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Long-term followup results of 1 cycle of adjuvant bleomycin, etoposide, and cisplatin chemotherapy for high risk clinical Stage I nonseminomatous germ cell tumors of the testis
D.L. Trump / Urologic Oncology: Seminars and Original Investigations 26 (2008) 561–572
563
study was quite arbitrary.) Does “holiday” impact survival? Is there something else to do during “holiday”? . . . or after “holiday”? And most of all— docetaxel is a mediocre drug— best we have, but mediocre. There are many more drugs that improve survival in advanced breast, colorectal, and lung, cancer. We have to do better! doi:10.1016/j.urolonc.2008.07.018 Donald L. Trump, M.D. Inherited variation in the androgen pathway is associated with the efficacy of androgen-deprivation therapy in men with prostate cancer. Ross RW, Oh WK, Xie W, Pomerantz M, Nakabayashi M, Sartor O, Taplin ME, Regan MM, Kantoff PW, Freedman M, Dana-Farber Cancer Institute, Boston, MA. J Clin Oncol 2008;26:842–7 Purpose: Androgen-deprivation therapy (ADT) is the most common and effective systemic therapy for advanced prostate cancer. We hypothesized that germline genetic variation in the androgen axis would improve the efficacy of ADT. Patients and Methods: A cohort of 529 men with advanced prostate cancer treated with ADT was genotyped for 129 DNA polymorphisms distributed across 20 genes involved in androgen metabolism. Results: Three polymorphisms in separate genes (CYP19A1, HSD3B1, and HSD17B4) were significantly (P ⬍ 0.01) associated with time to progression (TTP) during ADT, remaining so in multivariate analyses and after correcting for the number of hypotheses tested. Individuals carrying more than one of the polymorphisms associated with improved TTP demonstrated a better response to therapy than individuals carrying zero or one (P ⬍ 0.0001). Conclusion: This report is the first to examine the influence of inherited variation in the androgen metabolic pathway on the efficacy of ADT, establishing the importance of pharmacogenomics on individual’s response to this therapy. At least two potential clinical benefits may be realized from this study. The first is prognostic; genotyping patients at these loci may yield important information that could improve efficacy prediction. The second is therapeutic; these results shed light on the pathways that govern response to ADT. Drugs could be developed (or may already exist) to inhibit or augment these targets to improve ADT efficacy.
Commentary Ross and colleagues report an important study seeking to define biologic predictors of response/time to progression following androgen-deprivation. Variations in the androgen metabolism pathway (CYP19A1, HSD3B1, and HSD1TB4) would logically be expected to influence the duration of response to androgen-deprivation—as was the case with these agents. This is an important study, which takes a crucial first step toward understanding and individualizing the approach to androgen-deprivation. doi:10.1016/j.urolonc.2008.07.019 Donald L. Trump, M.D. Long-term followup results of 1 cycle of adjuvant bleomycin, etoposide, and cisplatin chemotherapy for high risk clinical Stage I nonseminomatous germ cell tumors of the testis. Westermann DH, Schefer H, Thalmann GN, Karamitopoulou-Diamantis E, Fey MF, Studer UE, Department of Urology, University of Bern, Bern, Switzerland. J Urol 2008 Jan;179:163– 6 Purpose: We evaluated the long-term outcome after 1 cycle of adjuvant modified bleomycin, etoposide, and cisplatin chemotherapy in patients who underwent orchiectomy for high risk clinical Stage I nonseminomatous germ cell tumor of the testis. Materials and Methods: Between 1995 and 1999, a consecutive series of 44 patients underwent orchiectomy for clinical Stage I nonseminomatous germ cell tumor of the testis, followed by a single postoperative cycle of adjuvant modified bleomycin, etoposide, and cisplatin for vascular or lymphatic tumor invasion, and/or a predominance (50% or greater) of embryonal carcinoma. Results: Four of the 44 patients were excluded from analysis. Of the patients, 35 had no evidence of disease at a median followup of 99 months (range 60 –134). One patient with progression after 13 months showed complete remission after 3 cycles of salvage bleomycin, etoposide, and cisplatin chemotherapy but he died of pneumonia 4 weeks after the third course. Two patients underwent orchiectomy for contralateral testis cancer at 18 and 42 months, respectively, followed by an additional 3 cycles of adjuvant chemotherapy. They remained relapse-free for 4 and 92 months, respectively. The former patient was lost to follow-up after 4 months. Two other patients were disease-free at 10 and 31 months, respectively, and were lost to follow-up thereafter. Late side effects were tinnitus in 3 patients and involuntary childlessness in 3, of whom 2 had cryptorchidism of the contralateral testis. Nine patients fathered children. Conclusions: One cycle of bleomycin, etoposide, and cisplatin effectively decreases the risk of relapse in patients with high risk Stage I nonseminomatous germ cell tumor of the testis. It has minimal side effects and can be a valuable alternative to retroperitoneal lymph node dissection.
