Metastatic seminoma treated with either single agent carboplatin or cisplatin-based combination chemotherapy: a pooled analysis of two randomised trials.

To study the role of single agent carboplatin chemotherapy in patients with metastatic seminoma based on the data from two randomised trials. In subgroup analyses in patients with different disease characteristics, the outcome treated with either single agent carboplatin or cisplatin-based combination chemotherapy was compared. Individual patient data from two randomised European trials involving patients with metastatic seminoma were gathered. The primary endpoint for all analyses was progression-free survival. The source data of 361 patients, 184 treated with cisplatin-based combinations and 177 treated with carboplatin single agent therapy, were entered into the analysis. Patient characteristics were comparable among the cisplatin-based and the carboplatin single agent treated patient groups with lymph nodes and lungs being the most frequent metastatic sites in 92 and 8% of patients, respectively. Overall, patients treated with single agent carboplatin had an inferior 5-year overall (89 and 94%; P=0.09) and progression-free survival rate (72 and 92%; P< 0.0001) compared with patients receiving cisplatin-based combinations. For all investigated subgroups (based on age, prior radiation therapy, metastatic sites), carboplatin single agent therapy was found to be inferior to cisplatin-based combination chemotherapy. In conclusion, carboplatin single agent therapy cannot be recommended as standard treatment for any patient subgroup with advanced metastatic seminoma and cisplatin-based combination regimens remain the standard of care.

Double-blind randomised placebo-controlled phase III study of an E. coli extract plus 5-fluorouracil versus 5-fluorouracil in patients with advanced colorectal cancer.

The primary aim of this study was to evaluate the toxicity (mucositis, diarrhea and leucopenia) of a therapy with 5-fluorouracil (CAS 51-21-8; 5-FU) plus an E. coli extract (LC-Extract, Laves coli extract, Colibiogen inject, cell-free soluble fraction from lysed E. coli, Laves strain) in comparison with 5-FU plus placebo. Secondary endpoints included general toxicity, response rate according to WHO, survival time and quality of life. 164 patients with advanced colorectal cancer were enrolled in this randomised, placebo-controlled, double-blind, multicenter phase III study. The treatment consisted of 0.167 ml/kg/d LC-Extract or placebo followed by 500-750 mg/m2/d 5-FU on five consecutive days, repeated every three weeks for up to six treatment cycles. 158 (77 verum, 81 placebo) patients were evaluable for toxicity, 144 (72 verum, 72 placebo) evaluable for response. The therapy with LC-Extract was well tolerated. Adverse events that occurred during the study were mainly judged as 5-FU- or tumor-related. Toxicity from treatment with 600 mg/m2/d 5-FU in both treatment groups was very low. After treatment with 750 mg/m2/d 5-FU patients in the placebo-group experienced a higher CTC toxicity than in the LC-Extract groups. Remission rate and survival time showed a slight trend in favour of LC-Extract. These results suggest a positive benefit-risk ratio of the additional application of LC-Extract to 5-FU in the treatment of advanced colorectal cancer especially for administration of high doses of 5-FU.

Validity of predictions of residual retroperitoneal mass histology in nonseminomatous testicular cancer.

PURPOSE: To validate predictions of the histology (necrosis, mature teratoma, or cancer) of residual retroperitoneal masses in patients treated with chemotherapy for metastatic nonseminomatous testicular germ cell tumor. PATIENTS AND METHODS: We studied 172 testicular cancer patients who underwent resection while tumor markers were normal. Predictive characteristics for the residual histology were registered, including the presence of teratoma elements in the primary tumor, the prechemotherapy level of tumor markers (alpha-fetaprotein [AFP], human chorionic gonadotropin [HCG], lactate dehydrogenase [LDH]), the size of the residual mass, and the percentage of shrinkage in mass diameter. We calculated the predicted probability of necrosis and the ratio of cancer and mature teratoma with previously published logistic regression formulas. RESULTS: The distribution of the residual histology was necrosis in 77 (45%), mature teratoma in 72 (42%), and cancer in 23 (13%). Necrosis could be well distinguished from other tissue, with an area under the receiver operating characteristic (ROC) curve of 82%. No tumor was found in 15 patients with a predicted probability of necrosis over 90%. The predicted probabilities corresponded reliably with the observed probabilities (goodness-of-fit tests, P > .20), although a somewhat higher probability of necrosis was observed in patients treated with chemotherapy containing etoposide. Conversely, cancer could not reliably be predicted or adequately discriminated from mature teratoma. CONCLUSION: The predicted probabilities of necrosis have adequate reliability and discriminative power. These predictions may validly support the decision-making process regarding the need and extent of retroperitoneal lymph node dissection.

