- Email: [email protected]
Liver Metastases in Germ Cell Cancer: Defining a Role for Surgery After Chemotherapy
148
TESTIS CANCER AND ADVANCES IN ONCOLOGICAL THERAPY
ADRENAL AND RENAL PHYSIOLOGY, AND MEDICAL RENAL DISEASE An Evaluation of Intermediate-Dose Ketoconazole in Hormone Refractory Prostate Cancer S. WILKINSON AND G. CHODAK, Midwest Prostate and Urology Health Center, Weiss Memorial Hospital, Chicago, Illinois Eur Urol, 45: 581–585, 2004 Objectives: The management of hormone refractory prostate cancer remains controversial. Among the options, second-line hormonal therapy is commonly used. We investigated the efficacy of ketoconazole, an inhibitor of testicular and adrenal androgen biosynthesis, for treating patients with advanced hormone refractory prostate cancer. Methods: The study comprised 38 patients with progressive disease despite combined androgen blockade. Treatment consisted of intermediate-dose ketoconazole (300 mg three times daily) and replacement hydrocortisone. Patients were monitored clinically and with serial PSA measurements every 3 months. The principal endpoint was PSA response. Results: Of the 38 patients, 21 (55.3%) showed a decrease in PSA ⬎50% (95% confidence interval 38.3%–71.4%) with a median duration of 6 months (range 3– 48 months). A PSA reduction ⬎50% was seen in 21 of 34 patients (61.8%) with established metastases. Thirteen patients (34.2%), all of whom had metastases, exhibited a PSA decrease ⬎80% (95% confidence interval 19.6%–51.4%) with a median duration of 9 months (range 3– 48 months). Age, PSA at diagnosis, Gleason score and bone scan result were not significantly associated with response to ketoconazole treatment in univariate or multivariate analyses. For the entire study group, the median time to progression was 5 months (range 0 –27 months) and the median survival was 12 months (range 3– 48 months). Overall, 12 patients (31.6%) reported toxicity related to intermediate-dose ketoconazole but only 6 patients (15.8%) discontinued therapy due to intolerable side effects. Conclusion: It is apparent from this study that a reasonable percentage of patients failing standard hormonal therapy respond favourably to intermediate-dose ketoconazole and that toxicity is mild. In the absence of studies demonstrating better survival with chemotherapy, we believe that a trial of ketoconazole should be considered when progression occurs on hormone therapy. Editorial Comment: In patients with prostate cancer who have failed ablative hormonal therapy ketoconazole is a reasonable next step. One of the difficulties is with higher doses there are a number of side effects. The side effects generally involve nausea, fatigue, diarrhea, visual disturbances and abnormal liver function studies. The authors used a lower dose, ie 300 mg 3 times daily, and replacement hydrocortisone in 38 patients. Approximately 16% of the patient population discontinued use of the drug due to side effects. Approximately half of the patients showed a greater than 50% decrease in prostate specific antigen. If they had greater than a 50% decrease in prostate specific antigen, the median survival time was 24 months, compared to 9 months for nonresponders. It is unclear as to whether the beneficial effects are due to hydrocortisone or ketoconazole. This therapy certainly is a reasonable next step in the treatment of hormone refractory prostate cancer. W. Scott McDougal, M.D.
UROLOGICAL ONCOLOGY: TESTIS CANCER AND ADVANCES IN ONCOLOGICAL THERAPY Liver Metastases in Germ Cell Cancer: Defining a Role for Surgery After Chemotherapy E. COPSON, J. MCKENDRICK, N. HENNESSEY, K. TUNG AND G. Z. MEAD, CRC Wessex Medical Oncology Unit and Department of Radiology, Southampton General Hospital, Southampton, United Kingdom, and Department of Haematology and Medical Oncology, Box Hill Hospital, Melbourne, Victoria, Australia BJU Int, 94: 552–558, 2004 OBJECTIVE To review the clinical course and outcome of patients with germ cell cancer and liver metastases treated at one centre, as the presence of hepatic metastases, although rare, is a poor prognostic feature in germ cell cancer. PATIENTS AND METHODS The case records of all patients with germ cell cancer and liver metastases at presentation, and treated with chemotherapy at a medical oncology unit between 1984 and 2001, were reviewed. The treatment regimens, tumour responses and patient outcome were recorded.