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D.L. Trump / Urologic Oncology: Seminars and Original Investigations 26 (2008) 561–572
Commentary This study contends that 1 cycle of bleomycin, etoposide, and cisplatin (BEP) in patients with Stage I testicular GCT at “high risk” of relapse reduces risk of relapse and has “minimal side effects”. Reflection emphasizes that this was a poor study: (1) The regimen evaluated is untested—120 mg/m2 ⫻ 3 etoposide, by available evidence, would be predicted to be inferior to 100 mg/m2 ⫻ 5 (the standard), and continuous infusion bleomycin is not known to be safer or equivalent to weekly ⫻3— but it is much more inconvenient; (2) 3 patients were not even eligible for this high risk study, but got chemotherapy “by mistake”; (3) 1 patient recurred, got salvage therapy with BEP ⫻3 and died— of pneumonitis. One cannot help but wonder about continuous infusion of bleomycin ¡ BEP ⫻3 and pneumonitis; (4) the proportion lost to follow-up was unacceptably high. The overall prognosis of Stage I GCT is excellent. In this reviewer’s opinion, no study should be considered unless a sufficient number of patients can be randomized (hundreds, not dozens) such that a statistically valid conclusion can be drawn. Single arm retrospectively controlled trials using toxic treatments in diseases with good prognosis are unconscionable. In an adjuvant trial, where one accepts that many patients do not need therapy, the regimen must be well tested. doi:10.1016/j.urolonc.2008.07.020 Donald L. Trump, M.D. Lapatinib versus hormone therapy in patients with advanced renal cell carcinoma: A randomized Phase III clinical trial. Ravaud A, Hawkins R, Gardner JP, von der Maase H, Zantl N, Harper P, Rolland F, Audhuy B, Machiels JP, Pétavy F, Gore M, Schöffski P, El-Hariry I, Department of Medical Oncology, Hôpital Saint André, Bordeaux, France. J Clin Oncol 2008;26:2285–91 Purpose: Lapatinib is an orally reversible inhibitor of epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER-2) tyrosine kinases with demonstrated activity in patients with HER-2-positive breast cancer. In the current Phase III open-label trial, lapatinib was compared with hormone therapy (HT) in patients with advanced renal cell carcinoma (RCC) that express EGFR and/or HER-2. Patients and Methods: Patients with advanced RCC who had experienced disease progression through first-line cytokine therapy— stratified by Karnofsky performance status and number of metastatic sites—were randomly assigned to lapatinib 1,250 mg daily or HT. The primary end point was time to progression (TTP); secondary end points included overall survival (OS), safety, and biomarker analyses. Results: Four hundred sixteen patients were enrolled into the study. Median TTP was 15.3 weeks for lapatinib versus 15.4 weeks for HT (hazard ratio [HR] ⫽ 0.94; P ⫽ 0.60), and median OS was 46.9 weeks for lapatinib versus 43.1 weeks for HT (HR ⫽ 0.88; P ⫽ 0.29). In a biomarker analysis of patients with EGFR-overexpressed tumors (3⫹ by immunohistochemistry [IHC]; n ⫽ 241) median TTP was 15.1 weeks for lapatinib versus 10.9 weeks for HT (HR ⫽ 0.76; P ⫽ 0.06), and median OS was 46.0 weeks for lapatinib versus 37.9 weeks for HT (HR ⫽ 0.69; P ⫽ 0.02). These results were confirmed by Cox regression analysis. No unexpected toxicities were observed; the most commonly reported drug-related adverse events (all grades) for lapatinib were rash (44%) and diarrhea (40%). Conclusion: Lapatinib was well tolerated with equivalent overall efficacy to HT in advanced RCC patients who had experienced disease progression while receiving cytokines, and the study supports that lapatinib prolonged OS relative to HT in patients with 3⫹ EGFR status determined by IHC.
