No OS Benefit With Chemoradiotherapy in High-Risk Endometrial Cancer

Adjuvant chemotherapy given during and after radiotherapy did not improve 5-year overall survival (OS) for patients with high-risk endometrial cancer in the phase III PORTEC-3 trial, although the treatment increased failure-free survival (FFS).¹

At a median follow-up of 60.2 months (IQR, 48.1-73.1), the 5-year OS was 81.8% (95% CI, 77.5-86.2) with chemoradiotherapy versus 76.7% (95% CI, 72.1-81.6) with radiotherapy (adjusted HR, 0.76, 95% CI, 0.54-1.06; P = .11). Five-year FFS was 75.5% (95% CI, 70.3-79.9) with chemoradiotherapy versus 68.6% (95% CI, 63.1-73.4) with radiotherapy (HR, 0.71, 95% CI, 0.53-0.95; P = .022).

“For each patient [with high-risk endometrial cancer], the cost in terms of increased toxicity and longer treatment duration should be weighed against the benefit in terms of improvement in failure-free survival,” first study author Stephanie M de Boer, MD, department of Radiation Oncology, Leiden University Medical Center, the Netherlands, and coinvestigators wrote.

PORTEC-3 was an open-label, international, randomized, phase III trial involving 103 centers collaborating in the Gynecological Cancer Intergroup. Eligible women had high-risk endometrial cancer with FIGO 2009 stage I, endometrioid-type grade 3 disease with deep myometrial invasion or lymph-vascular space invasion (or both), endometrioid-type stage II or III, or stage I to III with serous or clear cell histology.

From November 2006 to December 2013, patients were randomly assigned to radiotherapy alone with 48.6 Gy in 1.8 Gy fractions given 5 days per week (n = 343) or radiotherapy and chemotherapy consisting of 2 cycles of 50 mg/m² of cisplatin given during radiotherapy, followed by 4 cycles of AUC5 of carboplatin and 175 mg/m² of paclitaxel (n = 343). The intent-to-treat population included 660 patients, 330 in both groups.

Stage, histological type and grade, type of surgery, participating groups, lymph-vascular space invasion, and age were included with treatment in the multivariate analysis. In the presence of these factors, combined chemotherapy and radiotherapy significantly improved FFS. Most factors, except lymphadenectomy, were significantly correlated with FFS.

In multivariate analysis for FFS, only age group was found to be predictive of treatment effect, with a strong treatment-by-age effect (P_interaction = .012). Women aged 70 years or older derived the greatest benefit from chemoradiotherapy.

In a subgroup analysis, women with stage III endometrial cancer had significantly lower OS (HR, 2.41; 95% CI, 1.66-3.51) and FFS than those with stage I-II disease. Five-year OS for patients with stage III disease was 78.7% (95% CI, 72.2-85.7) in the chemoradiotherapy group versus 69.8% (95% CI, 62.4-78.1) in the radiotherapy group (HR, 0.71; 95% CI, 0.45-1.11; P = .13; adjusted P = .074).

Five-year FFS for stage III cancer was 69.3% (95% CI, 61.1-76.2) in the chemoradiotherapy group versus 58.0% (49.3-65.7) in the radiotherapy group (HR, 0.66; 95% CI, 0.45-0.97; P = .031; adjusted P = .014). 5-year FFS for stage I-II patients was 80.8% (95% CI, 74.1-86.0) in the chemoradiotherapy group versus 76.6% (95% CI, 69.5-82.2) in the radiotherapy group (HR, 0.85; 95% CI, 0.54-1.33; P = .47).

Patients assigned to chemoradiotherapy were more like to experience grade 3 (45% vs 12%) and grade 4 toxicity (15% vs 0%). This chemoradiotherapy arm was more likely to experience grade 3/4 diarrhea (11% vs 4%), leucocytes (23% vs <1%), lymphocytes (33% vs 5%), and neutrophils (20% vs <1%).

“By contrast with the benefit conferred to stage III patients, the addition of chemotherapy did not improve outcomes for stage I or II patients,” Sean C. Dowdy, MD, and Gretchen E. Glaser, MD, wrote in an accompanying editorial.² “Although PORTEC-3 might have been underpowered to identify differences in failure-free survival in this subgroup, the small magnitude of benefit does not seem to justify the accompanying increase in adverse events, impairment in long-term quality of life, and longer treatment duration.

“Future trials should investigate regimens to maximize the local control advantages of radiotherapy with distant control improvements seen with chemotherapy for patients with high-risk endometrial cancer,” they wrote. “Continued assessment of toxicity, quality of life, and cost will be paramount to define optimal adjuvant therapy.”

References

1. de Boer SM, Powell ME, Mileshkin L, et al. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial [published online February 12, 2018]. Lancet Oncol. doi: 1 0.1016/S1470-2045(18)30079-2.
2. Dowdy SC, Glaser GE. Adjuvant therapy for women with high-risk endometrial carcinoma [published online February 12, 2018]. Lancet Oncol. doi: 10.1016/S1470-2045(18)30091-3.