German Testicular Cancer Study Group Research Articles

Risk factors for relapse in clinical stage I nonseminomatous testicular germ cell tumors: results of the German Testicular Cancer Study Group Trial.

To prospectively assess potential risk factors for relapse in clinical stage I nonseminomatous germ cell tumors of the testis (CS I NSGCT). From September 1996 to May 2002, 200 patients with CS I NSGCT were prospectively assigned to retroperitoneal lymph node dissection (RPLND), and risk factor assessment was performed within a multicenter protocol. One hundred sixty-five patients had an adequate minimum follow-up of 12 months (mean, 34.5 months) or had pathologic stage II. Pathologic stage II disease was found in 27.9% of patients. Only 0.6% of patients relapsed in the retroperitoneum after confirmation of pathologic stage I disease. With reference pathology, vascular invasion (VI) was most predictive of stage in multifactorial analysis (accuracy, 65.1%). However, the positive predictive value (PPV) of VI to predict patients who have metastatic disease or relapse during follow-up was only 52.7%. With absent VI, low-risk patients had a negative predictive value (NPV) of 76.9%. With a combination of several risk factors, the PPV increased to 63.6% and the negative predictive value increased to 86.5%. Even with an optimal combination of prognostic factors and reference pathology, more than one third of patients predicted to have pathologic stage II or relapse during follow-up will not harbor metastatic disease and, therefore, would be overtreated with adjuvant therapy. However, patients at low risk may be predicted at an 86.5% level, and thus, surveillance in highly compliant patients would be a valuable option. For high-risk patients, further reduction of adjuvant treatment is necessary.

Surgery in testis cancer: laparoscopic and open techniques.

The review focuses on the current developments of the management of patients with testis cancer regarding surgery. For clinical stage I and stage II disease, the pros and cons of surgery as a diagnostic and therapeutic tool are updated. Additionally, the emerging role of laparoscopic techniques in the staging of the disease is critically discussed. The review presents the currently changing indications for surgery in addition to chemotherapy in metastatic disease. The complication rates of primary retroperitoneal lymph node dissection have recently been assessed by the German Testicular Cancer Study Group. These data confirm the excellent results of the Indiana series published some years ago. Laparoscopic surgery has been performed in a larger cohort of patients in specialized centers, and, concomitantly, operative times and complication rates have dropped. Indications for surgery in the post-chemotherapy setting have been more clearly defined recently. Seminoma patients usually do not need surgical removal of the residual tumor after chemotherapy, whereas patients with non-seminoma disease probably need surgery even in cases of complete radiological remission after chemotherapy. In view of the recent data on late relapse, complete surgical removal of residual disease for non-seminoma seems of the utmost importance. Larger series of surgical procedures, laparoscopic as well as open, have helped to define the role of this approach in the management of testis cancer. Long-term data on patients with complete response to initial treatment and late relapse have shown the danger of limiting the treatment of metastatic disease to chemotherapy alone. These data have also shown the importance of proper surgical techniques for all stages of testis cancer.

Treatment of patients with metastatic germ cell tumors relapsing after high-dose chemotherapy

