit from liver surgery. Only male patients with masses that measure 10-29 mm in greatest dimension and all female patients with masses that measure > 10 mm in greatest dimension should be considered for liver resection., (Copyright 2001 American Cancer Society.)

The majority of patients with a metastatic germ cell tumour can be successfully treated with a combination chemotherapy containing cisplatin. For more than a decade the combination of cisplatin, etoposide and bleomycin (BEP) has been the gold standard of treatment. In both the United States and Europe, a number of studies have been carried out, with the purpose of reducing the toxicity of the treatment for patients with a good prognosis as well as improving the treatment result for patients with intermediate or unfavourable prognostic characteristics, by intensifying the chemotherapy regimen or by adding new cytotoxic agents. The standard treatment for patients with a good prognosis consists at present of three BEP cycles, which can be administered in a shortened schedule of three days per cycle. Bleomycin is essential for the success of the therapy and cisplatin cannot be replaced by carboplatin. Efforts to increase the dose of cisplatin per cycle, reduce the interval between cycles, the addition of ifosfamide and sequential/alternating therapy do not provide any additional benefit compared to the standard treatment with BEP.

Purpose: High-dose chemotherapy (HD-Ctx) followed by autologous peripheral-blood stem-cell (PBSC) transplantation is currently investigated in patients with poor prognosis or relapsed metastatic germ cell tumor (GCTs). This study analyzed the presence and the clinical importance of contaminating tumor cells in PBSC preparations used to support HD-Ctx in GCT patients., Patients and Methods: Seven targets for reverse transcription polymerase chain reaction (RT-PCR)-based detection of GCT cells were able to detect seminomatous and different histologic variants of nonseminomatous tumor cells. PBSC preparations from 57 patients were investigated for the presence of contaminating tumor cells using this set of targets, including beta human chorionic gonadotropin (beta-hCG), fibronectin (EDB variant), epidermal growth factor receptor (EGFR), CD44 (v8 to 10 variant), germ cell and placental alkaline phosphatase (AP), human endogenous retrovirus type K (ENV and GAG), and XIST. Samples of PBSC preparations from four healthy donors for allogenic transplantations as well as blood specimens from 10 healthy volunteers served as negative controls., Results: Fifty patients (43 first-line and seven second-line Ctx) were assessable. Combining all RT-PCR results, 29 PBSC preparations (58%) were positive for tumor-specific amplification products (HERV-K 0, fibronectin 4, XIST 14, beta-hCG 19, AP 19, CD44 24, EGFR 26). Ten (35%) of 29 patients who underwent transplantation with positive PBSC preparations and seven (33%) of 21 patients with negative PBSC preparations have suffered relapse or progression (not significant [ns]). With a median follow-up of 22 months (2 to 66) post-HD-Ctx projected 3-year survival rates are 68% (RT-PCR+) and 58% (RT-PCR-) (ns). None of the 10 control peripheral-blood samples showed positivity for any of the targets studied., Conclusion: GCT cells can be detected in more than 50% of PBSC preparations using a RT-PCR approach with multiple targets. Despite the presence of tumor cells, retransplantation of the PBSC products did not effect long-term outcome. Factors such as responsiveness to chemotherapy and tumor mass seem to overcome the importance of potentially re-infused tumor cells.

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.

Purpose: The prognostic significance of the rate of decline of the serum tumor marker alpha-fetoprotein (AFP) and human chorionic gonadotrophin (HCG) during the first two cycles of chemotherapy in germ cell tumor (GCT) patients was initially reported by us, but its value has been debated. We re-examined this issue in the context of the International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification system and investigated the role of including in the analysis patients whose markers normalized early., Patients and Methods: One hundred eighty-nine GCT patients with elevated AFP/HCG marker values treated with platinum-based chemotherapy between 1986 and 1998 were included in this analysis. Patients were classified as good, intermediate, or poor risk by the IGCCCG criteria and as having satisfactory or unsatisfactory marker decline. Risk and marker decline were correlated with response, event-free survival, and overall survival., Results: Satisfactory marker decline predicted improved complete response (CR) proportion and event-free and overall survival (P <.0001). The CR proportion, 2-year event-free, and 2-year overall survival rates for patients with a satisfactory and unsatisfactory marker decline were 92% versus 62%, 91% versus 69%, and 95% versus 72%, respectively. Marker decline remained a significant variable for all three end points when adjusted for risk (P <.01) with the outcome differences most pronounced in the poor-risk group., Conclusion: The rate of marker decline during chemotherapy has prognostic value independent of risk and may play a significant role in the management of poor-risk patients. It is appropriate to include patients whose markers normalized early.

Objectives: To evaluate the patterns of care and management of testicular cancer in Victoria., Design and Setting: Retrospective analysis of all cases of testicular cancer in Victoria from 1988 to 1993 identified through the Victorian Cancer Registry., Main Outcome Measures: Description of patient characteristics, staging investigations, initial management, and outcome., Results: 667 eligible cases of testicular cancer were identified and questionnaires were returned for 633 of these patients (94.9% response rate). There were 357 (56.4%) patients with pure seminoma; 271 (42.8%) with non-seminomatous germ cell tumours, 3 (0.5%) with stromal tumours, and 2 (0.3%) with other tumours. The median age was 32 years (range, 0-80 years). Preoperative marker levels were not available for 8% of patients, and initial staging was considered inadequate in 6%. Surveillance programs used for patients with Stage I disease were considered inadequate in most. Relative survival at five years was 99% for patients with seminoma and 91% for non-seminoma., Conclusions: There was considerable variation in the investigation, treatment, and follow-up of these patients, which is likely to have resulted in unnecessary morbidity. Clinical practice guidelines should be developed and implemented to promote optimal management.

