From the Journals

Benefit of chemo + RT for high-risk endometrial cancer increases with time

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Research is resolving gray areas in adjuvant therapy

Results of PORTEC-3 are potentially practice changing but generate several questions relevant to optimizing adjuvant therapy for high-risk endometrial cancer, Marcus Randall, MD, contends in a commentary (Lancet Oncol. 2019 Jul 22. doi: 10.1016/S1470-2045[19]30416-4).

One question is applicability of the findings across trial subgroups, which is still uncertain. “However, taking into account the statistical limitations of subgroup analyses, the therapeutic benefit of combined chemotherapy and radiotherapy (vs. radiotherapy alone) appeared to remain confined to patients with stage III disease and those with serous carcinomas of all stages,” he noted.

Another question is whether chemotherapy alone is sufficient. Here, results from trials conducted by the Gynecologic Oncology Group (now NRG Oncology) suggest that omitting pelvic radiotherapy increases the risk of locoregional failure, according to Dr. Randall.

A final question is whether there is a preferred approach for combining chemotherapy with radiotherapy. “Increasing evidence supports the use of upfront systemic therapy, when combined with radiotherapy, as a strategy to maximise both systemic and local control. ... Many clinicians often use this regimen as a preferred adjuvant approach in locally advanced endometrial cancer,” he noted.

“Based on outstanding work done by the PORTEC Study Group and others, we have made good progress in improving outcomes for women with high-risk and locally advanced endometrial cancers. However, we are not there yet,” Dr. Randall concludes.

Marcus Randall, MD, is with the department of radiation medicine, University of Kentucky, Lexington. He has no disclosures related to the commentary.



Benefits of adding chemotherapy to pelvic radiotherapy in localized high-risk endometrial cancer increase with follow-up, finds an updated analysis of the randomized PORTEC-3 trial.

The relative risk-benefit profile of chemoradiotherapy is uncertain, with some evidence suggesting it varies according to disease histology and stage, noted lead investigator Stephanie de Boer, MD, department of radiation oncology, Leiden (the Netherlands) University Medical Center, and coinvestigators.

PORTEC-3, a multicenter phase 3 trial, enrolled women who had undergone surgery for high-risk endometrial cancer: FIGO 2009 stage I, endometrioid grade 3 cancer with deep myometrial invasion, lymphovascular space invasion, or both; stage II or III disease; or stage I to III disease with serous or clear cell histology. In all, 660 women were evenly assigned to external-beam radiotherapy alone (48.6 Gy in 1.8-Gy fractions, on 5 days per week) or radiotherapy and chemotherapy (two cycles of cisplatin given during radiotherapy, followed by four cycles of carboplatin and paclitaxel).

A previous analysis, at a median follow-up of 60.2 months (5.0 years), showed a significant 5-year failure-free survival benefit of chemoradiotherapy over radiotherapy (hazard ratio [HR], 0.71; P = .022) but only a trend toward an overall survival benefit (Lancet Oncol. 2018;19[3]:295-309).

The updated analysis, now at a median follow-up of 72.6 months (6.1 years), was reported in Lancet Oncology and showed that chemoradiotherapy was still significantly superior to radiotherapy alone in terms of 5-year failure-free survival (76.5% vs. 69.1%; adjusted HR, 0.70; P = .016) but was now also significantly superior in terms of 5-year overall survival (81.4% vs. 76.1%; adjusted HR, 0.70; P = .034)

The 5-year probability of distant metastasis was lower with chemoradiotherapy than with radiotherapy alone (21.4% vs. 29.1%; HR, 0.74; P = .047). The two groups did not differ significantly with respect to isolated vaginal recurrence as first site (0.3% in each group) or isolated pelvic recurrence as first site (0.9% in each group).

Only a single patient, in the chemoradiotherapy group, experienced a grade 4 adverse event (ileus or obstruction). The chemoradiotherapy and radiotherapy-only groups were similar on the rate of grade 3 adverse events (8% vs. 5%; P = .24), the most common of which was hypertension. However, the former had a higher rate of grade 2 or worse adverse events (38% vs. 23%; P = .002), such as persistent sensory neuropathy (6% vs. 0%). None of the patients died from treatment-related causes.

“Combined adjuvant chemotherapy and radiotherapy should be discussed and recommended as a new standard of care, especially for women with stage III endometrial cancer or serous cancers, or both,” Dr. de Boer and coinvestigators maintained. “Shared decision making between doctors and their patients remains essential to weigh the costs and benefits for individual patients.

“Molecular analysis has the potential to improve risk stratification and should be used to identify subgroups that can derive the greatest benefit from chemotherapy and to select patients for targeted therapies; molecular studies on tissue samples donated by PORTEC-3 trial participants are ongoing,” they noted.

Dr. de Boer disclosed no competing interests in relation to the study. The study was supported in part by the Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Cancer Australia, the Italian Medicines Agency, and the Canadian Cancer Society Research Institute.

SOURCE: de Boer SM et al. Lancet Oncol. 2019 July 22. doi: 10.1016/S1470-2045(19)30395-X.

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