With the use of cisplatin-based combination chemotherapy, metastatic testicular germ cell tumors can be cured in 70-80% of patients. Patients refractory to cisplatin-based chemotherapy have a very poor prognosis. Several mechanisms have been discussed for the development of platinum resistance such as a decreased intracellular concentration of the drug, increased repair of the drug induced damage, or an altered apoptotic response to this damage. Various chemotherapeutic agents have been evaluated in intensively pretreated or cisplatin-refractory patients. Neither the antracyclines nor vinorelbine, bendamustine, topotecan, nor biological agents such as suramin and retinoic acid have demonstrated clinical activity. Paclitaxel has been evaluated at different doses and schedules and yielded a response rate of 21% (range 11-30%) with individual patients achieving complete remissions. This has led to the inclusion of paclitaxel in salvage regimens in combination with cisplatin and/or ifosfamide. Two recent studies have evaluated gemcitabine in refractory germ cell tumors, demonstrating a response rate of 17% (95% CI: 7-28%) in 52 intensively pretreated patients, two-thirds of whom had relapsed after previous high-dose chemotherapy plus autologous stem cell transplantation. The nonhematologic toxicity of weekly gemcitabine at doses of 1000-1250 mg/m2 was tolerable and hematologic side effects included thrombocytopenia in approximately 20% of patients. Ongoing studies in refractory germ cell tumors performed by the German Testicular Cancer Study Group (GTCSG) are evaluating oxaliplatin, a platinum derivative with incomplete cross-resistance to cisplatin. Future trials combining new active agents may make it possible to test the use of alternating treatment strategies in patients with "poor prognostic" disease or as salvage treatment. It is hoped that the increase in knowledge of the molecular mechanism of testicular cancer may lead to the development of new therapeutic options.

Treatment of patients with cisplatin-refractory testicular germ-cell cancer

With the use of cisplatin-based combination chemotherapy, metastatic testicular germ-cell tumors can be cured in 70% to 80% of patients. The combination of cisplatin, etoposide and bleomycine (PEB) is considered standard therapy. Patients refractory to cisplatin-based chemotherapy have a markedly poor prognosis. Several chemotherapeutic agents have been evaluated in intensively pre-treated or cisplatin-refractory patients. Neither the anthracyclines nor vinorelbine, topotecan or biological agents such as suramin and retinoic acid have demonstrated clinical activity. Paclitaxel has been evaluated at different doses and schedules and yielded a response rate of 21% (range 11-30%), with single patients achieving complete remissions. This has led to the inclusion of paclitaxel in salvage regimens in combination with cisplatin and/or ifosfamide. Two studies have evaluated gemcitabine in refractory germ-cell tumors and demonstrated a response rate of 17% (95% CI 7-28%) in 52 intensively pre-treated patients, two-thirds of whom had relapsed after previous high-dose chemotherapy plus autologous stem-cell transplantation. The non-hematological toxicity of weekly gemcitabine at doses of 1,000 to 1,250 mg/m2 was tolerable, and hematological side effects included thrombocytopenia in approximately 20% of patients. Ongoing studies in refractory germ-cell tumors performed by the German Testicular Cancer Study Group are evaluating bendamustine, an alkylating agent with activity in breast and small-cell lung cancer, and oxaliplatin, a platinum derivative with incomplete cross-resistance to cisplatin. Future trials combining new active agents may examine alternating treatment strategies in patients with poor-prognostic disease or as salvage treatment.

Treatment of patients with cisplatin-refractory testicular germ-cell cancer. German Testicular Cancer Study Group (GTCSG).

With the use of cisplatin-based combination chemotherapy, metastatic testicular germ-cell tumors can be cured in 70% to 80% of patients. The combination of cisplatin, etoposide and bleomycine (PEB) is considered standard therapy. Patients refractory to cisplatin-based chemotherapy have a markedly poor prognosis. Several chemotherapeutic agents have been evaluated in intensively pre-treated or cisplatin-refractory patients. Neither the anthracyclines nor vinorelbine, topotecan or biological agents such as suramin and retinoic acid have demonstrated clinical activity. Paclitaxel has been evaluated at different doses and schedules and yielded a response rate of 21% (range 11-30%), with single patients achieving complete remissions. This has led to the inclusion of paclitaxel in salvage regimens in combination with cisplatin and/or ifosfamide. Two studies have evaluated gemcitabine in refractory germ-cell tumors and demonstrated a response rate of 17% (95% CI 7-28%) in 52 intensively pre-treated patients, two-thirds of whom had relapsed after previous high-dose chemotherapy plus autologous stem-cell transplantation. The non-hematological toxicity of weekly gemcitabine at doses of 1,000 to 1,250 mg/m2 was tolerable, and hematological side effects included thrombocytopenia in approximately 20% of patients. Ongoing studies in refractory germ-cell tumors performed by the German Testicular Cancer Study Group are evaluating bendamustine, an alkylating agent with activity in breast and small-cell lung cancer, and oxaliplatin, a platinum derivative with incomplete cross-resistance to cisplatin. Future trials combining new active agents may examine alternating treatment strategies in patients with poor-prognostic disease or as salvage treatment.