Purpose: To evaluate a multimodal approach including surgery and cisplatinum chemotherapy for treatment of children with malignant sacrococcygeal germ cell tumors (GCT) and to compare adjuvant and neoadjuvant strategies in advanced tumors., Patients and Methods: Between 1983 and 1995, 71 patients with malignant sacrococcygeal GCT were prospectively enrolled onto the German protocols for nontesticular GCT Maligne Keimzelltumoren 83/86 and 89. Five patients who received no chemotherapy (n = 2) or nonplatinum chemotherapy (n = 2) or who did not undergo tumor resection (n = 1) were excluded from this analysis. Among the 66 patients analyzed were 14 boys and 52 girls. The median age was 17.4 months (range, 7 months to 119 months). Median follow-up was 79 months (range, 4 months to 145 months)., Results: Fifty-two patients presented with locally advanced stage T2 tumors, and 30 patients had distant metastases at diagnosis. Patients received a median of eight cycles (range, four to nine cycles) of cisplatinum-based chemotherapy. Thirty-five patients underwent tumor resection at diagnosis and received adjuvant cisplatinum-based chemotherapy (group A). Thirty-one patients received up-front chemotherapy followed by delayed tumor resection (group B). Group B included more metastatic tumors than group A (group B, 19 of 31 patients; group A, 11 of 35 patients, P =.01). Preoperative chemotherapy facilitated complete tumor resections (group B, 20 of 31 patients; group A, five of 35 patients, P <.001) and avoided second-look surgery. Metastases at diagnosis and completeness of the first attempt of tumor resection were significant prognostic predictors; however, metastases were not predictive for patients treated with up-front chemotherapy. At 5 years follow-up, event-free survival was 0.76 +/- 0.05 (50 of 66 patients), and overall survival was 0.81 +/- 0.05 (54 of 66 patients). Four patients died as a result of therapy-related complications, and eight patients died of their tumors. Patients with locally advanced and metastatic tumors (T2b M1) fared better with neoadjuvant treatment [overall survival: 0.83 +/- 0.09 (16 of 19 patients) versus 0.45 +/- 0.15 (five of 11 patients), P =.01]., Conclusion: Even locally advanced and metastatic sacrococcygeal GCT can be successfully treated with up-front cisplatinum-based chemotherapy followed by delayed but complete tumor resection.

Purpose: To determine the incidence, pattern, and predictive factors for relapse in patients with low-volume nodal metastases (stage pN1) at retroperitoneal lymphadenectomy (RPLND) and identify who may benefit from chemotherapy in the adjuvant or primary setting., Patients and Methods: Fifty-four patients with testicular nonseminomatous germ cell tumor had low-volume retroperitoneal metastases (pathologic stage pN1, 1997 tumor-node-metastasis classification) resected at RPLND, 50 of whom were managed expectantly without adjuvant chemotherapy. The dissection was bilateral in 12 and was a modified template in 38 patients. Retroperitoneal metastases were limited to microscopic nodal involvement in 14 patients. Follow-up ranged from 1 to 106 months (median, 31.4 months)., Results: Eleven patients (22%) suffered a relapse at a median follow-up of 1.8 months (range, 0.6 to 28 months). The most frequent form of recurrence was marker elevation in nine (18%) patients. Persistent marker elevation after orchiectomy and before retroperitoneal lymphadenectomy was a significant independent predictor of relapse (relative risk, 8.0; 95% confidence interval, 2.3 to 27.8; P =.001). Four of five (80%) patients with elevated markers (alpha-fetoprotein alone in three, alpha-fetoprotein and beta human chorionic gonadotropin in one) suffered a relapse, compared with seven of 45 (15.6%) patients with normal markers., Conclusion: Clinical stage I and IIA patients with normal markers who have low-volume nodal metastases have a low incidence of relapse and can be managed by observation only if compliance can be assured. In contrast, patients with elevated markers before retroperitoneal lymphadenectomy have a high rate of relapse and should be considered for primary chemotherapy.

Background: Because patients with germ cell tumors expect an additional life span of around 50 years after successful treatment, attention is now focused on potential long term toxicity. Limited data are available on Leydig cell function in long term survivors., Methods: The authors measured testosterone, sex hormone binding-globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels in 244 patients with germ cell tumors. Patients were divided into three groups: Group 1 had received no chemotherapy (n = 58 patients), Group 2 had received cumulative doses of cisplatin < or = 400 mg/m(2) (n = 117 patients), and Group 3 had received cumulative doses of cisplatin > 400 mg/m(2) (n = 69 patients). The median times from chemotherapy were 74 months and 75 months in Groups 2 and 3, respectively., Results: Subnormal testosterone levels (< 10 nmol/L) were found in 5%, 11%, and 20% in Groups 1, 2, and 3, respectively (Group 1 vs. Group 3; P = 0.02). The mean testosterone level and the testosterone/SHBG ratio did not differ significantly between Groups 1 and 2; however, they did differ between Groups 1 and 3 (testosterone: 17.0 nmol/L vs. 14.9 nmol/L, respectively; P = 0.02; testosterone/SHBG ratio: 0.70 vs. 0.59; P < 0.05). There was a significant inverse correlation between the testosterone/SHBG ratio and LH (correlation coefficient [r] = -0.25; P = 0.0002). A significant positive correlation was found for LH and FSH (r = 0.78; P < 0.0001), indicating a strong association between Leydig cell dysfunction and germinal epithelial damage., Conclusions: Standard doses of cisplatin-based chemotherapy do not lead to a significant deterioration of Leydig cell function in long term survivors of germ cell tumors. In contrast, high cumulative doses of chemotherapy cause a significant and persistent impairment of Leydig cell function. More data are needed regarding the clinical relevance of moderate testosterone deficiency. Further research is necessary to determine whether some patients may benefit from testosterone replacement., (Copyright 2001 American Cancer Society.)

Background: The current study reviews chronologic changes in the long term outcome of patients with metastatic nonseminomatous testicular germ cell tumors (NSTGCT) who were treated at a single institution during the past two decades. The 10-year survival of prognostic subgroups according to the classification of the International Germ Cell Consensus Classification Group (IGCCCG) and various other prognostic classifications is examined in time to evaluate whether cumulative experience has led to an improved outcome of patients with metastatic NSTGCT and to explore differences in outcome of prognostic subgroups., Methods: Two hundred ninety-nine patients with metastatic NSTGCT who were treated with cisplatin-based polychemotherapy during the period from 1977 to 1996 were staged retrospectively according to the Royal Marsden (RM) classification and the following prognostic classifications: IGCCCG, Indiana, Medical Research Council (MRC), and European Organization for Research and Treatment of Cancer (EORTC). The numbers of patients who were treated during the periods 1977-1986 and 1987-1996 were 146 and 153, respectively. Survival curves were constructed using the Kaplan-Meier method, and disease specific 10-year survival rates of prognostic subgroups treated during the two consecutive 10-year periods were compared using the log rank test., Results: The median follow-up of surviving patients during the periods 1977-1986 and 1987-1996 was 14.7 years (range, 0.2-20.6 years) and 7.0 years (range, 0.4-11.4 years), respectively. The actuarial disease specific 10-year survival rate of patients with metastatic NSTGCT increased from 76% during the period 1977-1986 to 88% during the period 1987-1996 (relative risk [RR], 0.51; 95% confidence interval [95% CI], 0.29-0.89; P < 0.05). The 10-year survival rates of patients with good, intermediate, and poor prognoses according to the IGCCCG classification were 95%, 74%, and 37%, respectively, during the period 1977-1986 and 94%, 87%, and 66%, respectively, during the period 1987-1996. Patients with a poor prognosis according to the IGCCCG classification showed the greatest increase in 10-year survival (RR, 0.43; 95% CI, 0.18-1.04; P = 0.06). Analysis using the RM, Indiana, and EORTC classifications also showed an improved 10-year survival rate of patients with a poor prognosis who were treated during 1987-1996 compared with those who were treated during 1977-1986., Conclusions: The 10-year survival rate of patients with metastatic NSTGCT who were treated with cisplatin-based chemotherapy significantly increased from 76% during the period 1977-1986 to 88% during the period 1987-1996. This improvement during the cisplatin era resulted mainly from an increase in the survival of patients with metastatic disease who had a poor prognosis. These results indicate that the management of patients with NSTGCT is still improving., (Copyright 2001 American Cancer Society.)

