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Chemo Alone in Advanced Endometrial Cancer?

Among patients with advanced endometrial carcinoma, chemotherapy plus radiation was not associated with longer relapse-free survival than chemotherapy alone, according to new findings.

At 60 months, 59% of patients were alive and relapse free in the chemoradiotherapy group, vs 58% in the chemotherapy-only group (hazard ratio [HR], 0.90).

“Radiation has been used historically in this group of patients who are considered to be at high risk of both local and distant metastasis,” said lead author Daniela Matei, MD, Diana Princess of Wales Professor in Cancer Research, Department of Obstetrics and Gynecology, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois.

“After the results of a previous study (GOG 122) that were reported approximately 15 years ago, systemic chemotherapy started to be included in the treatment of this patient population along with radiation,” she told Medscape Medical News.

“The results of the current study (GOG 258) show that the combined-modality regimen did not result in an improvement in recurrence-free survival over chemotherapy alone and confirm the benefit of chemotherapy alone for patients with stage III uterine cancer,” she said.

The study was published June 13 in the New England Journal of Medicine.

Approached for comment, Kevin Holcomb, MD, associate professor of clinical obstetrics and gynecology at Weill Cornell Medical College, New York City, said that radiation has been a mainstay of treatment for endometrial cancer, but this is changing.

If you can get the same result by using one therapy, there is no reason to use two.
Dr Kevin Holcomb

“In general, in cancer care, if you can get the same result by using one therapy, there is no reason to use two,” he told Medscape Medical News. “If survival is similar, then you need to look at quality of life, and this will question the benefit of adding radiation.”

Radiation and/or Chemotherapy

Pelvic or whole-abdominal radiotherapy has traditionally been used after surgical resection. Although it prevents pelvic recurrence, it has been less effective for preventing systemic recurrence, Matei explained. A randomized trial conducted by the Gynecologic Oncology Group (GOG) found that chemotherapy was superior to radiotherapy for treating locally advanced disease, and it subsequently became part of the standard protocol (J Clin Oncol. 2006;24:36-44).

However, chemotherapy alone has been associated with an increased risk for locoregional recurrence. Thus, note the authors, it was logical to hypothesize that the combined strategy might improve outcomes by preventing both local (pelvic) and distant recurrences.

Guidelines on the diagnosis, treatment, and follow-up of endometrial cancer were issued a few years ago by the European Society for Medical Oncology, the European Society for Radiotherapy and Oncology, and the European Society of Gynaecological Oncology.

“The most controversial areas related to the indications for brachytherapy or external-beam radiotherapy and the use of chemotherapy combined with, or instead of, radiotherapy,” the lead author of the guidelines, Nicoletta Colombo, MD, from the European Institute of Oncology, University of Milan-Bicocca, Italy, told Medscape Medical News at the time.

For example, one previous study in women with early-stage, high-risk endometrial cancer showed that adding chemotherapy to radiotherapy was not superior to the standard treatment of radiotherapy alone.

No Difference in Treatment Arms

In the current trial (GOG 258), Matei and her colleagues evaluated the use of concurrent tumor volume–directed external-beam radiotherapy and chemotherapy compared with chemotherapy alone in women with advanced-stage endometrial cancer.

A total of 707 patients with stage III or IVA endometrial carcinoma were randomly assigned to receive either chemoradiotherapy (n = 346) or chemotherapy only (n = 361).

The chemoradiotherapy regimen included cisplatin (50 mg/m2 administered intravenously on days 1 and 29) and volume-directed external-beam radiotherapy, followed by carboplatin (dosed to achieve an area under the concentration–time curve [AUC] of 5 to 6 ) plus paclitaxel (175 mg/m2 administered every 21 days for four cycles). The chemotherapy-only regimen consisted of carboplatin (to achieve an AUC of 6) plus paclitaxel (175 mg/m2 given every 21 days for six cycles).

The results for the primary endpoint of relapse-free survival did not reach significance. The null hypothesis that chemoradiotherapy is not superior to chemotherapy alone could not be rejected (P = .20 by one-tailed test).

To date, there have been a total 165 deaths — 86 in the chemoradiotherapy group, and 79 in the chemotherapy-only group. In the chemoradiotherapy group, 73% deaths occurred as a result of the progression of endometrial cancer progression; in the chemotherapy-only group, 81% such deaths occurred. However, between-group comparisons of overall survival could not be made because the data are not sufficiently mature, the authors comment.

Exploratory subgroup analyses failed to identify a subgroup of patients who may have benefited more from chemoradiotherapy than from chemotherapy alone.

Other analyses showed that the cumulative incidence of vaginal disease recurrence at 60 months was 2% in the chemoradiotherapy group and 7% in the chemotherapy-only group (HR, 0.36). For pelvic or para-aortic node recurrence, the cumulative incidence was 11% with chemotherapy-only, vs 20% with chemoradiotherapy (HR, 0.43).