Is serum tumor marker half-life a guide to prognosis in metastatic nonseminomatous germ cell tumors?

BACKGROUND: The value of serum tumor marker kinetics of AFP and HCG assessed by marker half-life (MHL) analysis for diagnosis and in the follow-up of patients with nonseminomatous germ cell tumors (NSGCT) is still debated controversally. The aim of this retrospective study was therefore to investigate the influence of serum MHL during the first two cycles of chemotherapy on the long-term outcome in metastatic NSGCT. MATERIAL AND METHODS: 147 patients with at least 2 abnormal marker values > 7 days after start of chemotherapy were investigated for HL analysis (HL cut off 3.5 days for HCG and 7 days for AFP). HCG and AFP determinations were performed by a double monoclonal IRMA (HCG) and conventional RIA (AFP) developed by our laboratory. RESULTS: According to these cut offs 35/108 patients (32.4%) had a prolonged HCG HL and 41/114 patients (36%) a prolonged AFP HL. Patients with either MHL prolonged had a significantly inferior overall survival (OS; 10 year OS 37% vs. 75%, p = 0.0005) and progression-free survival (PFS; 10 year PFS 29% vs. 69%, p < 0.0001) than those with a prolonged HCG MHL (OS; 10 year OS 36% vs. 65%, p = 0.003; 10 year PFS 28% vs. 56%; p = 0.001) and even more than those with a prolonged AFP MHL (10 year OS 39% vs. 70%, p = 0.02; 10 year PFS 32% vs. 56%, p = 0.01). CONCLUSION: The remarkable prognostic information assessed by MHL analysis in this retrospective study merits further confirmation by a prospective study for its appropriateness in selecting patients for high dose chemotherapy.

Late relapse of germ cell tumors after cisplatin-based chemotherapy.

BACKGROUND: Sparse data are available with regard to the incidence, clinical characteristics, therapeutic management and prognosis of male patients with germ cell tumors, who relapse more than two years after completion of cisplatin-based chemotherapy. PATIENTS AND METHODS: A review of 530 patients treated at two institutions from 1978 to April 1994 was conducted. Twenty-five cases of late relapse were identified. Cumulative risk of late relapse was calculated according to the Kaplan-Meier method. RESULTS: 418 of 523 patients (80%) who received their first-line treatment at our institutions were relapse-free at two years. Among these 418 patients 18 cases (4.3%) developed a late relapse. The cumulative risk of late relapse was 1.1% at five years and 4.0% at ten years excluding patients with prior early relapses who carried risks of 9.4% and 29%, respectively (P < 0.0001). No case of late relapse was observed among patients receiving adjuvant chemotherapy. The risk of late relapse was lower in patients with good-risk non-seminomatous germ cell tumors than in poor-risk patients according to Medical Research Council criteria (P < 0.01). Seven further patients were referred from other institutions for treatment of late relapse. At a median follow-up of 38 months (range, 3 to 121) after treatment of late relapse 9 of 25 patients (36%) are continuously disease-free. Six of these nine patients had surgical resection of carcinoma or teratoma as a component of their therapy. CONCLUSION: The incidence of late relapse after cisplatin-based chemotherapy of germ cell tumors is related to initial tumor burden and is somewhat higher than previously expected. Chemotherapy seems to have only minor curative potential, but localized resectable disease can be cured by surgery. Annual follow-up evaluations allow to detect the majority of late relapses at an asymptomatic stage and should be extended throughout the patient's life.