Background: Most patients with metastatic germ-cell tumours are cured with chemotherapy. However, the optimum chemotherapy regimen is uncertain, and there is variation in international practice. We did a multicentre randomised trial to compare two standard chemotherapy regimens for men with good-prognosis germ-cell tumours., Methods: Good prognosis was defined by modified Memorial Sloan-Kettering criteria. The first regimen (regimen A) was based on treatment recommendations from Indiana University and comprised three cycles of 20 mg/m2 cisplatin on days 1-5, 100 mg/m2 etoposide on days 1-5, and 30 kU bleomycin on days 1, 8, and 15, repeated every 21 days. The second regimen (regimen B) was based on the control regimen of a published randomised clinical trial and comprised four cycles of 100 mg/m2 cisplatin on day 1, 120 mg/m2 etoposide on days 1-3, and 30 kU bleomycin on day 1, repeated every 21 days. The primary outcome measure was overall survival. Analysis was by intention to treat., Findings: 166 patients were randomised, 83 to each regimen. The trial was stopped when the second planned interim analysis met predefined stopping rules. The median follow-up was 33 months. Overall survival was substantially better with regimen A (three vs 13 deaths, hazard ratio 0.22 [95% CI 0.06-0.77], p=0.008). This difference was due to deaths from cancer (one vs nine), and not deaths from treatment (two vs two) and remained significant after adjustment for other prognostic factors (0.25 [0.07-0.88], p=0.03)., Interpretation: In men with good-prognosis germ-cell tumours, the regimen developed at Indiana University is superior to the alternative regimen studied in this trial. The lower total dose and dose-intensity of bleomycin and the lower dose-intensity of etoposide in regimen B could be responsible for the worse outcome.

Objectives: To examine incidence, mortality and survival trends in England and Wales for testicular cancer, using the recently developed national cancer and national mortality databases., Methods: The directly age-standardized incidence rates for testicular cancer in England and Wales were calculated for the period 1971-97 and age-standardized mortality for years 1971-99. Trends in the data were then assessed, including the influence of social deprivation on testicular cancer incidence and survival., Results: The number of newly diagnosed cases of testicular carcinoma in 1971-97 in England and Wales increased from almost 650 to 1400. The age-standardized rates were 2.9 per 100000 cases in 1971 and 5.4 per 100000 in 1997, an increase of 88% over 26 years. There was a large decrease in mortality since the mid-1970s, with an age-standardized mortality of < 0.5 per 100000 since 1985. For men with testicular carcinoma diagnosed in 1991-93, the 1-year relative survival was almost 98% and 5-year relative survival almost 95%, compared with 82% and 69%, respectively, for men diagnosed during 1971-75. There is a 'deprivation gap' for the 5-year survival of > 6% in favour of the most affluent socio-economic group, with no significant change over recent years., Conclusions: The incidence of testicular cancer is increasing in England and Wales, consistent with the trend documented in other developed countries. The reduction in mortality has been marked since the mid-1970s, reflecting improved cancer management, in particular the introduction of platinum-based chemotherapy regimens for advanced disease. Survival rates in England and Wales are as good as in other European countries. Further developments in chemotherapy are unlikely to produce such a marked improvement in survival rates again, and minimizing the effect of social status on survival rates should be an important target of future care.

Childhood brain tumors are collectively the most common solid neoplasm and the leading cause of cancer-related death in children. They are a diverse group of diseases and outcome is extremely variable. Current treatment is dependent on histology, location, and in some instances, patient age. Advances in treatment have led to improved survival for some patients, but for many the outcome remains dismal despite aggressive treatment. A growing body of work is aimed at improving the outcome for children with brain tumors not only through clinical trials, but also by focusing on the biologic underpinning of these diseases that have been poorly understood.

Purpose: To prospectively investigate whether intracranial germinomas, except large ones, can be cured with radiation doses lower than 50 Gy and to determine 10-year follow-up results., Materials and Methods: Between 1985 and 1995, 38 patients with intracranial germinoma diagnosed histologically or with established criteria were enrolled. Total radiation doses to the primary tumor site were 36 Gy after total removal, 40 Gy for tumors less than 2.5 cm in diameter, 45 Gy for those 2.5-4.0 cm, and 50 Gy for those greater than 4.0 cm, with 1.6-1.8-Gy daily fractions. Patients underwent irradiation of the primary tumor site or cerebrospinal axis (20-24 Gy), depending on findings at diagnosis. No chemotherapy was allowed., Results: All patients completed radiation therapy. Thirty-five patients were treated according to protocol, and three with relatively slow tumor regression or presence of a cyst received additional radiation (5-7 Gy, 50-52 Gy total). Ten-year overall and relapse-free survival rates were 91% and 95%, respectively. Two patients developed meningeal dissemination, but none had local failure. Treatment complications included chordoma in one patient and internal carotid artery occlusion in another. No treatment-related decline of performance status was observed in the other patients., Conclusion: All tumor volume-based radiation doses were effective, without risk of local failure. Intracranial germinoma 4 cm or less in diameter can be cured with doses of 40-45 Gy. Investigation of further dose reduction seems worthwhile. Radiation therapy alone with these doses should be compared with ongoing chemotherapeutic protocols plus low-dose (24-30-Gy) irradiation in future studies.

The prognosis of intracranial germinoma producing the human chorionic gonadotropin (hCG) is controversial due to limited information. We undertook a retrospective analysis to determine whether this type of tumor has similar clinical course and prognosis to hCG non-secreting germinoma. Thirty-one histologically confirmed intracranial germinoma patients who had pretreatment hCG examination in serum/CSF were treated with radiotherapy between 1980 and 1996. hCG level was measured by immunoradioassay of beta subunit of hCG. Six patients had elevated serum hCG levels and were defined as having hCG secreting germinoma. All except three patients received craniospinal axis irradiation. The follow-up ranged from 19-175 months with a median of 63 months. hCG secreting germinoma accounted for 19% of intracranial germinoma cases. Elevated hCG levels ranged from 39-260 IU/l in serum. No difference was found between hCG non-secreting germinoma and hCG secreting germinoma in terms of patient or treatment characteristics. There was no recurrence among the six hCG secreting germinoma patients. The 5-year overall and disease-free survival rates were 96% for patients with hCG non-secreting germinomas and 100% for the patients with hCG secreting germinomas. The survival difference was not significant (p = 0.59). Our results suggest that elevated level of hCG did not result in any differences in the clinical characteristics or survival after radical radiotherapy in histologically confirmed intracranial germinoma.

