A recent study investigated whether chemoradiotherapy or radiotherapy alone would be effective for women diagnosed with high-risk endometrial cancer.
Endometrial cancer, also known as uterine cancer, is a type of cancer that begins in the endometrium, which is the lining of the uterus. Since the first sign of endometrial cancer is abnormal vaginal bleeding when a woman is not expecting a menstrual period, it is often discovered early. Many women diagnosed with endometrial cancer have a favourable prognosis, although approximately 15% are diagnosed with the high-risk disease that increases their risks significantly of metastasis and cancer-related death.
Despite a lack of evidence showing improvement in survival rates, for many decades pelvic external beam radiotherapy has been the standard adjuvant treatment. Standard adjuvant treatment is additional cancer treatment given to a patient after their primary treatment, to help reduce the risk of cancer recurrence in high-risk endometrial cancer patients.
Previous studies have shown while pelvic recurrence can be delayed by radiotherapy, and chemotherapy delays distant metastases, neither resulted in a significant difference in survival. Also, chemotherapy treatment alone has been reported to result in an increased incidence of pelvic relapse.
The PORTEC 3 Trial
Hence a focus of current research explores the combination of both external beam radiotherapy and adjuvant chemotherapy as a treatment protocol for high-risk endometrial cancer patients. A phase-2 trial that combined the two treatments resulted in disease-free survival of 81% and 85% after four years. Based upon these results, researchers around the world recently collaborated on an international, randomised, open-labelled, multicentre phase 3 trial called PORTEC-3, to investigate whether chemoradiotherapy (the combination of chemotherapy and radiotherapy) compared to radiotherapy alone can increase the overall survival of high-risk endometrial cancer patients. Their results were published in The Lancet Oncology.
The PORTEC-3 randomised trial included 660 women over the age of 18 years diagnosed with high-risk endometrial cancer from 103 centres involved in six clinical trials collaborating in the Gynaecological Cancer Intergroup. The participants were randomly assigned to either radiotherapy treatment alone which was administered five days per week or a combination of radiotherapy and chemotherapy which included administering two cycles of the chemotherapy drug cisplatin during radiotherapy, followed by administering four cycles of carboplatin and paclitaxel (adjuvant chemotherapy drugs). The primary endpoint was overall survival and failure-free survival with an absence of relapse.
Few benefits of chemoradiotherapy
With the average follow-up after five years, the five-year survival rate for the participants in the chemoradiotherapy group was 81.8% compared to 76.7% for the participants in the radiotherapy alone group. The five-year failure-free survival also increased in the chemoradiotherapy group, with 75.5% versus 68.8% in the radiotherapy alone group. However, of the 330 patients assigned the chemoradiotherapy treatment, 60% experienced grade three or higher adverse events during their treatment, which was significantly higher than the number of patients who received only radiotherapy, with only 12% of adverse events reported.
Also, patients with stage-III cancer who are at high risk of disease recurrence were reported to have an 11% improvement in failure-free survival in the chemoradiotherapy group. Overall, 136 patients survived and 186 patients were reported with failure-free survival, which was a limitation of the study as both were lower than the required and expected number of both events for the trial resulting in the final analysis based on time rather than events.
The cause of death for most patients was endometrial cancer, but the cause of death for four patients was unknown and three deaths were attributed to pre-existing disease or late treatment-related toxicity. One death in the radiotherapy alone group was also due to either complications from late treatment or disease progression.
Chemoradiotherapy is not recommended for patients with stage I and stage II endometrial cancer
Therefore, these results indicate that high-risk endometrial cancer patients who received the treatment protocol of a combination of chemotherapy given during and after with radiotherapy did not significantly improve the overall survival of patients after five years. However, it did increase the failure-free survival. These factors need to be weighed against the benefits for improvement in failure-free survival, given there was also a reduction in health-related quality of life in the chemoradiotherapy group and the cost of treatment in regard to increased toxicity and longer treatment duration.
In conclusion, as radiotherapy was sufficient in controlling pelvic recurrence this trial reported that the introduction of chemoradiotherapy as a new standard treatment protocol for high-risk endometrial cancer patients is not recommended for patients with stage I-II cancer. However, for patients with stage-III endometrial cancer who are at a higher risk of recurrence, chemoradiotherapy would be a potential option but needs to be considered on an individual case-to-case basis.
Written by Lacey Hizartzidis, PhD
Reference: de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C,Ottevanger PB, Ledermann JA, Khaw P, Colombo A, Fyles A, Baron MH,Jürgenliemk-Schulz IM, Kitchener HC, Nijman HW, Wilson G, Brooks S, Carinelli S, Provencher D, Hanzen C, Lutgens LCHW, Smit VTHBM, Singh N, Do V, D’Amico R, Nout RA, Feeney A, Verhoeven-Adema KW, Putter H, Creutzberg CL; PORTEC study group. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Mar;19(3):295-309.doi: 10.1016/S1470-2045(18)30079-2. Epub 2018 Feb 12. Erratum in: Lancet Oncol.2018 Apr;19(4):e184.