Future prospects in the chemotherapy of metastatic nonseminomatous testicular germ-cell cancer.

The current aims of chemotherapy in metastatic testicular cancer are to reduce treatment-related toxicity in patients with "good-prognosis" metastatic disease without compromising the efficacy and to improve treatment results in "poor-prognosis" patients according to the IGCCCG classification by the use of more dose-intensive regimens. Three cycles of PEB chemotherapy, consisting of cisplatin, etoposide, and bleomycin, remain the standard treatment for good-prognosis patients despite a number of randomized studies trying to avoid the toxicity of bleomycin or to abandon cisplatin-associated side effects by substitution with the less toxic analogue carboplatin. In patients with intermediate- and poor-prognosis criteria, four cycles of PEB given at 3-weekly intervals are considered routine treatment. The role of high-dose chemotherapy with peripheral blood stem-cell (PBSC) transplantation (HDCT) is currently being investigated for patients who initially present with poor-prognosis metastatic disease and for patients with relapse after previous chemotherapy. Favorable results with long-term survival rates of approximately 75% have been achieved with up-front sequential HDCT in a phase I-II trial of the German Testicular Cancer Study Group (GTCSG) in such patients. A randomized phase III trial comparing conventional dose chemotherapy (4x PEB) with HDCT (2x PEB + 2x HD-CEC) was initiated as a United States intergroup trial in 1996. In patients with relapsed disease, conventional salvage chemotherapy results in only an approximately 20% long-term survival rate. Particularly, primary mediastinal disease and chemotherapy refractoriness represent variables associated with a very poor outcome. HDCT is also employed in relapsed patients to improve the long-term outcome. Long-term toxicity of treatment has become an important issue due to the large group of patients with metastatic disease now being cured with modern treatment strategies. The cumulative dose of cisplatin applied has been identified as a major risk factor for the development of many types of late toxicity. Despite the major advances made in the last 20 years, evaluation of the role of HDCT in both first-line and salvage treatment, investigation of new cytotoxic agents in refractory patients, and assessment of the long-term toxicities are major tasks that remain to be addressed in controlled clinical trials.

A randomized trial of cisplatin, etoposide and bleomycin (PEB) versus carboplatin, etoposide and bleomycin (CEB) for patients with ‘good-risk’ metastatic non-seminomatious germ cell tumors