We reviewed the treatment results in 44 patients with germ cell tumor and the significance of % dose intensity of Cisplatin and tumor marker half-life of induction chemotherapy and discussed the necessity of surgical resection of the postchemotherapy residual tumor. The 5-year survival rate calculated by the Kaplan-Meier method was 83.6% in total, and 95.2, 75.8 and 47.6% for good, intermediate and poor prognosis, respectively. Of the 29 metastatic cases treated by chemotherapy, 5 (17.2%) achieved complete response (CR) and 15 (51.7%) partial response, and % dose intensity of Cisplatin were 75.4% in total and 86.4 +/- 8.6, 71.6 +/- 11.1, 84.3 +/- 8.3 and 62.2 +/- 11.0% in CR, PR, NC and PD. Dose intensity was correlated with the clinical response and the prognosis. Of the 12 PR cases without teratoma elements, two had salvage surgery, five had additional chemotherapy and five were followed by surveillance. One case followed by surveillance died of the disease, another one with additional chemotherapy was alive with the disease and the others were alive with no evidence of disease. Surgical resection is an effective treatment to remove residual masses, but observation may also be considered in the cases without teratoma elements.

Objective: To study the results of surgical treatment of pulmonary metastases in our department., Patients and Methods: We retrospectively studied 44 patients undergoing surgery between 1986 and 1999 for complete resection of pulmonary metastases. Primary tumors had been eradicated, no metastasis to other organs was evident, and functional respiratory capacity was adequate. The patients were assigned to different prognostic groups based on the criteria of the International Registry of Lung Metastases., Results: Forty-eight operations were performed on the 44 patients (21 men and 23 women) whose mean age was 58 years (31-74 years). The most frequent type of primary tumor was epithelial (82%); other types in order of frequency were sarcoma (9%), thyroid gland (4.4%), germ cell (2.2%) and melanoma (2.2%). The mean disease-free interval was 37.7 months (0.168) and the median was 30 months. A single site of metastasis was seen in 66.7% of the cases whereas 33.3% had multiple metastases (17.9% of them bilateral). Posterolateral thoracotomy was the surgical approach in over half the cases (66.7%). We performed wedge resections in 86.6% and lobectomies in 11.1%. Perioperative mortality was 4.4%. Mean survival was 70 months, with 87% alive at one year and 29% at 10 years. For group I (resectable, no risk factors; n = 13) survival was 100% at one year and 75% at 10 years. For group II (resectable, one risk factor; n = 16) the actuarial survival was 78% at one year and 12% at 10 years. For group III (resectable, two risk factors; n = 8), survival was 87% at one year, 62% at three years, 15% at four years and 0% at five years (Log-rank chi 2 9.8 [df = 2)], p = 0.0097)., Conclusions: Surgical resection of pulmonary metastasis is a treatment and diagnostic procedure associated with low mortality and good survival. Prognostic grouping that takes into account number of metastases, disease-free interval and resectability correlates significantly with expected survival regardless of histological typing of the primary tumor.

Objectives: The IGCCCG classification has identified three prognostic groups of patients with metastatic germ-cell tumors. 'Poor prognosis' is based on primary tumor localization, the presence of visceral metastases, and/or high tumor-marker levels. The overall survival rate of these patients is about 45%-55%. The present analysis attempts to identify subsets of patients with a more or less favorable outcome among the 'poor-prognosis' group., Patients and Methods: We retrospectively explored prognostic subgroups in 332 patients with 'IGCCCG' poor-risk GCT using the classification-and-regression-tree model (CART). The following variables were included: primary tumor localization, presence of visceral or lung metastases, presence of an abdominal tumor, number of metastatic sites, serum levels of beta-HCG, AFP and LDH. All patients had been treated with cisplatin-etoposide-based chemotherapy within controlled clinical trials between 1984 and 1997., Patient Characteristics: gonadal/retroperitoneal (G/R) primary tumor 260 patients (78%), mediastinal primary tumor 72 patients (22%), visceral metastases 205 patients (62%) including 33 patients with CNS metastases, lung metastases 247 patients (74%), abdominal tumor 241 patients (72%), elevated AFP, beta-HCG or LDH levels 235 (71%), 253 (76%) and 275 (83%) of patients, respectively. Patients with primary mediastinal disease plus lung metastases exhibited the worst two-year PFS (28%), whereas patients with a primary G/R tumor and without visceral metastases showed the highest chance of two-year PFS (75%). The latter group of patients without visceral metastases and with a primary G/R tumor also had the most favourable two-year OS (84%). In contrast, patients with a primary mediastinal tumor and visceral metastases displayed the worst two-year OS (49%)., Conclusions: Different prognostic subsets of patients can be identified among the group of 'poor-prognosis' GCT patients. The CART analysis model results in a hierarchy of prognostic factors which may allow to more precisely estimate the individual patient's prognosis. Identifying subgroups of 'very poor-prognosis' among 'poor-prognosis' patients may allow to test for new treatment strategies in selected subgroups.

Objectives: To assess the characteristics of patients with recurrent disease by a retrospective analysis., Methods: Between 1982 and 1998, 488 patients were treated in Nijmegen for testicular cancer. All patients underwent orchiectomy and adjuvant treatment when indicated. Patients were routinely followed up., Results: In 36 patients (7.4%), disease recurrence was found during follow-up; 12 had contralateral disease and 24 systemic recurrence. Contralateral testicular cancer occurred a median of 63.8 months (range 43.2 to 165.2) after orchiectomy and systemic recurrence at a median of 6.1 months (range 1.5 to 94.4). Contralateral testicular cancer was more frequent in patients with pure seminoma (odds ratio 4.3, 95% confidence interval 1.4 to 13.1); 8 of 9 patients with contralateral cancer received adjuvant radiotherapy. The best predictor of systemic recurrence after nonseminoma germ cell tumor was the presence of teratoma and embryonal cell components in the primary tumor. In the entire population, 19 patients (3.9%) died of the disease. None of the patients with contralateral testicular recurrence or systemic recurrence after Stage I seminoma died of the disease. One of 10 patients died of recurrent Stage I nonseminoma germ cell tumor. The chance of dying of recurrence after metastatic nonseminoma germ cell tumor was 36%., Conclusions: Recurrence after an initially complete response is rare in testicular cancer. Contralateral testicular cancer is associated with the presence of seminoma components in the primary tumor and occurs almost 10 times later than systemic recurrence. The prognosis after contralateral testicular cancer and after recurrence in Stage I seminoma is good.

