Chemotherapy is the mainstay of treatment for high-risk endometrial carcinoma, and it looks to stay that way, as adding radiation on top does not improve survival over that seen with chemotherapy alone, according to new findings.
A final analysis of data from the NRG258 trial, with a median follow-up of 112 months for overall survival, showed no significant difference between the two arms: the stratified ratio for death comparing chemoradiation therapy vs chemotherapy alone was 1.05 (log-rank two-sided P = .72).
“As previously reported, chemoradiation did not improve progression-free survival compared to chemotherapy alone,” said lead author Daniela Matei, MD, chief of reproductive science in medicine in the Department of Obstetrics and Gynecology, Feinberg School of Medicine, Chicago, Illinois.
“Chemoradiation did reduce the incidence of vaginal, pelvic, and para-aortic recurrences compared to chemotherapy, as we also previously reported, but distant recurrences were more common with chemoradiation,” she said.
The findings were presented at the Society of Gynecologic Oncology Annual Meeting on Women’s Cancers (SGO) 2023.
Approached for comment, Akila N. Viswanathan, MD, MPH, director, Johns Hopkins Radiation Oncology and Molecular Radiation Sciences, Baltimore, Maryland, noted that the management of stage III/IVA endometrial cancer is rapidly changing.
“The survival rates in this study, while lower than those reported in PORTEC III’s stage III population, where 5-year survival was 78.7%, are also negative for all endpoints, resulting in this trial not changing management from currently accepted standard of care,” she said.
“Multidisciplinary management will be refined in the future based on increased integration of molecular markers and an increased understanding of reliable prognostic and predictive factors,” she added.
Advanced Stage of Endometrial Cancer
Although stage III/IVA endometrial cancer accounts for only 10% to 15% of all cases, these patients account for more than 50% of related deaths, Matei told the meeting.
Five-year survival ranges from 50% to 70%, as these patients have a high risk of recurrence, both local (around 20% to 30%) and systemic (around 40%).
“Several seminal studies have examined the role of chemotherapy, radiation therapy, and a combined approach in this population,” Matei noted.
One of these is the PORTEC-3 trial, which investigated adjuvant chemoradiotherapy vs pelvic radiotherapy alone for women with high-risk endometrial cancer. That study showed improved progression-free and overall survival in the chemoradiotherapy arm. “However, the comparator was external-beam radiotherapy, and the study reaffirmed the role of chemotherapy for treating high risk endometrial cancer,” she said.
No Overall Survival Benefit
For this study, Matei and colleagues hypothesized that systemic chemotherapy and tumor volume–directed radiotherapy would improve recurrence-free survival and overall survival in comparison with systemic chemotherapy alone for patients with surgically staged III/IVA uterine cancer.
Interim results of the study have already been published. They show that chemotherapy plus radiation was not associated with longer relapse-free survival than chemotherapy alone (N Engl J Med. 2019 Jun 13;380:2317-2326). At this meeting, Matei reported on the final analysis of overall survival.
The study involved 813 patients with surgical stage III or IVA endometrial carcinoma of any histologic subtype. They were randomly assigned to receive either chemoradiotherapy or chemotherapy alone.
The chemoradiotherapy regimen consisted of cisplatin (50 mg/m2) on days 1 and 29 concurrent with volume-directed external-beam radiation therapy, followed by carboplatin given at a dose to achieve an area under the concentration-time curve (AUC) of 5–6 plus paclitaxel (175 mg/m2 every 21 days for four cycles).
The chemotherapy-only regimen consisted of carboplatin (to achieve an AUC of 6) plus paclitaxel (175 mg/m2) every 21 days for six cycles.
“Progression-free survival has already been reported, and there was no difference between the two groups,” said Matei.
At 60 months, the percentage of patients alive and relapse free was 59% in the chemoradiotherapy group and 58% in the chemotherapy-only group (hazard ratio [HR], 0.90).
Also as previously reported, chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs 7%; HR, 0.36) and pelvic and para-aortic lymph node recurrence (11% vs 20%; HR, 0.43) vs chemotherapy alone, but distant recurrence was more common with chemoradiotherapy (27% vs 21%; HR, 1.36).
No overall survival benefit was seen at this final analysis, Matei noted. The median follow-up for overall survival was 112 months (maximum, 155 months), and median overall survival was not achieved in either treatment arm (stratified HR for death comparing treatment arms, 1.05; two-sided P = .72).
“Multivariable analysis, including key clinical and histological factors, did not identify any subgroup where the combined approach was associated with improved survival,” said Matei.
As previously reported, rates of adverse events of grades 3, 4, or 5 were similar in both groups (58% in the chemoradiotherapy group vs 63% in the chemotherapy-only group).
Equivalent Outcomes
Also approached for comment, Jyoti S. Mayadev, MD, a radiation oncologist and professor of radiation medicine and applied sciences at the University of California, San Diego, noted that this is level I evidence with stage III and IV endometrial cancer, and it shows that outcomes were equivalent with both therapies.
“Toxicity was not worse in the radiation therapy arm, and chemotherapy reduced local relapses,” she said. “Reducing local relapses may be important to some women, so we can offer it to them.”
Mayadev also pointed out that molecular analysis had not yet been conducted and that the authors plan to do so. “In the ongoing RAINBOW study, they are also looking at molecular stratification, so we will also have more answers from that,” she said. “Right now we have two efficacious regimens, and we await stratification that will allow for more personalized therapy.”
The study was funded by the National Cancer Institute (NCI). Matei reported relationships with Glaxo SmithKline, CVS Health, AstraZeneca, Merck, Elsevier, and PinotBio. Myadev reported relationships with Merck, AstraZeneca, Primmune, Varian Medical Systems, and Kortuc. She has also received grants from NRG Oncology and the NCI. Viswanathan has received compensation from Seminars in Radiation Oncology: Editor in Chief, and honoraria from the Uterine Task Force (NCI).
Society of Gynecologic Oncology Annual Meeting on Women’s Cancers (SGO) 2023: March 27, 2023.
Roxanne Nelson is a registered nurse and an award-winning medical writer who has written for many major news outlets and is a regular contributor to Medscape.
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