San Francisco, CA USA (UroToday.com) Dr. Darren Feldman of Memorial Sloan Kettering Cancer Center presented a discussion of the approach to standard treatment of high-risk germ cell tumors, with an emphasis on whether dose intensification should be used routinely. Recently reported 5-year progression free survival for men with poor risk germ cell tumor is 50-50%, demonstrating clear room for improvement for poor risk patients. Standard of care has generally been unchanged for nearly 30 years and is 4 cycles of BEP (bleomycin, etoposide, cisplatin). Williams and colleagues established this regimen when they demonstrated that
treatment with 4 cycles of BEP was both more efficacious and was associated with less toxicity than 4 cycles of PVB (bleomycin, vinblastine, cisplatin). An alternative standard with equivalent efficacy for men for whom there is concern for bleomycin lung toxicity is 4 cycles of VIP (etoposide, ifosfamide, cisplatin). Although multiple clinical trials have been performed in unselected populations during the last few decades, none have demonstrated superiority to BEP. Dr. Feldman raises the question of whether we can identify high-risk patients who are not responding to traditional therapy during treatment, and if so, can we intensify their treatment and achieve better clinical outcomes.
Multiple groups have evaluated whether the rate of tumor marker decline during treatment could predict survival and progression free survival in this population. Investigators were able to demonstrate that a “favorable” or “satisfactory” decline in tumor markers was associated with improvements in both overall survival and progression free survival. Additional studies evaluated whether a change in treatment of patients with “unsatisfactory” or “unfavorable” decline could improve outcomes. A retrospective analysis by Motzer and colleagues demonstrated that treatment of these patients with high dose chemotherapy and autologous stem cell transplant was not associated with a significant improvement in overall survival, although there was a trend toward improved overall survival and a prolongation of progression free survival. GETUG 13 was a prospective trial in which poor-risk patients with unfavorable marker decline after one cycle of BEP were randomized to receive either 3 additional cycles of BEP per standard of care, or 4 cycles of a dose-intense chemotherapy regimen. The investigators found an improvement in 3 year progression free survival associated with the dose-intense chemotherapy regimen, though there was no significant difference in overall survival (3-year PFS 59% vs 48% for dose-intense vs BEP, p=0.05; 3 year OS 73% vs 65% for dose-intense vs BEP, p=0.34). The study did demonstrate that the rate of decline in tumor markers was predictive of survival, with a hazard ratio (HR) of 0.65 in favor of a favorable decline in tumor markers after BEP as compared with unfavorable decline (Fizazi Lancet Oncol 2014). The dose-intense regimen had greater toxicity than BEP, with 76% of patients developing sensory neuropathy vs 21% for patients receiving BEP. There was a similar rate of toxic deaths between treatments.
In conclusion, slow tumor marker decline is associated with poorer prognosis among men with high-risk testicular cancer as demonstrated prospectively in GETUG 13. However, there is no survival advantage associated with altering chemotherapy in patients with unfavorable marker decline. Additionally the more intense chemotherapy regimen used in GETUG 13 was associated with greater toxicity. Thus switching chemotherapy in patients with high-risk testicular cancer with unfavorable marker decline is not currently standard. Future trials aimed at identifying treatments that may improve survival in these high-risk patients will benefit from the design of GETUG13, potentially using tumor marker decline or other biomarkers to select populations at highest risk of disease progression. Multiple studies in patients with high-risk germ cell cancers are ongoing.
Presented By:
Dr. Darren R. Feldman, MD
Memorial Sloan Kettering Cancer Center
Reported By:
Alicia K. Morgans, MD, at the 2016 Genitourinary Cancers Symposium - January 7 - 9, 2016 – San Francisco, CA
Assistant Professor of Medicine Medical Oncologist
Vanderbilt - Ingram Cancer Center