Purpose: We evaluated the prognostic criteria for salvage surgery in patients with persistent marker elevation after chemotherapy for metastatic germ cell tumors., Materials and Methods: Of 125 men who underwent post-chemotherapeutic resection of residual tumors 30 had persistent marker elevation at surgery. This group was subdivided into 17 patients with no evidence of disease, 7 dead of disease and 6 others. Outcome analysis was performed in the subgroups with regard to preoperative and postoperative parameters. Mean followup was 120.3 months (range 1 to 228) after surgery., Results: Of the 30 patients 17 (57%) with persistently elevated tumor markers after chemotherapy were long-term survivors after salvage surgery. Overall persistent viable cancer and teratomatous elements were identified in 64% and 11% of cases, respectively. Significantly more patients died of disease who had a poor prognosis according to International Germ Cell Cancer Collaborative Group guidelines. Embryonal carcinoma was the predominant initial histology in this group and residual disease was more often located at various sites, for example the viscera, with a lower chance of complete surgical resection. Marker status before surgery, and chemotherapeutic pretreatment and postoperative histological findings did not differ significantly in patients with no evidence of disease and those dead of disease., Conclusions: Salvage surgery results in long-term success in greater than 50% of patients. Complete resection is the most important single parameter for a favorable outcome. Even patients with visceral metastasis benefit from surgery. Our data do not justify omitting surgery in certain subgroups.

The prognosis of germ cell tumors treated with chemotherapy depends on the presence of nonseminomatous tumor, clinical parameters based on the tumor volume and site, as well as on the level of the tumor markers AFP, betaHCG and LDH. We report here on the results of a risk-adapted approach to the chemotherapy of germ cell tumors. Patients with low-risk tumors, defined as seminomatous disease and/or nonseminomatous disease with a tumor mass <10 cm, less than 20 lung metastases, no liver, bone, or CNS metastases, and levels of AFP <1,000 IU/ml and betaHCG <10,000 IU/l, were to receive 4 cycles of carboplatin 400 mg/m(2) i.v. day 1, etoposide 120 mg/m(2) i.v. days 1-3 and bleomycin 30 IU i.v. days 1, 8 and 15 during the first 3 cycles (CEB(90)). Patients with high-risk disease were to receive 4 cycles of ifosfamide 1,500 mg/m(2) continuous infusion on days 1-4 together with mesna 1,200 mg/m(2) days 1-5, cisplatin 20 mg/m(2) i.v. days 1-5 and etoposide 100 mg/m(2) i.v. days 1-5 (VIP). Of the 60 patients treated with this risk-adapted approach, 51 had low-risk and 9 had high-risk disease. Forty-five of 51 patiens treated with CEB(90) achieved complete remission (CR), 4 achieved partial remission with marker negativity. Four patients with CR relapsed between 4 to 8 months after the start of chemotherapy. Of the 6 patients failing CEB(90), 3 were treated successfully with surgery or further chemotherapy. With a median follow-up of 52 months, the estimated cause-specific 3-year survival is 93% (95% confidence interval, CI, 80-98%). Seven of 9 high-risk patients treated with VIP achieved a CR and 1 patient relapsed. All 3 patients failing VIP had successful salvage therapy. With a medium follow-up of 63 months all patients remain alive and free of disease. Forty-six patients receiving CEB(90) were retrospectively classified to be in the good prognosis group according to the international germ cell consensus classification. Their estimated 3-year survival was 95% (CI 81-99%). We thus confirm that CEB(90) is a well-tolerated outpatient regimen with good results in good prognosis germ cell tumors. Bleomycin at a cumulative dose of 270 U might contribute substantially to the inferior effect of carboplatin as compared to cisplatin. However, in view of the results of randomized studies favoring cisplatin over carboplatin, it is not recommended to use this regimen outside a clinical trial., (Copyright 2000 S. Karger AG, Basel.)

About 3% to 5% of all germ cell tumors are thought to be primary extratesticular tumors, including a small group of benign tumors. Though the testes are clinically normal, diagnosing whether the tumor is primary or metastatic is problematic. Developments in ultrasonography have enabled the detection of tiny testicular lesions, and ultrasonography is applied to determine the biopsy sites. Nevertheless, burned-out tumor and carcinoma in situ are not always easy to find. Extratesticular germ cell tumors are usually treated using methods similar to those for advanced testicular tumors; however, the results are discouraging. Only limited cases are suitable for a monotherapy of surgery, so a combined treatment of cisplatin based chemotherapy and surgery is prevalent. Against seminomas, radiotherapy is effective. In addition to the advent of such pharmaceuticals as G-CSF and serotonin receptor antagonists, recent development of peripheral blood stem cell transplantation is expected to produce improved prognoses among patients burdened with this refractory disease. A prognostic factor-based staging system developed by the International Germ Cell Cancer Collaborative Group is reasonable and useful. Non-seminomas are classified as having good or intermediate prognoses if retroperitoneal tumors having no non-pulmonary visceral metastases show good or intermediate markers. A poor prognosis is associated with extratesticular tumors with mediastinal primary or non-pulmonary visceral metastases or poor markers. Seminomas with normal AFP are classified as having good or intermediate prognoses if no non-pulmonary visceral metastases are seen or discarded. No seminomas are classified in the poor prognosis group.

This article reviews the major advances in therapy for malignant ovarian germ-cell tumors. Most of the important developments such as greatly improved survival and the preservation of reproductive potential in most young patients have occurred during the past two decades. We will also describe the major unresolved issues in this field.

Intracranial germinoma has a relatively good prognosis when treated with radiotherapy and chemotherapy, whereas glioblastoma has a poor prognosis irrespective of these treatments. Cell proliferation and cell death are opposing processes in tumor growth, with tumor progression reflecting the balance between proliferating and apoptotic cells. We investigated cell proliferation and cell death using MIB-1 staining and nick-end labeling in 13 germinomas in comparison with 11 glioblastomas. Expression of BAX and Bcl-2, which regulate apoptosis, were studied by immunohistochemistry. Although germinomas showed strong MIB-1 immunostaining similar to that seen in glioblastomas, germinomas included significantly more apoptotic cells. The ratio of apoptotic ratio to MIB-1 labeling index for germinomas was 72.9 +/- 36.9 (mean +/- SD), a higher, statistically significant ratio as compared with glioblastomas (14.5 +/- 11.2; P < 0.01). Furthermore, germinomas showed greater expression of BAX than did glioblastomas, while the expression of Bcl-2 was weak in both tumor types. A comparison of these apoptotic-related proteins showed that immunoreactivity for BAX was relatively higher in germinomas than in glioblastomas (P < 0.01), corresponding well to numerous apoptotic cells identified in germinoma tissues. These findings may account for the prognostic difference between germinoma and glioblastoma in the face of a similar proliferation potential according to MIB-1 immunostaining. The balance between cell proliferation and death should be considered when predicting outcomes in patients with intracranial tumors.