Commentary The new “targeted” drugs do not work in every cancer! Ravaud et al. evaluated an EGF-R thymidine kinase inhibitor (lapatinib) in advanced RCC. The rationale was sound (EGF-R and HER2 are expressed in RCC) and patient selection required expression of EGF-R or HER2 by immunohistochemistry (ⱖ1⫹) confirmed by central review. Unfortunately, lapatinib failed to achieve the primary objective (reduced time to progression). However, in an exploratory (and therefore risky) subset analysis, patients whose tumors most overexpressed EGF-R (3⫹) [⬃58% of all patients studied] lapatinib seemed to improve survival. If you are a realist, you must conclude that these are only suggestive data; if you are an enthusiast, further evaluation of EGF-R antagonists in RCC is supported. Given the activity of agents such as sorafenib and sunitinib, one thinks of combination studies. It is wonderful (for those of us who launched their careers doing negative Phase II studies) to finally see agents with solid rationale and activity in patients with RCC. doi:10.1016/j.urolonc.2008.07.021 Donald L. Trump, M.D. Cost-effectiveness of prostate cancer chemoprevention: A quality of life-years analysis. Svatek RS, Lee JJ, Roehrborn CG, Lippman SM, Lotan Y, Department of Urology, The University of Texas Southwestern Medical Center, Dallas, TX. Cancer 2008;112:1058 – 65 Background: The Prostate Cancer Prevention Trial (PCPT) demonstrated that finasteride reduces the prevalence of prostate cancer by 24.8% (risk reduction) but questions remain regarding the cost-effectiveness of widespread utilization. The purpose of the current analysis was to evaluate the cost-effectiveness of chemoprevention utilizing a quality-of-life adjustment.
563
study was quite arbitrary.) Does “holiday” impact survival? Is there something else to do during “holiday”? . . . or after “holiday”? And most of all— docetaxel is a mediocre drug— best we have, but mediocre. There are many more drugs that improve survival in advanced breast, colorectal, and lung, cancer. We have to do better! doi:10.1016/j.urolonc.2008.07.018 Donald L. Trump, M.D. Inherited variation in the androgen pathway is associated with the efficacy of androgen-deprivation therapy in men with prostate cancer. Ross RW, Oh WK, Xie W, Pomerantz M, Nakabayashi M, Sartor O, Taplin ME, Regan MM, Kantoff PW, Freedman M, Dana-Farber Cancer Institute, Boston, MA. J Clin Oncol 2008;26:842–7 Purpose: Androgen-deprivation therapy (ADT) is the most common and effective systemic therapy for advanced prostate cancer. We hypothesized that germline genetic variation in the androgen axis would improve the efficacy of ADT. Patients and Methods: A cohort of 529 men with advanced prostate cancer treated with ADT was genotyped for 129 DNA polymorphisms distributed across 20 genes involved in androgen metabolism. Results: Three polymorphisms in separate genes (CYP19A1, HSD3B1, and HSD17B4) were significantly (P ⬍ 0.01) associated with time to progression (TTP) during ADT, remaining so in multivariate analyses and after correcting for the number of hypotheses tested. Individuals carrying more than one of the polymorphisms associated with improved TTP demonstrated a better response to therapy than individuals carrying zero or one (P ⬍ 0.0001). Conclusion: This report is the first to examine the influence of inherited variation in the androgen metabolic pathway on the efficacy of ADT, establishing the importance of pharmacogenomics on individual’s response to this therapy. At least two potential clinical benefits may be realized from this study. The first is prognostic; genotyping patients at these loci may yield important information that could improve efficacy prediction. The second is therapeutic; these results shed light on the pathways that govern response to ADT. Drugs could be developed (or may already exist) to inhibit or augment these targets to improve ADT efficacy.