Advances in the management of metastatic non-seminomatous germ cell tumours during the cisplatin era: a single-institution experience.

Long-term outcome was reviewed in 266 consecutive patients with metastatic non-seminomatous germ cell tumours treated at a single institution. The overall 3 year survival was 77%, and 3 year progression-free survival was 71%. Multivariate analysis identified the following clinical features as independent prognostic factors: the presence of liver, bone or brain metastasis, serum human chorionic gonadotropin > or = 10000 U l-1 and/or alpha-fetoprotein > or = 1000 ng ml-1, a mediastinal mass > 5 cm and the presence of 20 or more lung metastases. Age was not of prognostic significance. Patients without any of the above poor-risk factors had a 3 year survival of 91% regardless of etoposide- or vinblastine-containing chemotherapy compared with 61% for the remaining patients. However, etoposide-containing protocols led to significantly improved survival in patients with at least one poor risk factor. After 612 patient-years of observation no case of secondary leukaemia was observed among 119 surviving patients who had received etoposide as part of their treatment. With a median follow-up of 93 months, five patients developed a second germ cell tumour, two patients nongerm cell malignancies. Fourteen patients relapsed after a disease-free interval of more than 2 years, and nine patients died more than 5 years after commencement of treatment underscoring the need to report long-term results. There is some evidence that cumulative experience translates into improved survival and cure rates for patients with poor-risk metastatic disease.

Does serum tumor marker half-life complement pretreatment risk stratification in metastatic nonseminomatous germ cell tumors?

The goal of this study was to determine whether the serum tumor marker half-life (MHL) of human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) during initial chemotherapy can complement pretreatment risk stratification in metastatic nonseminomatous germ cell tumors. One hundred forty-seven patients were assessable for MHL during the first two cycles of platinum-based chemotherapy. MHL calculation was based on two consecutive values using Kohn's apparent half-life formula (MHL =ln 1/2/G, where G was the gradient of the marker slope) or on three (or more) values using simple linear regression. MHL was regarded as prolonged if it was more than 3.5 days for HCG or more than 7 days for AFP. The median MHL for HCG was 2.8 days (range, 0.7-16.7) and for AFP was 6.2 days (range, 2. 6-65.4). Thirty-five of 108 patients (32%) had a prolonged MHL for HCG, 41 of 114 (36%) had a prolonged MHL for AFP, and in 59 of 147 patients (40%), either or both MHLs were prolonged. If patients with both MHLs normal were compared against patients with either or both MHLs prolonged, highly significant differences in progression-free survival (P < 0.0001) and overall survival (P = 0.0005) were demonstrated. The test accuracy was 70% for both progression-free and overall survival, and it was slightly greater than the overall predictive value of the Medical Research Council prognostic classification. A combination of Medical Research Council criteria and MHL analysis allowed us to refine prognostic assessment. Because MHL analysis is able to complement pretreatment risk stratification and can support selection of patients for early-dose intensified chemotherapy, it should be included in prospective clinical trials for patients with poor-prognosis disease.

Testicular germ cell tumors in patients with human immunodeficiency virus infection.