Purpose: We investigated the effectiveness and toxicity of VIP therapy as a first-line chemotherapy for patients with metastatic germ cell tumor., Patients and Methods: From March 1994 to October 1997, we treated 16 patients with VIP therapy consisting of etoposide (100 mg/m2), ifosfamide, (1.2 g/m2) and cisplatin (20 mg/m2), all of which were generally given daily for 5 consecutive days every 3 weeks. Of the 16 patients, 6 were classified into a good, 5 into an intermediate, and 5 into a poor prognostic group according to the International Germ Cell Consensus Classification., Results: Thirteen patients (81%) achieved complete response with VIP alone or VIP plus surgery. Three-year survival rate was 100% in good and intermediate prognostic group, while 40% in poor prognostic group. Although all patients had Grade 3 or higher myelosuppression, the treatment was well tolerated and no patient died of treatment-related complications., Conclusions: VIP appears to be an effective and safe regimen as an induction chemotherapy for good and intermediate risk patients with germ cell tumor. However, more intensive regimen may be necessary for poor-risk patients.

In this study, we report the results of two consecutive protocols. TGM 55 and TGM 90, of the Société Fran¿aise d'Oncologie Pédiatrique ( SFOP) for patients with non-seminomatous germ cell tumours of the ovary and analyse the rationale for surgical indications. neoadjuvant or adjuvant chemotherapy. TGM 55 and 90 both utilised six drugs, bleomycin, cyclophosphamide, vinblastine, dactinomycin, etoposide and either cisplatin (TGM 55) or carboplatin TGM 90). Chemotherapy was given in ease of unresectable or incompletely resected tumour. Patients who had a complete resection of a localised tumour underwent expectant management and were only treated if progression occurred. 63 patients aged less than 18 sears old were enrolled between January 1955 and December 1994. 49 patients had alpha-fetoprotein (alphaFP) +/- beta-human chorionic gonadotropic hormone (betaHCG) secreting tumours and 14 had immature teratomas. Median follow-up for surviving patients is 60 months (range: 19-154). The 5-year overall survival is 85% +/- 5%. 13 out of 14 patients (93%) with immature teratoma are alive, including 3 of 4 patients (75%) who received chemotherapy for advanced disease. 41 patients (54%) with secreting tumours are alive, including 2 patients who required salvage treatment. Most failures occurred amongst patients with high initial alphaFP secretion ( > 15,000 ng/ml). 39 of 41 survivors (95%) in thc non-teratoma group had conservative surgery, allowing the possibility of future pregnancy. High cure rate can he achieved with a conservative approach in non-seminomatous germ cell tumour of the ovary. Whenever possible, fertility should he preserved during the primary operation in children suffering from these tumours.

Objective: To evaluate the efficacy of adjuvant therapy for ovarian germ cell tumors., Methods: We reviewed records of women who had malignant germ cell tumors of the ovary from 1977-1997., Results: Seventy-two women had surgical resections of malignant ovarian germ cell tumors and most received adjuvant therapy. Fifty-six women (78%) presented with stage I disease, and 16 (22%) had more advanced disease. Tumor subtypes included dysgerminoma (n = 20), yolk sac tumor (n = 8), immature teratoma (n = 29) and mixed germ cell tumor (n = 15). Surgical management of the 56 with stage I disease consisted of total abdominal hysterectomy, bilateral salpingo-oophorectomy, and extensive surgical staging in ten women, whereas a conservative surgical approach, consisting of unilateral adnexectomy with or without comprehensive surgical staging, was adopted in later years (n = 46). Fifty-six women were treated with postoperative chemotherapy, predominantly platinum-based regimens. The 5-year actuarial survival rate was 93%. None of the 36 women who presented after 1984 have died of disease., Conclusion: These data confirmed that platinum-based adjuvant treatments allow most women with ovarian germ cell malignancies to have conservative surgery without compromising survival.

Although the majority of patients with poor-risk germ-cell tumors (GCTs) will achieve a durable complete remission (CR) with standard first-line therapy, 20% to 30% of them will either relapse or fail to achieve an initial CR and eventually die. For this reason, the strategy of using high-dose (HD) chemotherapy with autologous stem-cell support has been investigated to improve the chances of cure attainable in the salvage setting, but at a cost of significant morbidity and mortality. Treatment using HD therapy in the first-line setting offers the promise of reducing morbidity and mortality while increasing efficacy. At Memorial Sloan-Kettering Cancer Center (MSKCC), trials were conducted to test this hypothesis. Patients at high risk of relapse following conventional therapy were identified, based on post-treatment serum marker concentrations that failed to appropriately decline by predicted half-life after several cycles of standard treatment. These patients received first-line HD treatment. Patients received a 2-drug HD regimen in one trial and an intensified 3-drug regimen in another, each with autologous bone marrow transplantation. These patients had improved overall and event-free survival rates (p = 0.001 and 0.003, respectively) compared with historical controls who underwent standard first-line treatment, with a lower incidence of treatment-related mortality than patients who received HD therapy in the salvage setting. Randomized trials are under way to prospectively verify these results.

Germ-cell tumors (GCTs) are very chemosensitive and highly curable cancers. For the small proportion of patients who fail conventional chemotherapy (CT), high-dose CT (HDCT) was introduced in France and elsewhere in 1982-1984. We report here on the French experience with HDCT in GCTs. At the Centre Léon Bérard, 75 patients were treated with HDCT between 1982 and 1996. Patients received HDCT in 2 different settings: 46 in consolidation of first-line treatment or in incomplete response, 29 in salvage of relapse or refractory disease. The most common regimens of HDCT were the combination of etoposide, double-dose cisplatin and either ifosfamide (VIC regimen, n = 46) or cyclophosphamide (PEC regimen, n = 9) and the combination of carboplatin, etoposide and cyclophosphamide (Carbo-PEC regimen, n = 17). Seven patients died of toxicity. The median follow-up was 42 months. Forty-five of 75 patients are alive and free of disease at long term, 2 of whom had refractory disease. The median time to recovery of a granulocyte count > or = 0.5 x 10(9)/l and a platelet count > or = 25 x 10(9)/l was 14 and 11 days, respectively. The French development was based on double-dose cisplatin until the results of the French randomized trial, which showed no advantage of HDCT in the first-line treatment of poor-risk group patients. Then carboplatin was associated with etoposide and cyclophosphamide in a phase I trial. A European randomized trial, which studies the role of HDCT in the first-line salvage treatment of non-refractory disease, is ongoing. So far, HDCT is not a standard treatment of GCT.

During the past 10 years, high-dose chemotherapy (HDCT) has emerged as a feasible and curative treatment option for patients with multiply relapsed and/or refractory germ-cell tumors. Increasing experience and the results from clinical trials have helped to optimize the application of HDCT and to define its role in the salvage concepts for germ-cell tumors.

