Evaluating the Effectiveness of Chemoradiotherapy for High-Risk Endometrial Cancer Treatment

Investigating Treatment Options for High-Risk Endometrial Cancer

Understanding Endometrial Cancer

Endometrial cancer, commonly referred to as uterine cancer, originates in the endometrium, the inner lining of the uterus. The initial symptom of this type of cancer is often abnormal vaginal bleeding unrelated to a menstrual cycle, which typically leads to early diagnosis. While many women with endometrial cancer have a favorable prognosis, approximately 15% are diagnosed with high-risk disease, which significantly heightens their chances of metastasis and cancer-related mortality.

Current Standard of Care

For decades, pelvic external beam radiotherapy has been the standard adjuvant treatment for high-risk endometrial cancer. Adjuvant treatment refers to supplementary therapy administered following the primary treatment to minimize the risk of cancer recurrence. Although previous research indicated that radiotherapy could delay pelvic recurrence and chemotherapy could delay distant metastases, neither approach demonstrated a significant improvement in overall survival rates. Moreover, studies have suggested that chemotherapy alone may lead to a higher incidence of pelvic relapse.

The PORTEC-3 Trial

To address these concerns, recent research has shifted towards evaluating the efficacy of combining external beam radiotherapy with adjuvant chemotherapy for high-risk endometrial cancer patients. The phase-2 trial that combined both treatments showed promising results, reporting disease-free survival rates of 81% and 85% after four years. These findings prompted an international collaboration on the PORTEC-3 trial, a randomized, open-label, multicenter phase 3 study published in The Lancet Oncology.

The PORTEC-3 trial involved 660 women aged 18 and older diagnosed with high-risk endometrial cancer, recruited from 103 centers participating in six clinical trials under the Gynaecological Cancer Intergroup. Participants were randomized into two groups: one receiving radiotherapy alone, administered five days per week, and the other receiving both radiotherapy and chemotherapy. The chemotherapy regimen included two cycles of cisplatin during radiotherapy, followed by four cycles of carboplatin and paclitaxel.

Results of the Trial

The primary endpoints of the trial were overall survival and failure-free survival, defined as the absence of relapse. After an average follow-up of five years, the chemoradiotherapy group exhibited a five-year survival rate of 81.8%, compared to 76.7% in the radiotherapy-only group. Additionally, failure-free survival improved in the chemoradiotherapy group, recording 75.5% versus 68.8% in the radiotherapy alone group.

However, the study also highlighted significant concerns regarding adverse events. Among the 330 patients in the chemoradiotherapy group, 60% experienced grade three or higher side effects, in stark contrast to only 12% in the radiotherapy group. Furthermore, patients with stage III cancer at high risk for recurrence saw an 11% improvement in failure-free survival with chemoradiotherapy.

Study Limitations and Conclusions

Despite the encouraging results, the study faced limitations, as the number of patients who survived and those with failure-free survival fell short of the anticipated figures necessary for robust analysis. Most patient deaths were attributed to endometrial cancer, while a few were linked to unknown causes or pre-existing conditions. Notably, one death in the radiotherapy group was due to complications from late treatment or disease progression.

The findings suggest that while chemoradiotherapy may not significantly enhance overall survival for high-risk endometrial cancer patients, it does offer improved failure-free survival. However, the increased toxicity, longer treatment duration, and subsequent reduction in health-related quality of life must be carefully considered.

In conclusion, as radiotherapy alone effectively controls pelvic recurrence, the trial indicates that chemoradiotherapy is not recommended as a new standard treatment for patients with stage I and II endometrial cancer. Conversely, for stage III patients at a higher risk of recurrence, chemoradiotherapy may present a viable option, albeit one that requires individualized assessment.

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.