BACKGROUND: There has been evidence of a higher incidence of testicular germ cell tumors (GCT) in human immunodeficiency virus (HIV)-seropositive men than in the non HIV-infected male population. Most authors recommend standard therapy for HIV-positive patients with GCT but the immumosuppressive effects of chemotherapy and/or radiotherapy must be considered. METHODS: The records of all patients in whom testicular cancer was diagnosed and/or treated at a single institution between January 1986 and July 1995 were reviewed with regard to HIV seropositivity. Tumor histology, initial staging, treatment, and the patients' outcomes were analyzed in connection with a review of the literature. RESULTS: Six patients with GCT and documented HIV seropositivity at the time of tumor diagnosis (four homosexuals, one bisexual, and one heterosexual former intravenous drug abuser) of 192 documented cases of testicular cancer are reported. In addition, 1 patient proved to be HIV seropositive 34 months after completing chemotherapy (vinblastine, ifosfamide, and cisplatin) for Stage IIB (minimal disease) seminoma. Intensified platinum-based chemotherapy was administered to two patients with clinical Stage IIIC (advanced disease) nonseminomatous germ cell tumors (NSGCT). Both patients achieved a transient partial response but suffered from progressive HIV disease and died 24 and 7 months, respectively, after orchiectomy. One patient with Stage IIIA (moderate disease) seminoma received four courses of chemotherapy (etoposide, ifosfamide, and cisplatin) and has remained in complete remission for 40 months. One patient with bilateral Stage I seminoma underwent adjuvant radiotherapy but was lost to follow-up. One patient with clinical Stage IIA (minimal disease) NSGCT refused any further treatment after hemiorchiectomy, but four courses of chemotherapy (cisplatin, etoposide and bleomycin) had to be given 32 months later because of symptomatic abdominal disease. A partial remission was obtained and there was no evidence of active tumor 16 months after the completion of chemotherapy. A retroperitoneal lymph node dissection was performed in 1 patient with Stage I NSGCT who was free of disease 111 months after diagnosis. The Centers for Disease Control classification for HIV infection and acquired immune deficiency syndrome (AIDS) did not change after therapy in two patients, whereas three patients suffered from progressive HIV disease. CONCLUSIONS: HIV infection should be considered in patients with testicular cancer who belong to an urban population. Oncologic therapy based on a patient's individual situation is recommended.

Cisplatin-based chemotherapy of primary extragonadal germ cell tumors. A single institution experience.

BACKGROUND: Extragonadal germ cell tumors account for only 2-5% of all germ cell neoplasms in adult males. Because these tumors are rare and, in part, biologically distinct from their testicular counterparts, their optimal management continues to be defined. METHODS: The medical records of 51 patients with extragonadal germ cell tumors were reviewed. All patients were treated with cisplatin-based chemotherapy at a single institution between 1981 and 1994. RESULTS: Thirty-five patients had nonseminomatous germ cell tumors and 16 had pure seminomas. Sixteen tumors arose in the mediastinum (12 nonseminomas, 4 seminomas), and 35 in the retroperitoneum (23 nonseminomas, 12 seminomas). Six of 12 patients (50%) with mediastinal nonseminomas survived with no evidence of disease (NED) at 33-137 months (median, 96 months); all had undergone surgery as part of their treatment. Fifteen of 23 patients (65%) with retroperitoneal nonseminomas are alive with NED at 2-145 months (median, 39 months). Fifteen of 16 patients (94%) with extragonadal seminomas survived with NED at 2-141 months (median, 66 months), and 1 patient died from late irradiation-related toxicity. Three patients with retroperitoneal nonseminomas developed a testicular seminoma at 35, 42, and 77 months, respectively; all are currently disease free. CONCLUSIONS: Mediastinal and retroperitoneal nonseminomas have distinct clinical features. As in other series, clinical outcome is somewhat inferior for mediastinal nonseminomas compared with retroperitoneal nonseminomas. Regardless of the site of presentation, the vast majority of patients with extragonadal seminomas can expect cure. It remains controversial, however, whether retroperitoneal germ cell tumors are metastatic from a primary testicular germ cell tumor.

Prognosis after salvage treatment for unselected male patients with germ cell tumours.

Long-term outcome of salvage treatment was reviewed in 67 unselected male patients relapsing during or after their primary cisplatin-based chemotherapy for metastatic germ cell tumours. Seven patients underwent only surgery and/or radiotherapy as curatively intended salvage treatment. Thirty-five patients (52%) had a complete or partial response to salvage treatment, 20 (57%) of whom relapsed again. With a median follow-up of 90 months (range 3-143 months) 20 patients (30%) are alive with no evidence of disease, 15 continuously disease-free and five currently disease-free. The 5 year survival from start of salvage treatment is 37% for the group as a whole. Multivariate analysis identified age < or = 35 years, complete response to primary treatment and a relapse-free interval > 3 months as independent predictors of favourable outcome of salvage treatment. A group of patients with these good-risk factors (42%) had a 5 year survival of 72% compared with the remaining patients (58%) with a 5 year survival of only 11%. Whereas patients with good-risk features may be adequately managed by conventional salvage treatment, the remaining patients carry a very poor prognosis and require innovative and more aggressive approaches.