Background: Pediatric intracranial germinoma treated with radiotherapy is considered a standard treatment, but may cause significant delayed damage to the central nervous system. Chemotherapy has been shown to be effective for the treatment of an intracranial germinoma. In the past 10 years, we treated 11 cases of primary intracranial germinoma with chemotherapy alone. The purpose of this retrospective study is to review the clinical outcome of these patients., Methods: Eleven children with newly diagnosed, previously untreated primary intracranial germinomas were treated with six courses of chemotherapy (vinblastine bleomycin, cisplatin and etoposide, VBPE). The response to chemotherapy, relapses and outcomes are reviewed and evaluated., Results: All 11 assessable children achieved a complete response and are alive, with a median follow-up of 61 months. Five patients with tumors located in the midline position of the brain, including pineal, sellar, suprasellar and hypothalamic areas, had no relapse. Six patients had relapses, and all of them achieved a second complete remission after salvage focal radiotherapy. The time of onset of relapse was from nine to 24 months after chemotherapy, with an average of 16.8 months., Conclusions: VBPE chemotherapy was effective for treating newly diagnosed intracranial germinomas. Although a high rate of relapse (6/11) was observed, all of these patients survived with first or second complete remissions. It was beneficial for five children that focal radiation was eliminated and delayed post-irradiation neurologic sequelae were avoided.

Treatment of recurrent germ cell tumors is a complex undertaking. There are a number of clinical scenarios that can mimic relapse and, as such, a great deal of experience with management of germ cell tumors is required to recognize these rare but important situations that simulate recurrence. If recurrence is proven, standard chemotherapy with cisplatin, ifosfamide, and etoposide can result in approximately 30% of patients being long-term, disease-free survivors. Emerging technologies, e.g., high-dose chemotherapy and new drugs, may augment our current ability to salvage this patient population. Desperation surgery offers an additional opportunity for selected patients with localized chemotherapy-resistant relapse or those patients with late relapse of germ cell tumor., (Copyright 1999 Wiley-Liss, Inc.)

The success of combination chemotherapy in treating advanced metastatic germ cell tumors has led to new challenges for the genitourinary oncologic surgeon in the peri-operative care of patients. Surgery remains an integral part of the management of patients with advanced germ cell tumors. Retroperitoneal node dissections following chemotherapy or radiation, or both, are technically more demanding and subject to higher rates of peri-operative complications. Overall post-therapy surgical complication rates range from 33% to 75%, with the highest rates among patients who receive both radiation and chemotherapy. Although most patients with testicular cancer are young and healthy, residual pulmonary, renal, vascular, and neurologic toxicities from chemotherapy can increase the risk of peri-operative complications. In addition, the volume and location of tumor can increase the technical demands, especially when there is a tremendous soft tissue reaction to the chemotherapy. Identification of pre-operative risk factors for peri-operative complications is imperative and the first step in pre-operative planning. Pulmonary toxicity and vascular (cardiac or peripheral) events are the two most immediately life-threatening complications that can occur in the peri-operative period. Due to the high incidence of subclinical pulmonary toxicity, one must consider all patients who have received bleomycin pre-operatively at risk to develop postoperative pulmonary problems. Pre-operative evaluation and judicious fluid management have been shown to reduce the risk of life-threatening respiratory complications in the postoperative period., (Copyright 1999 Wiley-Liss, Inc.)

Today, the standard treatment for patients with clinical Stage I non-seminomatous testicular germ cell tumors (NSTGCT) following orchidectomy is either primary retroperitoneal lymph node dissection (RPLND) or close surveillance with cisplatin-based polychemotherapy in case of a relapse. Both treatment modalities provide excellent overall survival rates up to 100%. Consequently, selection of the most appropriate management option is not primarily guided by survival considerations. The choice between the available options, each having its merits and its drawbacks, should be made based on a number of factors including treatment-related morbidity, views and expertise of the physician, patient preferences, the expected degree of patient compliance, and prognostic factor analysis. To date, the role of adjuvant chemotherapy as an alternative management option for patients with clinical Stage I NSTGCT at high risk of occult metastases is limited. This systemic treatment modality would be a realistic alternative if the reliability of prognostic factors to identify high-risk Stage I patients could be improved. This review addresses relevant issues in the management of patients with clinical Stage I NSTGCT to provide information that will allow a rational selection of the most appropriate management option., (Copyright 1999 Wiley-Liss, Inc.)

Cisplatin appears to be the major cause for long-term toxicity in patients treated for testicular cancer. Long-term side effects consist mainly of nephrotoxicity, ototoxicity, and neurotoxicity as well as gonadal damage. Following standard-dose chemotherapy approximately 20% to 30% of patients will be affected by long-term side effects, although not all these side effects will cause an impaired quality of life. Several strategies have been or currently are being evaluated to reduce acute and long-term complications including the introduction of equally effective, but less toxic regimens, or the use of cytoprotective agents such as amifostine. Secondary acute myeloid leukemia and secondary myelodysplastic syndrome probably represent the worst possible long-term complications of cancer therapy in those patients who originally were cured of their primary testicular cancer. Therapy-related solid tumors are mainly associated with the use of radiation therapy and the risk for developing a therapy-related solid tumor is increased approximately two to three times compared to the general population. In contrast, therapy-related leukemias are predominantly associated with chemotherapy, particularly with the use of topoisomerase-II inhibitors and alkylating agents. In general, the cumulative incidence of therapy-related leukemia following treatment of germ cell cancer is low. It is approximately 0.5% and 2% at 5 years of median follow-up for patients receiving etoposide at cumulative doses< or = 2 g/m(2) and >2 g/m(2), respectively. The risk-benefit analysis in patients with testicular cancer clearly favors the use of current treatment regimens including high-dose chemotherapy. However, even the acceptably low number of therapy-related long-term complications should encourage the search for equally effective but less toxic therapies. This review will highlight important available data about therapy-related toxicity and particularly, therapy-related malignancies following cisplatin-etoposide-based chemotherapy., (Copyright 1999 Wiley-Liss, Inc.)

The majority of patients with disseminated germ cell cancer can be cured with cisplatin-based combination chemotherapy. For more than a decade the gold standard regimen is cisplatin, etoposide, and bleomycin (BEP). On both sides of the Atlantic, a number of studies have been carried out to either modify the toxicity of therapy in good prognosis patients or to improve the treatment outcome by intensifying the regimen or incorporating new agents in patients with intermediate or poor prognosis disease. This review discusses the trials that have been conducted in Europe, mainly through the European Organization of Research and Treatment of Cancer (EORTC) and Medical Research Council (MRC) in the United Kingdom, as well as the studies that are currently being conducted by the collaborative groups in Europe., (Copyright 1999 Wiley-Liss, Inc.)