TESTIS CANCER AND ADVANCES IN ONCOLOGICAL THERAPY
RESULTS Twenty-seven patients with germ cell cancer metastatic to the liver were identified. Complete biochemical and radiological responses were achieved in eight patients after initial chemotherapy and surgery for non-hepatic residual disease. Seven patients had only residual radiological hepatic abnormalities with normal tumour markers at the completion of initial treatment. There were no immediate hepatic resections and no further therapy was given. Serial computed tomography (CT) confirmed a progressive reduction in the size of hepatic lesions in six of seven patients. The persistence of residual hepatic abnormalities was not predictive of relapse, and overall survival of these patients (median survival 49 months, range 15–120) compared well with recent reports of such patients who have undergone hepatic resection. CONCLUSIONS Conservative management with regular assessment by CT is an acceptable alternative to immediate hepatic resection for patients with isolated residual radiological hepatic abnormalities on completing first-line therapy for metastatic germ cell cancer, and does not adversely affect their survival. Editorial Comment: Nonpulmonary visceral metastases, such as hepatic involvement, have generally been considered the poorest prognostic factor in patients with metastatic testicular cancer. Management of hepatic metastases after definitive chemotherapy has remained controversial, with the options being immediate hepatic resection versus followup with periodic CT scans. Five-year survival for patients with nonseminomatous germ cell tumor and liver metastases has generally been around 50%. Although resection of residual retroperitoneal and generally pulmonary masses after chemotherapy is well established, resection of residual hepatic metastases has limited published data. The authors have identified 27 patients with hepatic metastases at presentation out of a total of 1,205 patients evaluated at a single institution during a 23-year time frame. Of the 27 patients 22 had testicular primaries and the majority of patients had nonseminomatous germ cell elements. All patients received a minimum of 4 cycles of chemotherapy, usually bleomycin, etoposide and cisplatin, but other combinations including ifosfamide have been used. Seven patients had radiological complete response with the exception of liver metastases. Mean number of residual hepatic lesions was 13, with a range of 9 to 30. Serial CT confirmed progressive reduction in size and number of residual metastases in all but 1 patient. The authors have advocated conservative management with serial CT as an alternative to immediate hepatic resection. Given the morbidity of hepatic resection, conservative followup is reasonable for patients with multiple lesions. Solitary lesions that can be resected at the time of retroperitoneal lymph node dissection could be considered for wedge resection. Jerome P. Richie, M.D. Metastatic Seminoma Treated With Either Single Agent Carboplatin or Cisplatin-Based Combination Chemotherapy: A Pooled Analysis of Two Randomised Trials C. BOKEMEYER, C. KOLLMANNSBERGER, S. STENNING, J. T. HARTMANN, A. HORWICH, C. CLEMM, A. GERL, C. MEISNER, C.-P. RÜCKERL, H.-J. SCHMOLL, L. KANZ AND T. OLIVER, Department of Hematology/Oncology and Institute for Medical Information Processing, University of Tuebingen, Tuebingen, Department of Hematology/Oncology, University of Munich and Onkologische Praxis, Munich and Department of Hematology/ Oncology, University of Halle, Halle, Germany, Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, Canada, and MRC Trials Office, Medical Research Council, Cambridge, Radiotherapy Unit, Royal Marsden Hospital, Surrey, and Department of Medical Oncology, St. Barts and London Hospitals NHS Trust, London, England Br J Cancer, 91: 683– 687, 2004 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 progressionfree 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.
149
TESTIS CANCER AND ADVANCES IN ONCOLOGICAL THERAPY
ADRENAL AND RENAL PHYSIOLOGY, AND MEDICAL RENAL DISEASE An Evaluation of Intermediate-Dose Ketoconazole in Hormone Refractory Prostate Cancer S. WILKINSON AND G. CHODAK, Midwest Prostate and Urology Health Center, Weiss Memorial Hospital, Chicago, Illinois Eur Urol, 45: 581–585, 2004 Objectives: The management of hormone refractory prostate cancer remains controversial. Among the options, second-line hormonal therapy is commonly used. We investigated the efficacy of ketoconazole, an inhibitor of testicular and adrenal androgen biosynthesis, for treating patients with advanced hormone refractory prostate cancer. Methods: The study comprised 38 patients with progressive disease despite combined androgen blockade. Treatment consisted of intermediate-dose ketoconazole (300 mg three times daily) and replacement hydrocortisone. Patients were monitored clinically and with serial PSA measurements every 3 months. The principal endpoint was PSA response. Results: Of the 38 patients, 21 (55.3%) showed a decrease in PSA ⬎50% (95% confidence interval 38.3%–71.4%) with a median duration of 6 months (range 3– 48 months). A PSA reduction ⬎50% was seen in 21 of 34 patients (61.8%) with established metastases. Thirteen patients (34.2%), all of whom had metastases, exhibited a PSA decrease ⬎80% (95% confidence interval 19.6%–51.4%) with a median duration of 9 months (range 3– 48 months). Age, PSA at diagnosis, Gleason score and bone scan result were not significantly associated with response to ketoconazole treatment in univariate or multivariate analyses. For the entire study group, the median time to progression was 5 months (range 0 –27 months) and the median survival was 12 months (range 3– 48 months). Overall, 12 patients (31.6%) reported toxicity related to intermediate-dose ketoconazole but only 6 patients (15.8%) discontinued therapy due to intolerable side effects. Conclusion: It is apparent from this study that a reasonable percentage of patients failing standard hormonal therapy respond favourably to intermediate-dose ketoconazole and that toxicity is mild. In the absence of studies demonstrating better survival with chemotherapy, we believe that a trial of ketoconazole should be considered when progression occurs on hormone therapy. Editorial Comment: In patients with prostate cancer who have failed ablative hormonal therapy ketoconazole is a reasonable next step. One of the difficulties is with higher doses there are a number of side effects. The side effects generally involve nausea, fatigue, diarrhea, visual disturbances and abnormal liver function studies. The authors used a lower dose, ie 300 mg 3 times daily, and replacement hydrocortisone in 38 patients. Approximately 16% of the patient population discontinued use of the drug due to side effects. Approximately half of the patients showed a greater than 50% decrease in prostate specific antigen. If they had greater than a 50% decrease in prostate specific antigen, the median survival time was 24 months, compared to 9 months for nonresponders. It is unclear as to whether the beneficial effects are due to hydrocortisone or ketoconazole. This therapy certainly is a reasonable next step in the treatment of hormone refractory prostate cancer. W. Scott McDougal, M.D.