Outcome analysis after post-chemotherapy surgery in patients with non-seminomatous germ cell tumours.

BACKGROUND: The goal of the study was to analyse long-term outcome after post-chemotherapy surgery in male patients with non-seminomatous germ cell tumours (NSGCT). PATIENTS AND METHODS: We reviewed the charts of 111 patients with metastatic NSGCT treated at a single institution from 1979 to 1993 who underwent post-chemotherapy resection of residual masses after normalisation of tumour markers. The prognostic relevance of the extent of tumour residuals, the comprehensiveness of surgery and the histology at resection was analysed. RESULTS: Thirteen patients (12%) harboured viable cancer, and 46 patients (41%) mature teratoma at post-chemotherapy surgery. Only seven (54%) of the 13 patients with viable cancer remained continuously disease-free. Incomplete surgery predicted an impaired outcome (62% vs. 86% survival), although only one recurrence was observed at a site of an incompletely resected mass. Moreover, a progression-free interval < or = 3 months after post-chemotherapy surgery was correlated with worse subsequent survival (p = 0.0001). CONCLUSIONS: Post-chemotherapy surgery remains an essential part of the treatment for metastatic NSGCT. Resection of viable cancer and mature teratoma is of therapeutic benefit. Viable cancer at surgery defines the need for further chemotherapy.

The role of granulocyte-macrophage colony-stimulating factor in the treatment of germ cell tumors. German Testicular Cancer Study Group.

Hematopoietic growth factors, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), may gain increasing importance in the treatment of patients with malignant germ cell tumors. For patients with far advanced testicular cancer, who only have a chance of long-term cure in the range of 40% to 50% by standard induction chemotherapy, the German Testicular Cancer Study Group has shown that the application of GM-CSF after PEI chemotherapy has allowed the increase of dose intensity of this three-drug regimen by a factor of 1.4. In 75 evaluable patients an overall survival rate of 79% after a median follow-up of 27 months was achieved. The dose-limiting toxicity of this stepwise dose escalation protocol of the PEI regimen was severe mucositis/enteritis (World Health Organization [WHO] degrees 3/degrees 4) in 33% of the patients and prolonged thrombocytopenia (< 20,000/microL for more than 10 days). In future trials, hematopoietic growth factors will be used in the treatment of far-advanced testicular cancer to generate peripheral blood stem cells (PBSC) that can be used to overcome both granulocytopenia and thrombocytopenia. This approach with the use of PBSC and hematopoietic growth factors will allow us to apply multiple cycles of up-front dose-intensified PEI chemotherapy in this unfavorable subgroup of patients. However, with the establishment of an optimal hematopoietic support in these studies, the value of dose-intensified chemotherapy in advanced testicular cancer will have to be tested against standard dose regimens in prospective randomized trials.

Sequential resection of residual abdominal and thoracic masses after chemotherapy for metastatic non-seminomatous germ cell tumours.

Thirty-eight patients with advanced non-seminomatous germ cell tumours (NSGCTs) underwent multiple surgical interventions (two in 33 patients, three in four patients, four in one patient) after cisplatin-based chemotherapy. All patients had normal serum tumour markers but persistent radiographic masses. The larger mass was routinely resected first. Fifteen patients (39%) had dissimilar histological findings at sequential surgical procedures, 12 of whom demonstrated less favourable pathological features during the first operation and three at the second. Patients who underwent both retroperitoneal lymph node dissection (RPLND) and lung resection showed less favourable histological features in the retroperitoneum in nine cases and in the lung in three cases. Eight of 16 patients (50%) without mature teratoma in their primary tumours showed complete necrosis/fibrosis at all surgical interventions, whereas all patients whose primary tumour was classified as malignant teratoma intermediate demonstrated mature teratoma at least at one anatomical site. As histology of post-chemotherapy residual masses cannot be extrapolated from one anatomical site to another, patients usually are properly managed by excision of all residual masses. In particular, in patients with necrosis/fibrosis at lung resection omission of RPLND is not advised.

