ASCO GU 2017: Debate - Pro: Is There a Role for Treatment Intensification for Patients With Poor Prognosis Germ-Cell Tumors With Unfavorable Marker Decline?

Orlando, Florida USA (UroToday.com) According to Dr. Karim Fizazi, the management of International Germ Cell Cancer Collaborative Group’s poor-risk patients with nonseminomatous germ-cell tumor (NSGCT) is, perhaps, one of the most difficult aspects of advanced testis cancer care. Such patients are characterized by high tumor-marker levels, nonpulmonary visceral metastases, or primary mediastinal tumors. The standard-of-care treatment for these patients is bleomycin, etoposide, and cisplatin (BEP) x 4 or vinblastine, ifosfamide, and cisplatin or VIP x 4, and the 5-year overall survival is 48% to 57%. Given that tumor markers are so clinically meaningful in poor-risk NSGCT, studies have shown that the tumor-marker rate of decline during initial therapy can be prognostic of posttherapy outcomes. Evidence shows that favorable tumor-marker decline, measured after the 1st or 2nd cycle of BEP, is associated with better survival.

Dr. Fizazi discussed the evidence regarding intervention for patients with unfavorable tumor marker decline and advocated for treatment intensification for poor-risk patients in this setting.

Of all the attempted phase-III trials in this space, only GETUG 13 (multinational and accrued for a decade) was able to amass more than 200 patients. Unfortunately, because of the rarity of this poor-risk disease state, all trials were handicapped for need of statistical power. Nonetheless, evidence appeared to show at least some benefit with treatment intensification. In GETUG 13, patients were randomized after the first cycle of BEP and had an unfavorable decline in tumor markers. These patients were either given the standard four total doses of BEP or were randomized to the investigational arm with six treatment agents in a dose-intensive regimen. Investigators found, as expected, that those with favorable tumor-marker decline had improved survival versus patients with unfavorable tumor-marker decline when treated with standard BEP x 4 (70% vs. 48% 3-year progression-free survival [PFS]). More provocatively, individuals with an unfavorable tumor decline who were given dose-dense therapy had improved PFS compared with those same patients who received standard chemotherapy (59% vs. 48% 3-year PFS). At 5 years, this difference continued to be significant. Although overall-survival differences in these patients were not statistically significant, Dr. Fizazi pointed out that 16 more of them were alive at 5-year follow-up in the dose-dense group, which is a significant number in such a rare condition.

He argued that toxicities from dose-dense regimens are reversible, and these patients required less salvage chemotherapy with stem-cell support. He and his colleagues believe that treatment escalation after unfavorable marker decline minimizes the risk of treatment failure, reduces the risk of death by 30% (not statistically significant), requires less salvage chemotherapy, and has no excess toxicity. These findings are boosted by high-dose escalation paradigms that are well-accepted in other malignancies, such as Hodgkin’s lymphoma. Therefore, Dr. Fizazi concluded that treatment escalation should be considered the new standard of care for poor-risk NSGCT patients with unfavorable marker decline.

While these arguments are certainly well-received, he concluded, the lack of high-level prospective evidence demonstrating overall-survival benefits with this strategy has meant that most healthcare practitioners in the United States have not adopted dose-dense escalation. There is still room for improvement in these patients, and studies should continue to attempt better accrual to help us understand how to best make a major difference in survival.

Presenter: Karim Fizazi, MD, PhD; Gustave Roussy, University of Paris Sud

Written By: Shreyas Joshi, MD, Fox Chase Cancer Center

at the 2017 Genitourinary Cancers Symposium - February 16 - 18, 2017 – Orlando, Florida USA

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