“The optimal adjuvant therapy for women with advanced endometrial cancer remains controversial,” says Gretchen Glaser, MD. “It is unclear how to best sequence adjuvant chemotherapy and radiotherapy for this patient population, both from the standpoint of toxicity and outcomes. Most patients with stage III endometrial cancer are treated with a combination of chemotherapy and radiotherapy. Recent endometrial cancer trials have sequenced radiotherapy first with concurrent cisplatin, followed by combination chemotherapy. To date, however, no trials have directly compared sequencing approaches for chemotherapy and radiotherapy.”

Chemotherapy before radiotherapy, Dr. Glaser explains, may be delivered in a chemotherapy-first (chemotherapy for six cycles followed by radiotherapy) or “sandwich” approach (chemotherapy for three cycles followed by radiotherapy and then chemotherapy for three cycles). “Chemotherapy before radiotherapy approaches delay radiation beyond the immediate postoperative period, which could theoretically increase locoregional recurrences,” she says. “On the other hand, radiotherapy before chemotherapy delays the treatment of micro-metastatic disease outside the radiation field and compromises the delivery of chemotherapy due to radiation-related bone marrow suppression; this could increase distant recurrences.”

Sandwich Approach Vs Radiotherapy Before Chemo

For a paper published in the International Journal of Gynecological Cancer, Dr. Glaser and colleagues summarized the outcomes of patients treated with chemotherapy before radiotherapy in a chemotherapy-first or sandwich approach versus outcomes reported for radiotherapy before chemotherapy. The researchers looked retrospectively at the records of women with stage IIIC endometrial cancer (and no residual disease) treated with chemotherapy before radiotherapy between April 2003 and April 2016 at the Mayo Clinic. The Kaplan-Meier method was used to estimate recurrence and survival. They then performed a meta-analysis of endometrial cancer trials comparing chemotherapy and radiotherapy versus radiotherapy alone.

“We found that starting treatment with chemotherapy allowed a high proportion of patients to be able to complete four or more chemotherapy cycles,” Dr. Glaser notes. “In addition, there was a low locoregional recurrence rate, indicating that delaying radiotherapy (and not co-administering cisplatin) to begin chemotherapy was not detrimental to our patients.”  Among total patients, 82% received the chemotherapy first approach and 18% received the “sandwich” approach. Pelvic and para-aortic nodes were removed in 99% and 88.2% of patients, respectively. The researchers observed pelvic (1%), para-aortic (1%), and vaginal (4.9%) cancer recurrences. At 3 years, for the “sandwich” and chemotherapy-first approaches, the vaginal recurrence rates were 11.8% and 4.2%, pelvic recurrence rates were 0.0% and 1.5%, para-aortic recurrence rates were 0.0% and 1.2%, distant recurrence rates were 42.9% and 24.4%, and overall survival rates were 70.3% and 81.7%, respectively. With chemotherapy before radiotherapy, 94.9% completed four or more chemotherapy cycles (vs 71% to 90% reported in the literature for radiotherapy before chemotherapy). In the meta-analysis of endometrial cancer trials, distant recurrence rates were reduced with four or more chemotherapy cycles but not with three cycles.

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Improving Chemotherapy Delivery Is Key

The study team observed the location and rate of recurrence for both type 1 and type 2 endometrial cancer. “We found that the majority of locoregional recurrences were in the vagina,” Dr. Glaser says. “As would be expected, patients with endometrioid histology had lower 3-year distant recurrence rates and a higher 3-year overall survival than patients with non-endometrioid histology (Table).”

Chemotherapy before radiation sequencing for stage IIIC endometrial cancer was associated with a high proportion of patients completing four or more chemotherapy cycles and a low locoregional lymphatic recurrence rate, Dr. Glaser notes. “Improving chemotherapy delivery by sequencing chemotherapy before radiation could potentially improve the distant recurrence rate without compromising locoregional control of metastatic endometrial cancers. In addition, our uniform application of vaginal brachytherapy for women with risk factors may also improve vaginal disease control.”

For future research in this area, Dr. Glaser and colleagues would like to see prospective trials that study chemotherapy before radiotherapy sequencing for stage IIIC endometrial cancer.