[Primary extragonadal germ cell tumors. Clinical manifestations, differential diagnosis and therapy]. / Primär extragonadale Keimzelltumoren. Klinisches Erscheinungsbild, Differentialdiagnose und Therapie.

BACKGROUND: Primary extragonadal germ cell tumors are a rare malignant disease in young males. They account for only 1 to 4% of all germ cell tumors. PATIENTS AND METHODS: In this paper we describe three selected cases of primary extragonadal germ cell tumors. The literature is reviewed with regard to clinical features, differential diagnosis and treatment. RESULTS: Tumor markers alpha-fetoprotein and human chorionic gonadotropin are of considerable diagnostic value if disease distribution is considered. With cisplatin-based combination chemotherapy similar disease-free survival rates are achieved as for testicular tumors with poor-prognosis metastatic disease. Surgical procedures play a role as adjunctive modality. CONCLUSIONS: If young males present with a mass in the retroperitoneum or in the anterosuperior mediastinum, a primary extragonadal germ cell tumor, should be taken into consideration. Tumors of both localisations have distinct clinical features but carry a similar prognosis. Patients benefit from the cumulative experience of a specialist unit.

Central nervous system as sanctuary site of relapse in patients treated with chemotherapy for metastatic testicular cancer.

Isolated central nervous system relapse in patients treated successfully with cisplatin-based chemotherapy for testicular cancer has been described infrequently. In a retrospective analysis we identified this complication in six of 417 patients. Five of the six patients had advanced pulmonary dissemination at onset of chemotherapy, and post-chemotherapy surgery did not reveal viable tumour tissue in any of these cases. All six patients developed a single cerebral metastasis during complete remission a median four months after discontinuation of chemotherapy. Five patients were treated with surgery and subsequent radiotherapy, one patient with irradiation alone. Three patients are alive relapse-free 19, 62 and 86 months after diagnosis of cerebral relapse. One patient was alive with cerebral disease for 12 months without evidence of systemic recurrence. Our data demonstrate that the brain may act as a sanctuary site in chemotherapy-treated testicular cancer. A review of the literature shows that an isolated cerebral relapse is an extremely rare complication, but carries a relatively favourable prognosis.

Testicular tumor after cisplatin-based chemotherapy for germ cell malignancy.

Among 417 patients treated with cisplatin-based chemotherapy for germ cell malignancy (median follow-up 7 years) we observed 6 patients who developed a second tumor of the testis. In 3 cases the first tumor was of testicular origin, whereas in the other cases the initial tumor presented in the retroperitoneal space. Although cisplatin-based chemotherapy may reduce or delay the development of a contralateral testicular tumor, the risk apparently is not completely eliminated. Patients with primary retroperitoneal germ cell tumors need a close and careful follow-up, as they appear to be at an increased risk for developing a testicular tumor.

Adjuvant chemotherapy of stage-ii nonseminomatous testicular cancer.

85 patients with resected stage II non-seminomatous testicular cancer were treated with adjuvant cisplatin-based chemotherapy. Only one patient developed a relapse 14 months after discontinuation of adjuvant chemotherapy, which was successfully treated with salvage chemotherapy. One patient developed a contralateral testicular tumor 6 years after primary therapy. After a median observation time of 6 years (range 2 months to 13 years) 84 patients are alive without evidence of testicular cancer; one died from an unrelated cause. In conclusion, adjuvant cisplatin-based chemotherapy for resected stage Il nonseminomatous testicular cancer almost always prevents relapse.