The cumulative incidence of distant recurrence at 60 months’ follow-up was 27% in the chemoradiotherapy group and 21% in the chemotherapy-only group (HR, 1.36). Coincident local and distant recurrences at first presentation were found in 2.2% and 4.9%, respectively.

Adverse events of grade 3 or greater were reported in 202 patients (58%) in the chemoradiotherapy group and 227 patients (63%) in the chemotherapy-only group. Both groups reported symptoms of neurotoxicity in association with treatment.

“Physicians may consider addition of radiation for selected patients considered at very high risk for local recurrence,” said Matei. “However, completion of systemic chemotherapy in all patients remains key to achieving best outcomes.”

Doesn’t Close the Door

Commenting to Medscape Medical News, Holcomb said that radiotherapy has historically had a role in the adjuvant treatment in locally advanced endometrial cancer and has been the mainstay therapy for many years.

However, he pointed out that radiotherapy “has never been shown to improve overall survival, and many patients had distant recurrences that were not likely to be prevented by radiation.”

Then the GOG 122 trial changed things. Whole-abdominal irradiation was compared with doxorubicin-cisplatin chemotherapy in women with stage III or IV endometrial carcinoma. “Many of us thought that radiation would be proven superior, given its historical role, but that wasn’t the case,” said Holcomb. “There was a significant improvement in survival with chemotherapy.”

Although the current study used relapse-free survival as an endpoint, it is unlikely this will translate to a difference in survival between the two groups, he said.

In addition, although the chemotherapy group experienced a higher rate of adverse effects, these were acute events, whereas for the combination group, the rate of long-term events was higher. “While we always strive to limit acute toxicities during treatment,” he said, “we really want to avoid the ones that ‘hang around’ long term.”

However, Holcomb also noted that even though this study demonstrated that chemoradotherapy was not superior to chemotherapy alone, it does not close the door entirely on combination therapy.

“The study only looked at one way that chemotherapy and radiation therapy can be combined,” he said. “There are other ways to give combination therapy.”

For example, one method is to “sandwich” radiotherapy in between treatments with chemotherapy — give half of the chemotherapy, then give the radiation, and then give the remaining cycles. Another method is to administer chemotherapy and combination therapy sequentially. “We need better data on these methods, which will probably be studied in future trials,” he said.

Unanswered Questions

Another expert feels that this is a complex topic and that the article leaves a number of questions unanswered. “Combined therapy is frequently used to treat subsets of patients included in this trial, and retrospective studies have repeatedly strongly suggested that radiation therapy is important for the subset of patients with involved nodes,” said Patricia Eifel, MD, professor, Department of Radiation Oncology, Division of Radiation Oncology, the University of Texas MD Anderson Cancer Center, Houston. “These represented about 75% of patients.”

She also pointed out that these results “certainly indicate that patients treated in the ways employed in this trial had similar relapse rates with or without radiation therapy. However, there is a lot of missing information in this study, which makes it difficult to know how to generalize the results to high, modern, optimized, multidisciplinary practice.”

Eifel said that there is reason to think the radiotherapy given in the trial may not have been optimal, although the details are sparse. For example, the authors do not fully explain what was meant by “volume-directed RT,” and that needs to be clarified.

More importantly, the maximum dose delivered was 45 Gy, even if there was gross residual disease (anything ≥1 cm), and “45 Gy would rarely be expected to control nodes of this size, even when combined with chemotherapy,” she said. “It may seem that this would have little impact, since the rate of gross residual reported in the paper (2%) is so low. However, in our experience, this 2% rate is much lower than expected, particularly in a population that was not required to have a full, or even any, lymph node dissection.”

The article did not clearly outline how patients were assessed for residual disease, she continued. Because postoperative imaging was not required, it must be assumed that assessment was based on surgical findings, she said. “In our experience, surgical assessment is inadequate, because some of the most frequently involved sites are behind the renal, aortocaval, and iliac vessels,” said Eifel. “We often find residual positive or suspicious nodes on postoperative imaging, even when the surgeon failed to appreciate residual disease.”

Eifel added that adjuvant radiotherapy is almost always ineffective for treating gross residual disease if the dose is not boosted higher, usually to 60 Gy. “This was not permitted in the trial, even if gross residual was known to be present,” she noted.

The study was supported by grants from the National Cancer Institute (NCI) to the Gynecologic Oncology Group Administrative Office, the Gynecologic Oncology Group Statistical and Data Center, NRG Oncology, NRG Operations, and the NCI Community Oncology Research Program. Matei has received personal fees and nonfinancial support from Genentech, AstraZeneca, Clovis, Astex Inc, and the European Commission, and personal fees from Tesaro, all outside the submitted work. Several coauthors have also reported relationships with industry. Eifel has disclosed no relevant financial relationships.

N Engl J Med. 2019;390:24.

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