The management of germ cell tumors (GCT) in men has been the focus of intense clinical investigation over the past 25 years. Following clinical trials which demonstrated that GCTs are curable, considerable effort has been directed at refinement of the multidisciplinary treatment plan. During the past decade, there has been a major emphasis on identifying those clinical prognostic features most closely associated with a high likelihood of a complete response (good risk) and a low likelihood of complete response (poor risk). Randomized good- and poor-risk clinical trials have been conducted which clarify the role of bleomycin and the number of cycles of therapy in good-risk patients and the role of high-dose cisplatin (200 mg/m(2)/cycle) and ifosfamide in poor-risk patients. The efficacy of high-dose chemotherapy with stem cell rescue has led to a randomized trial of its use following standard induction therapy as compared to standard induction therapy in previously untreated poor-risk patients. Salvage chemotherapy for patients in first or second relapse, or those who have not achieved an initial complete response, initially tested the role of ifosfamide; efforts are now focused on the role of paclitaxel and high-dose therapy in specific patient subgroups. High-dose chemotherapy with stem cell rescue is the treatment of choice for patients in second relapse with gonadal primary tumors who have responsive disease and factors which predict a reasonable likelihood of achieving a disease-free status. A general understanding of tumor biology and specific knowledge regarding GCTs will be very important in the next decade of discovery as the pathways of malignant transformation, progression, and drug resistance become better known and serve as targets for new therapy., (Copyright 1999 Wiley-Liss, Inc.)

Between January 1997 and December 1998, six patients with germ cell tumor were treated with high-dose CEC: carboplatin (1,500 mg/m2), etoposide (1,200 mg/m2) and cyclophosphamide (100 mg/kg), followed by peripheral blood stem cell transplantation (PBSCT) at Nagoya University Hospital. Four patients received one cycle of high-dose CEC and two received two cycles. The reasons why the high-dose CEC was administered included: 1) refractory to the induction chemotherapy (AFP/beta-HCG elevated during the induction chemotherapy or prolonged half-life of each marker) in three patients, 2) relapse in two patients, and 3) consolidation in one with unresectable mediastinal residual tumor. There were no treatment-related deaths and grade 1 hepatotoxicity occurred in one (17%) patient. The median duration (range) from PBSCT until a granulocyte count of 500/microL and a platelet count of 50,000/microL was 8.5 (8-11) and 11 (9-16) days, respectively. Of the six patients studied, 5 responded to the treatment; two achieved a complete response (CR) and three achieved a partial response (PR). One patient achieving a CR and two achieving a PR remained in complete remission after 23 to 24 months of follow-up, while the remaining patients with a CR, a PR and an incomplete response died of the disease. High-dose CEC could be administered without serious toxicity but the effectiveness of high-dose CEC for the poor-risk patients with germ cell tumor needs to be further investigated.

The efficacy and toxicity of a single cycle of high-dose chemotherapy with peripheral blood stem cell autotransplantation (PBSCT) in patients with poor-risk testicular germ cell tumors (GCT) enrolled in the Japan Blood Cell Transplantation Study Group was investigated. Previously untreated poor-risk testicular GCT patients were treated with BEP therapy (cisplatin, etoposide and bleomycin) with or without high-dose chemotherapy (carboplatin, etoposide and ifosphamide) followed by PBSCT. Patients were qualified for a change to high-dose chemotherapy if elevated serum tumor markers (human chorionic gonadotropin-beta, alpha-fetoprotein and lactate dehydrogenase) was observed after 3 cycles of BEP therapy. Eighteen patients were treated with BEP therapy alone and 16 with BEP and high-dose chemotherapy. At the completion of high-dose chemotherapy, all tumor markers had returned to normal in 6 patients. Among them, 1 had only teratoma found at resection and 5 had carcinoma resected. Nine patients who had persistent elevation of any tumor marker were treated with high-dose chemotherapy or another anticancer drug. Thirteen are alive (81%) and 9 (56%) are continuously disease-free at a median follow up of 11 months. The median time from PBSCT to a granulocyte count > 500/microL was 9.5 days and to a platelet count > 50,000/microL was 13 days.

To assess the efficacy and toxicity of chemotherapy for advanced germ cell tumors, 115 patients with testicular and extragonadal germ cell tumors were reviewed. Five-year survival rates of 19 seminoma patients and 96 non-seminoma patients were 84% and 68%, respectively. According to the analysis using three sets of prognostic criteria, Indiana University Classification, International Germ Cell Consensus Classification and K Classification, the 5-year survival rate of poor-prognosis patients was 42-45%. BEP regimen (bleomycin, etoposide and cisplatin) salvaged with VIP (etoposide, ifosfamide and cisplatin) would be the standard therapy for advanced germ cell tumors since high-dose chemotherapy had no advantage on survival over the standard-dose regimen. Early serious toxicities were observed in 18 patients (15.7%), including pulmonary fibrosis, respiratory distress, and sepsis. Poor performance status and prior radiotherapy were risk factors for fatal adverse effects. In terms of late toxicites, out of 76 patients in complete remission for at least one year after cessation of chemotherapy, 31 had numbness of extremities and 29 had tinnitus. Serial semen analyses of 38 patients showed continuous azoospermia or severe oligozoospermia in 22. These data indicated that less toxic therapy was required for good-risk patients to improve the quality of life, while more intensive therapy for poor-risk patients to be cured. Several prognostic criteria should be utilized to properly distinguish good- from poor-risk patients, and decide how to treat each patient.

We examined the clinical results of super high-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) in 14 patients with poor-risk advanced germ cell tumors. The mean number of nadir white blood cells was 205 +/- 126/microliter; the mean period of number of white blood cells fewer than 1,000/microliter was at 8-10 days (mean +/- SD; 9.2 +/- 0.92). The nadir number of blood platelet cells was 1.7 +/- 0.70 x 10(4)/microliter; the mean period of number of platelet cells fewer than 5 x 10(4)/microliter was at 12.6 +/- 2.17 days. Of 10 patients treated with super high-dose chemotherapy with PBSCT as induction therapy, 8 patients (80%) showed that the serum tumor marker returned within the normal range after super high-dose chemotherapy. Of 8 patients, 7 underwent resection of the residual tumor. Surgical or pathological CR was obtained in 5 of these 7 patients, 4 patients of whom were alive with no evidence of disease 29 to 49 months after initial consultation: the other patient died with recurrence 20 months after initial visit. On the other hand, super high-dose chemotherapy with PBSCT was performed for one patient as consolidation, and for 3 patients with recurrence. Of these 4 patients, one died from disease 6 months after detection of recurrence. The other 3 patients were alive with no evidence of disease at 7-37 months after initial visit. The 1- and 3-year disease-free survival rates were 88% and 72%, respectively. In conclusion, super high-dose chemotherapy with PBSCT can be done safely and could be useful for patients with poor-risk germ cell tumor.