Radiation Role Remains Uncertain in High-Risk Endometrial Cancer

David G. Mutch, MD

Following the results of a number of clinical studies, researchers are still debating the role of radiation therapy for patients with high-risk endometrial cancer.

According to David G. Mutch, MD, data from the GOG-258 study demonstrate that there is not a relapse-free survival (RFS) benefit from adding radiation therapy to chemotherapy versus chemotherapy alone in patients with optimally debulked stage III/IVa endometrial carcinoma.

GOG-258 randomized 813 patients to cisplatin and tumor volume—directed radiation followed by carboplatin and paclitaxel for 4 cycles (C-RT) versus carboplatin and paclitaxel for 6 cycles (CT). Although C-RT reduced the rate of local recurrence versus CT, data from a median follow-up of 47 months showed that there was no RFS benefit with the addition of radiation to chemotherapy (HR, 0.9; 95% CI, 0.74-1.1). The estimated 5-year overall survival (OS) rate was 70% with C-RT versus 73% with CT.

“My argument is simply that there is little role for upfront treatment of endometrial cancer with radiation therapy at this time,” explains Mutch.

OncLive: Please discuss the use of external beam radiation therapy in high-risk patients with endometrial cancer.

In an interview with OncLive during the 2018 Society of Gynecologic Oncology Annual Winter Meeting, Mutch, the Ira C. and Judith Gall Professor, vice chair of obstetrics and gynecology, chief of the Division of Gynecologic Oncology, Washington University School of Medicine in St. Louis, Siteman Cancer Center, discussed ongoing questions surrounding the role of radiation therapy for patients with high-risk endometrial cancer.Mutch: I am in a debate [at this meeting] on whether there is utility in giving patients with high-risk endometrial cancer radiation therapy. My argument against this is supported by several trials beginning with GOG-99, which identified a high- and intermediate-risk group of patients with endometrial cancer. There was a decreased risk of central disease but not an OS benefit to postoperative external beam radiation therapy.

Somehow, we got the notion that it is standard of care to give radiation therapy to this group because it decreased the risk of local recurrence, but the OS was the same. That theme has been carried through PORTEC-1, which is the European data showing, likewise, that vaginal brachytherapy will decrease the local recurrence rate, as will external beam radiation therapy. However, there are more complications associated with external beam radiation therapy. The Europeans have gone to giving brachytherapy in this group of patients.

Now, we have GOG-258, which shows that there is no benefit to delivering external beam therapy as opposed to chemotherapy. My argument is simply that there is little role for upfront treatment of endometrial cancer with radiation therapy at this time.

There are Norwegian data demonstrating that there are long-term complications and short-term complications of radiation therapy. Those long-term complications are that overall, the group of patients who received external beam radiation therapy were more likely to die, to have secondary malignancies, and their overall lifespan was shorter. The conclusion of that trial is that we should not give radiation therapy unless there is a clear survival benefit, which I believe there is not.

Speaking on the molecular data, are there any biomarkers that can help determine which treatment to give?

Therefore, chemotherapy and/or targeted therapy is clearly the way to treat this group of patients. We need to define our groups better. There are efforts underway to make that happen. PORTEC-4a for instance, is utilizing molecular data to stratify patients. We will anxiously await that data. We had a clinical trial planning meeting and proceeds of that were published recently. That will also help us develop new trials for targeted therapy.Unfortunately, there are not. We have not gone far in utilizing conventional markers. Conventional markers would be lymphovascular space involvement, depth of invasion, grade of the tumor, or histologic type—whether it is papillary, serous, or clear cell. Those would typically be done.

We do have molecular data from The Cancer Genome Atlas study showing that patients who have a POLE [polymerase epsilon] mutation, though they often have poorly differentiated tumors, almost never recur. If we routinely screen for POLE mutations, those patients do not need adjuvant therapy.

Is there a certain frontline regimen that you go to for these patients?

By utilizing molecular characterizations, we can eliminate many patients who might not need any additional therapy.In patients who have high-risk endometrial cancer, I would argue that based on GOG-209, which randomized patients to [cisplatin, paclitaxel, and doxorubicin] versus carboplatin and paclitaxel, that the survival is the same in both arms. Toxicity is greater in the triplet therapy group; therefore, standard therapy for upfront treatment would be carboplatin and paclitaxel in the high-risk patients.

However, patients need to be monitored for a cuff recurrence. Cuff recurrences, if monitored carefully, have a cure rate of 100%. Then, radiation therapy is certainly indicated.

Matei D, Filiaci VL, Randall M, et al. A randomized phase III trial of cisplatin and tumor volume directed irradiation followed by carboplatin and paclitaxel vs. carboplatin and paclitaxel for optimally debulked, advanced endometrial cancer. J Clin Oncol. 2017;35 (suppl; abstr 5505).