Cisplatin-based combination chemotherapy will cure 70% to 80% of patients with metastatic non-seminomatous germ cell tumors but is associated with the possibility of severe neuro-, oto- and nephro-toxicities. Carboplatin, a cisplatin analogue, is an active drug in testicular cancer with a more favourable spectrum of side effects. In a randomized trial, the German Testicular Cancer Study Group compared a combination regimen of carboplatin, etoposide and bleomycin (CEB) to standard cisplatin, etoposide and bleomycin (PEB) chemotherapy for patients with 'minimal-' and moderate-disease' non-seminomatous germ cell tumors, according to the Indiana University classification. PEB was given for three cycles at standard doses (given days 1-5), and the CEB regimen consisted of carboplatin (target AUC of 5 mg/ml x min) on day 1, etoposide 120 mg/m2 on days 1 to 3 and bleomycin 30 mg on days 1, 8 and 15. Four cycles of CEB were given, with the omission of bleomycin in the fourth cycle. Thus, the cumulative doses of etoposide and bleomycin applied in the two treatment arms were comparable. Fifty-four patients were entered on the trial, 29 were treated with PEB and 25 with CEB chemotherapy. Patients were stratified according to disease extent (minimal versus moderate) and the degree of tumor marker elevation. Thirty-two patients (59%) belonged to the group with minimal disease and low markers. No significant difference in response to chemotherapy was seen between the two arms, with CR rates of 81% for the PEB arm and 76% for CEB treatment. However, more patients treated with CEB (32% versus 13%) have relapsed after therapy, and 4 patients (16%) have died of disease progression after CEP in contrast to 1 (3%) after PEB therapy. The first interim analysis of negative events (relapse, vital tumor at secondary resection, death from disease and therapy-associated death) showed a significantly higher rate after CEB than after PEB therapy, and the trial was terminated early. After a median follow-up of 33 months for all patients, the calculation of negative events is still significantly in favour of PEB-treated patient, particularly since three late relapses > 2 years have been observed in the CEB arm (P = 0.03). This randomized trial demonstrates that even with the use of adequate doses of etoposide and full-dose bleomycin, carboplatin cannot altogether replace cisplatin in patients with testicular cancer. Treatment with the PEB regimen remains the standard approach in patients with 'good-risk' non-seminomatous germ cell tumors.

The role of paclitaxel in chemosensitive urological malignancies: current strategies in bladder cancer and testicular germ-cell tumors.

Recent results demonstrate an emerging role for paclitaxel in patients with urothelial-tract cancer and in patients with testicular cancer. Yielding response rates in the range of 40-50% as a single agent, paclitaxel is one of the most active drugs in metastatic bladder cancer. Ongoing trials of paclitaxel combination chemotherapy with cisplatin or cisplatin and ifosfamide demonstrate substantial objective remission rates above 70% and, in addition, a high range of complete responses. Thus, paclitaxel appears to be an important drug when used as part of first-line combination chemotherapy for metastatic bladder cancer. Ongoing clinical trials focus on the combination of paclitaxel with cisplatin, ifosfamide, gemcytabine, and carboplatin. Furthermore, paclitaxel administration has been demonstrated to be easily applicable to patients with reduced renal function, requiring no dose reduction and producing no increase in toxicity. Future strategies will have to compare the most active paclitaxel combination regimen with first-line MVAC (methotrexate, vinblastine, adriamycin, cisplatin) chemotherapy. Finally, the role of paclitaxel combination regimens needs to be explored in the adjuvant and neoadjuvant setting in patients with bladder cancer. In testicular cancer, paclitaxel has initially been tested in patients with cisplatin-refractory disease. Among 4 consecutive trials involving a total of 83 patients a response rate of 26% has been observed using dose schedules varying from 3-h to 24-h infusions and doses ranging from 175 to 250 mg/m2. The major toxicities of paclitaxel include neutropenia, neurotoxicity, and fatigue syndrome. Currently, combinations of paclitaxel with cisplatin +/- ifosfamide are used as first- or second-line salvage therapy in patients with relapsed metastatic testicular cancer. The German Testicular Cancer Study Group uses a paclitaxel (Taxol, ifosfamide, cisplatin; TIP) combination regimen as salvage treatment. Following the TIP regimen and the application of granulocyte colony-stimulating factor (G-CSF), peripheral blood stem cells (PBSC) are harvested and the patients subsequently receive high-dose chemotherapy with PBSC rescue. Since only a few drugs have demonstrated substantial activity in cisplatin-refractory disease, paclitaxel will be used in early salvage strategies and, possibly, as first-line chemotherapy as a part of platinum-based combination regimens in patients with testicular cancer. Further trials confirming the important role of paclitaxel in this highly curable malignancy and a thorough investigation of its acute and long-term toxicity will be the future tasks.

Hematopoietic growth factors and treatment of testicular cancer: biological interactions, routine use and dose-intensive chemotherapy.

