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Chemoradiotherapy fails to improve outcomes for advanced endometrial cancer
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The addition of radiation to platinum-based chemotherapy did not improve RFS among women with stage III or IVA endometrial cancer, according to results of a randomized phase 3 study published in The New England Journal of Medicine.
“The results of the study show that the combined modality regimen failed to improve RFS in women with stage III endometrial cancer. Thus, completion of systemic chemotherapy alone remains the standard of care for this group of patients,” Daniela Matei, MD, professor of medicine and gynecologic oncology at Northwestern University’s Feinberg School of Medicine, told HemOnc Today.
The study by Matei and colleagues included 736 women with stage III or stage IVA endometrial cancer randomly assigned to chemoradiation over 21 weeks (n = 370; median age, 60.5 years; 78.6% white) or six cycles of chemotherapy alone over 17 weeks (n = 366; median age, 60 years; 76.2% white).
Twenty-nine eligible patients, including 24 in the chemoradiotherapy group, did not receive treatment.
RFS served as the study’s primary endpoint. Secondary endpoints included OS, acute and chronic toxic effects, and quality of life.
Median follow-up was 47 months.
At 60 months, Kaplan-Meier estimates showed RFS rates of 59% (95% CI, 53-65) for the chemoradiotherapy group and 58% (95% CI, 53-64) for the chemotherapy group (HR = 0.9; 95% CI, 0.74-1.1).
Researchers observed lower 5-year incidence in the chemoradiotherapy vs. chemotherapy group of vaginal recurrence (2% vs. 7%; HR = 0.36; 95% CI, 0.16-0.82) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%; HR = 0.43; 95% CI, 0.28-0.66), but higher incidence of distant recurrence (27% vs. 21%; HR = 1.36; 95% CI, 1-1.86).
A total of 165 deaths occurred, including 86 in the chemoradiotherapy group (73% due to disease progression) and 79 in the chemotherapy group (81% due to progression). OS data were immature for comparison.
Both groups experienced similar acute adverse events, the most common of which were blood or bone marrow events (any grade, 96% chemoradiotherapy vs. 90% chemotherapy only; grade 3 or higher, 40% vs. 52%). Constitutional symptoms, fatigue, and gastrointestinal, renal, genitourinary and musculoskeletal events occurred significantly more often in the chemoradiotherapy group, whereas hematologic adverse events occurred more frequently and were more severe in the chemotherapy-only group.
Overall, grade 3 or higher adverse events occurred in 58% of patients in the chemoradiotherapy arm and 63% in the chemotherapy arm.
“In our study, approximately 25% of patients who received the combined regimen did not complete the full intended course of chemotherapy. These patients also had diminished quality-of-life indices at the completion of treatment, persisting for at least 70 weeks,” Matei said. “Although local control was better for patients receiving both treatment modalities, the risk for distant metastasis was higher. Therefore, completion of chemotherapy remains key for patients with stage III uterine cancer.” – by John DeRosier
For more information:
Daniela Matei, MD, can be reached at Northwestern University Feinberg School of Medicine, Center Room 5-121, 303 E. Superior St., Chicago, IL 60611; email: daniela.matei@northwestern.edu.
Disclosures: Matei reports consultant/advisory roles with and research funding from Astex Inc., AstraZeneca, Clovis, Genentech and Tesaro. Please see the study for all other authors relevant financial disclosures.
Perspective
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Christina S. Chu, MD
Even after surgery, women with locally advanced endometrial cancer are at risk for both local recurrence (in the pelvic area) and distant recurrence (in areas such as the abdomen or lungs). It is still not clear what approach is best to address these concerns. Although radiation can reduce the risk for local recurrence in the radiated areas, only chemotherapy can address possible local and distant recurrences. This study compared the use of chemotherapy alone with chemotherapy plus local radiation to see which is better at extending the time to recurrence.
After a median of almost 4 years of follow-up, women with stage III or IVA endometrial cancer who received chemotherapy and radiation did not experience a longer time to recurrence than those receiving chemotherapy alone. Although women who received the combination therapy had lower rates of vaginal and lymph node recurrence, women who received chemotherapy alone had fewer recurrences outside of the radiation field. Serious adverse events between the two groups appeared to be equivalent.
Thus, based on this study, completion of chemotherapy appears to be a very important part of treatment for women with these cancers.
In terms of study limitations, some might argue that the women in the radiation-plus-chemotherapy group received less chemotherapy (chemotherapy with radiation plus four cycles of treatment after radiation) than those in the chemotherapy-only group (six cycles of treatment). The trial was designed this way because radiation and chemotherapy together may cause more side effects than chemotherapy alone. It is unclear if adding more chemotherapy to the radiation-chemotherapy regimen would improve outcomes for that group.
The discussion section of the paper speculates that radiation should be delivered after chemotherapy rather than before, or in a “sandwich” regimen of chemotherapy-radiation-chemotherapy. Both acute and chronic side effects of the two treatment regimens need to be considered.
Additional trials in the future will help to answer other questions that remain, including: What is the best sequencing of therapy? Can vaginal radiation plus chemotherapy — rather than whole-pelvic radiation as performed in this study — be effective? What is the best treatment to improve OS?
Perspective
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Linus Chuang, MD
We have come a long way in the debate about chemotherapy or radiation for metastatic endometrial cancer, a cancer that has been rising in incidence over the last few decades. It has been ingrained in everyone’s mind that radiation reduces the risk for local recurrence, but without chemotherapy, it does not cover the risk for distant metastases.
Researchers of this study asked if we could address both local and distant metastases by giving radiation chemotherapy compared with chemotherapy alone.
As the results show, giving radiation first is not the right thing to do because we sacrifice valuable time we need to control the spread of distant metastases. This especially applies in stage III and stage IV cases.
Because this study showed no difference between the two treatments, some are saying we should revert to giving only chemotherapy because it has been shown to be superior to radiation.
But, I think we need to look at “sandwich” treatments, in which we start with three cycles of chemotherapy, switch to radiation, and go back to chemotherapy for three more cycles. This idea has been suggested in previous studies and by these researchers in the discussion section of the study.
We also need to ask whether these patients should receive the same treatment or if there should be targeted treatments, with some immunotherapies combined with chemotherapy, but there is still a way to go before we get to a point where we lump them together.
Many of these patients do not die of endometrial cancer, but rather of other comorbid conditions. Radiation has shown that it can be harmful in the long run when it comes to developing a second malignancy, so that is concerning.
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