Commentary Ross and colleagues report an important study seeking to define biologic predictors of response/time to progression following androgen-deprivation. Variations in the androgen metabolism pathway (CYP19A1, HSD3B1, and HSD1TB4) would logically be expected to influence the duration of response to androgen-deprivation—as was the case with these agents. This is an important study, which takes a crucial first step toward understanding and individualizing the approach to androgen-deprivation. doi:10.1016/j.urolonc.2008.07.019 Donald L. Trump, M.D. Long-term followup results of 1 cycle of adjuvant bleomycin, etoposide, and cisplatin chemotherapy for high risk clinical Stage I nonseminomatous germ cell tumors of the testis. Westermann DH, Schefer H, Thalmann GN, Karamitopoulou-Diamantis E, Fey MF, Studer UE, Department of Urology, University of Bern, Bern, Switzerland. J Urol 2008 Jan;179:163– 6 Purpose: We evaluated the long-term outcome after 1 cycle of adjuvant modified bleomycin, etoposide, and cisplatin chemotherapy in patients who underwent orchiectomy for high risk clinical Stage I nonseminomatous germ cell tumor of the testis. Materials and Methods: Between 1995 and 1999, a consecutive series of 44 patients underwent orchiectomy for clinical Stage I nonseminomatous germ cell tumor of the testis, followed by a single postoperative cycle of adjuvant modified bleomycin, etoposide, and cisplatin for vascular or lymphatic tumor invasion, and/or a predominance (50% or greater) of embryonal carcinoma. Results: Four of the 44 patients were excluded from analysis. Of the patients, 35 had no evidence of disease at a median followup of 99 months (range 60 –134). One patient with progression after 13 months showed complete remission after 3 cycles of salvage bleomycin, etoposide, and cisplatin chemotherapy but he died of pneumonia 4 weeks after the third course. Two patients underwent orchiectomy for contralateral testis cancer at 18 and 42 months, respectively, followed by an additional 3 cycles of adjuvant chemotherapy. They remained relapse-free for 4 and 92 months, respectively. The former patient was lost to follow-up after 4 months. Two other patients were disease-free at 10 and 31 months, respectively, and were lost to follow-up thereafter. Late side effects were tinnitus in 3 patients and involuntary childlessness in 3, of whom 2 had cryptorchidism of the contralateral testis. Nine patients fathered children. Conclusions: One cycle of bleomycin, etoposide, and cisplatin effectively decreases the risk of relapse in patients with high risk Stage I nonseminomatous germ cell tumor of the testis. It has minimal side effects and can be a valuable alternative to retroperitoneal lymph node dissection.
564
D.L. Trump / Urologic Oncology: Seminars and Original Investigations 26 (2008) 561–572
Commentary This study contends that 1 cycle of bleomycin, etoposide, and cisplatin (BEP) in patients with Stage I testicular GCT at “high risk” of relapse reduces risk of relapse and has “minimal side effects”. Reflection emphasizes that this was a poor study: (1) The regimen evaluated is untested—120 mg/m2 ⫻ 3 etoposide, by available evidence, would be predicted to be inferior to 100 mg/m2 ⫻ 5 (the standard), and continuous infusion bleomycin is not known to be safer or equivalent to weekly ⫻3— but it is much more inconvenient; (2) 3 patients were not even eligible for this high risk study, but got chemotherapy “by mistake”; (3) 1 patient recurred, got salvage therapy with BEP ⫻3 and died— of pneumonitis. One cannot help but wonder about continuous infusion of bleomycin ¡ BEP ⫻3 and pneumonitis; (4) the proportion lost to follow-up was unacceptably high. The overall prognosis of Stage I GCT is excellent. In this reviewer’s opinion, no study should be considered unless a sufficient number of patients can be randomized (hundreds, not dozens) such that a statistically valid conclusion can be drawn. Single arm retrospectively controlled trials using toxic treatments in diseases with good prognosis are unconscionable. In an adjuvant