With the use of aggressive cis-platinum-based combination chemotherapy the majority of patients with metastatic testicular cancer will be cured. Hematopoietic growth factors (HGFs), particularly G- and GM-CSF, have been investigated for the treatment of testicular cancer in order to (a) ameliorate chemotherapy-induced myelosuppression, (b) increase the dose intensity of treatment, or (c) generate peripheral blood stem cells (PBSC) as hematopoietic support for mega-dose chemotherapy. Results from in vitro and animal models have excluded a significant influence of both factors, G-CSF and GM-CSF, on tumor growth and response to cytotoxic treatment. For the group of 'good-risk' patients with metastatic testicular cancer, 85-90% of whom will reach long-term survival, the incidence of granulocytopenic infections after standard chemotherapy regimens appears to be lower than 20%. The prophylactic use of HGFs for these patients is not routinely recommended but may be considered in case of an increased risk for infections. For 'poor risk' patients, who will achieve 50% survival following standard chemotherapy, different attempts of treatment intensification have been investigated. The use of aggressive multidrug regimens is associated with granulocytopenic infections in 20-70% of patients. A randomized trial has demonstrated that the prophylactic use of G-CSF significantly reduces granulocytopenia, the number of septic infections, and the infection-related death rate. For 'poor risk' patients the prophylactic use of HGFs, particularly G-CSF due to its favorable side effect profile, is recommended. The availability of G- and GM-CSF has made it possible to develop dose-intensified chemotherapy regimens. Demonstrated particularly for GM-CSF, a 1.5 fold dose increase can be achieved by the use of a myeloid growth factor alone, and thrombocytopenia and other organ toxicity will become dose limiting. Mobilization of PBSC, either after stimulation with HGFs alone or with HGFs, following chemotherapy has been successfully used in patients with testicular cancer. For the treatment of patients with relapsed disease PBSC support followed by HGFs has allowed the use of mega-dose therapy in multiple phase-II studies. This has prompted the investigation of high-dose therapy as first-line treatment for 'poor-risk' patients. In these patients sequential high-dose treatment with cis-platinum, etoposide, and ifosfamide for four consecutive cycles, each supported by G- or GM-CSF and PBSC, is currently being investigated by the German Testicular Cancer Study Group. HGFs have substantially reduced treatment-associated morbidity and mortality in patients receiving chemotherapy for testicular cancer. They make it possible for the first time to clinically explore the true value of dose-intensified chemotherapy regimens in testis cancer, serving as a model of a highly chemotherapy sensitive disease. Enrollment of patients in prospective clinical trials evaluating the role of high-dose therapy is strongly recommended.

Treatment of Advanced Germ Cell Tumours by Dose Intensified Chemotherapy with Haematopoietic Growth Factors or Peripheral Blood Stem Cells (PBSC)

Dose intensification of the most active drugs may improve the treatment results of patients (pts.) with far advanced metastatic testicular cancer. At Hannover University pts. with advanced testicular cancer (Indiana University criteria) were entered in a phase I/II study of a step-wise dose-intensified regimen of platinum, etoposide, and ifosfamide (PEI) with s.c. GM-CSF (5-10 micrograms/kg/day). Due to thrombocytopenia and mucositis the MTD was reached at dose level 3 with P 30 mg/m2, E 200 mg/m2, and I 1.6 g/m2 (d 1-5, q 21 d, 4 cycles). Overall, 49 of 75 pts. (65.3%) achieved CR/NED. 11 pts. (14.6%) failed PEI therapy, but 4 of these achieved CR/NED by salvage treatment. After a median follow-up of 22 months 66% of pts. are alive and free of disease. The dose intensity was 1.42 compared to a standard PEI regimen. A further increase of dose-intensity will require additional haematopoietic support, e.g. peripheral blood stem cells (PBSC). PBSC following dose-intensified PEI-chemotherapy plus G- or GM-CSF are used in the current study of the German Testicular Cancer Study Group for the treatment of advanced germ cell tumours.