Dose-dense Chemotherapy Improves Outcomes in Poor-prognosis Germ Cell Tumors 


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For poor-prognosis patients with germ-cell tumors, dose intensification of chemotherapy based on slow decline of tumor markers can increase progression-free survival, according to the first randomized trial of a “personalized” treatment strategy for this tumor.1 At the 2013 ASCO Annual Meeting, investigators called this approach—which enlists dose-dense chemotherapy for “slow decliners”—a game-changer in patients with poor-prognosis germ cell tumors.

“Dose-dense chemotherapy reduces the risk of progression or death by 34% in young patients with poor-risk germ cell tumors and slow tumor marker decline. An early switch in chemotherapy regimen for patients with slow tumor marker decline is the new standard,” said Karim Fizazi, MD, PhD, Head of the Department of Cancer Medicine at the Institut Gustave Roussy, Villejuif, France, who presented the late-breaking abstract.

GETUG 13 Study

The phase III GETUG 13 trial—conducted in France, the United States, and Slovakia—enrolled 263 patients with poor-prognosis germ cell cancers, defined as advanced nonseminomas associated with elevated serum tumor markers (human chorionic gonadotropin [hCG], alpha-fetoprotein [AFP], and lactate dehydrogenase [LDH]), evidence of nonpulmonary visceral metastases or primary mediastinal nonseminomas. For such patients, the 5-year progression-free survival rate is about 40% and 5-year overall survival rate is less than 50%, Dr. Fizazi noted.

Four cycles of BEP (bleomycin, etoposide, platinum) has long been the standard treatment for this cancer, and other attempts to improve upon it have been largely disappointing, Dr. Fizazi said.

“In the last 25 years, a number of randomized phase III trials have all been negative,” he said. These studies have evaluated new drugs, alternative regimens, and high-dose chemotherapy plus stem cell transplant.

Switch to Different Regimen

GETUG 13 evaluated a strategy of early tumor marker assessment, with a switch to a more intensified (dose-dense) regimen for patients with slow declines in markers. Tumor markers can be reliably assessed as early as 3 weeks after starting chemotherapy.

The scheme was as follows: BEP for one cycle, followed by tumor marker assessment on day 21. In the study, 51 patients had favorable declines and they continued on three more cycles of BEP; 203 patients (80% of the population) had unfavorable declines and were randomly assigned to switch to dose-dense chemotherapy (n = 105) or to continue on BEP for three more cycles. The BEP regimen was bleomycin at 30 U/wk plus etoposide at 100 mg/m2 on days 1 to 5 plus cisplatin at 20 mg/m2 on days 1 to 5.

The dose-dense regimen included paclitaxel at175 mg/m2 on day 1 plus BEP plus oxaliplatin at 130 mg/m2 on day 10, with growth factor support; this was given every 3 weeks for two cycles. Patients were then switched to cisplatin at 100 mg/m2 on day 1 plus ifosfamide at 2 g/m2 on days 10, 12, and 14 plus bleomycin at 25 U/d on days 10 to 14.

The study was amended to use growth factors in all patients, due to a high incidence of neutropenic fever among the patients (many with poor performance status), and oxaliplatin was deleted from cycles 3 and 4 of the dose-dense regimen because of excess neurotoxicity observed in the first 10 patients.

Benefits of Dose-dense Chemotherapy

At a median follow-up of 4.1 years, the primary endpoint was met, with 3-year progression-free survival being 59% in the dose-dense arm, compared to 48% in patients continuing BEP (hazard ratio [HR] = .66; P = .05). All subgroups benefited from the switch.

“At the last follow-up, 63 patients in the dose-dense arm were still alive and free of progression, vs 46 patients in the BEP arm,” Dr. Fizazi announced.

Overall survival followed this trend, but the difference was not significant: 73% vs 65%, respectively (HR = .78; P = .34).

Toxicities in the dose-dense vs control arm included neutropenic fever (17% each), neurotoxicity ≥ grade 2, mostly reversible (23% vs 4%), toxic deaths (1% each), and secondary cancers (1% vs 4%). Need for salvage high-dose chemotherapy plus transplant was lower in the dose-dense arm (6% vs 16%, P = .015).

The study also validated the prognostic value of tumor marker decline, as this was associated with outcomes. Among patients treated with BEP, 3-year progression-free survival was 70% for those with favorable declines but only 48% for those with unfavorable declines (HR = .66; P = .01); overall survival was 84% and 65%, respectively (HR = .65; P = .024).

“We believe an early switch in the chemotherapy regimen should become the new standard treatment for these patients,” Dr. Fizazi concluded. ■

Disclosure: Dr. Fizazi has had a consulting or advisory role with AstraZeneca.

Reference

1. Fizazi K, Pagliaro LC, Flechon A, et al: A phase III trial of personalized chemotherapy based on serum tumor marker decline in poor-prognosis germ-cell tumors: Results of GETUG 13. 2013 ASCO Annual Meeting. Abstract LBA4500. Presented June 1, 2013.


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