trial, where one accepts that many patients do not need therapy, the regimen must be well tested. doi:10.1016/j.urolonc.2008.07.020 Donald L. Trump, M.D. Lapatinib versus hormone therapy in patients with advanced renal cell carcinoma: A randomized Phase III clinical trial. Ravaud A, Hawkins R, Gardner JP, von der Maase H, Zantl N, Harper P, Rolland F, Audhuy B, Machiels JP, Pétavy F, Gore M, Schöffski P, El-Hariry I, Department of Medical Oncology, Hôpital Saint André, Bordeaux, France. J Clin Oncol 2008;26:2285–91 Purpose: Lapatinib is an orally reversible inhibitor of epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER-2) tyrosine kinases with demonstrated activity in patients with HER-2-positive breast cancer. In the current Phase III open-label trial, lapatinib was compared with hormone therapy (HT) in patients with advanced renal cell carcinoma (RCC) that express EGFR and/or HER-2. Patients and Methods: Patients with advanced RCC who had experienced disease progression through first-line cytokine therapy— stratified by Karnofsky performance status and number of metastatic sites—were randomly assigned to lapatinib 1,250 mg daily or HT. The primary end point was time to progression (TTP); secondary end points included overall survival (OS), safety, and biomarker analyses. Results: Four hundred sixteen patients were enrolled into the study. Median TTP was 15.3 weeks for lapatinib versus 15.4 weeks for HT (hazard ratio [HR] ⫽ 0.94; P ⫽ 0.60), and median OS was 46.9 weeks for lapatinib versus 43.1 weeks for HT (HR ⫽ 0.88; P ⫽ 0.29). In a biomarker analysis of patients with EGFR-overexpressed tumors (3⫹ by immunohistochemistry [IHC]; n ⫽ 241) median TTP was 15.1 weeks for lapatinib versus 10.9 weeks for HT (HR ⫽ 0.76; P ⫽ 0.06), and median OS was 46.0 weeks for lapatinib versus 37.9 weeks for HT (HR ⫽ 0.69; P ⫽ 0.02). These results were confirmed by Cox regression analysis. No unexpected toxicities were observed; the most commonly reported drug-related adverse events (all grades) for lapatinib were rash (44%) and diarrhea (40%). Conclusion: Lapatinib was well tolerated with equivalent overall efficacy to HT in advanced RCC patients who had experienced disease progression while receiving cytokines, and the study supports that lapatinib prolonged OS relative to HT in patients with 3⫹ EGFR status determined by IHC.
Commentary The new “targeted” drugs do not work in every cancer! Ravaud et al. evaluated an EGF-R thymidine kinase inhibitor (lapatinib) in advanced RCC. The rationale was sound (EGF-R and HER2 are expressed in RCC) and patient selection required expression of EGF-R or HER2 by immunohistochemistry (ⱖ1⫹) confirmed by central review. Unfortunately, lapatinib failed to achieve the primary objective (reduced time to progression). However, in an exploratory (and therefore risky) subset analysis, patients whose tumors most overexpressed EGF-R (3⫹) [⬃58% of all patients studied] lapatinib seemed to improve survival. If you are a realist, you must conclude that these are only suggestive data; if you are an enthusiast, further evaluation of EGF-R antagonists in RCC is supported. Given the activity of agents such as sorafenib and sunitinib, one thinks of combination studies. It is wonderful (for those of us who launched their careers doing negative Phase II studies) to finally see agents with solid rationale and activity in patients with RCC. doi:10.1016/j.urolonc.2008.07.021 Donald L. Trump, M.D. Cost-effectiveness of prostate cancer chemoprevention: A quality of life-years analysis. Svatek RS, Lee JJ, Roehrborn CG, Lippman SM, Lotan Y, Department of Urology, The University of Texas Southwestern Medical Center, Dallas, TX. Cancer 2008;112:1058 – 65 Background: The Prostate Cancer Prevention Trial (PCPT) demonstrated that finasteride reduces the prevalence of prostate cancer by 24.8% (risk reduction) but questions remain regarding the cost-effectiveness of widespread utilization. The purpose of the current analysis was to evaluate the cost-effectiveness of chemoprevention utilizing a quality-of-life adjustment.