UROLOGICAL ONCOLOGY: TESTIS CANCER AND ADVANCES IN ONCOLOGICAL THERAPY Liver Metastases in Germ Cell Cancer: Defining a Role for Surgery After Chemotherapy E. COPSON, J. MCKENDRICK, N. HENNESSEY, K. TUNG AND G. Z. MEAD, CRC Wessex Medical Oncology Unit and Department of Radiology, Southampton General Hospital, Southampton, United Kingdom, and Department of Haematology and Medical Oncology, Box Hill Hospital, Melbourne, Victoria, Australia BJU Int, 94: 552–558, 2004 OBJECTIVE To review the clinical course and outcome of patients with germ cell cancer and liver metastases treated at one centre, as the presence of hepatic metastases, although rare, is a poor prognostic feature in germ cell cancer. PATIENTS AND METHODS The case records of all patients with germ cell cancer and liver metastases at presentation, and treated with chemotherapy at a medical oncology unit between 1984 and 2001, were reviewed. The treatment regimens, tumour responses and patient outcome were recorded.
TESTIS CANCER AND ADVANCES IN ONCOLOGICAL THERAPY
RESULTS Twenty-seven patients with germ cell cancer metastatic to the liver were identified. Complete biochemical and radiological responses were achieved in eight patients after initial chemotherapy and surgery for non-hepatic residual disease. Seven patients had only residual radiological hepatic abnormalities with normal tumour markers at the completion of initial treatment. There were no immediate hepatic resections and no further therapy was given. Serial computed tomography (CT) confirmed a progressive reduction in the size of hepatic lesions in six of seven patients. The persistence of residual hepatic abnormalities was not predictive of relapse, and overall survival of these patients (median survival 49 months, range 15–120) compared well with recent reports of such patients who have undergone hepatic resection. CONCLUSIONS Conservative management with regular assessment by CT is an acceptable alternative to immediate hepatic resection for patients with isolated residual radiological hepatic abnormalities on completing first-line therapy for metastatic germ cell cancer, and does not adversely affect their survival. Editorial Comment: Nonpulmonary visceral metastases, such as hepatic involvement, have generally been considered the poorest prognostic factor in patients with metastatic testicular cancer. Management of hepatic metastases after definitive chemotherapy has remained controversial, with the options being immediate hepatic resection versus followup with periodic CT scans. Five-year survival for patients with nonseminomatous germ cell tumor and liver metastases has generally been around 50%. Although resection of residual retroperitoneal and generally pulmonary masses after chemotherapy is well established, resection of residual hepatic metastases has limited published data. The authors have identified 27 patients with hepatic metastases at presentation out of a total of 1,205 patients evaluated at a single institution during a 23-year time frame. Of the 27 patients 22 had testicular primaries and the majority of patients had nonseminomatous germ cell elements. All patients received a minimum of 4 cycles of chemotherapy, usually bleomycin, etoposide and cisplatin, but other combinations including ifosfamide have been used. Seven patients had radiological complete response with the exception of liver metastases. Mean number of residual hepatic lesions was 13, with a range of 9 to 30. Serial CT confirmed progressive reduction in size and number of residual metastases in all but 1 patient. The authors have advocated conservative management with serial CT as an alternative to immediate hepatic resection. Given the morbidity of hepatic resection, conservative followup is reasonable for patients with multiple lesions. Solitary lesions that can be resected at the time of retroperitoneal lymph node dissection could be considered for wedge resection. Jerome P. Richie, M.D. Metastatic Seminoma Treated With Either Single Agent Carboplatin or Cisplatin-Based Combination Chemotherapy: A Pooled Analysis of Two Randomised Trials C. BOKEMEYER, C. KOLLMANNSBERGER, S. STENNING, J. T. HARTMANN, A. HORWICH, C. CLEMM, A. GERL, C. MEISNER, C.-P. RÜCKERL, H.-J. SCHMOLL, L. KANZ AND T. OLIVER, Department of Hematology/Oncology and Institute for Medical Information Processing, University of Tuebingen, Tuebingen, Department of Hematology/Oncology, University of Munich and Onkologische Praxis, Munich and Department of Hematology/ Oncology, University of Halle, Halle, Germany, Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, Canada, and MRC Trials Office, Medical Research Council, Cambridge, Radiotherapy Unit, Royal Marsden Hospital, Surrey, and Department of Medical Oncology, St. Barts and London Hospitals NHS Trust, London, England Br J Cancer, 91: 683– 687, 2004 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 progressionfree 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.
149