Maureen E. Roberts, MD

Christina S. Chu, MD

Endometrial cancer remains the most common gynecologic malignancy affecting women in the United States. There are over 60,000 new cases diagnosed and more than 12,000 deaths annually. Traditional management includes surgical staging, with optimal disease cytoreduction as able, and adjuvant therapy for advanced-stage or high-risk disease. However, due to the heterogeneity of the disease, regimens for adjuvant therapy have been variable, with different combinations of chemotherapy and radiation therapy utilized.

In March 2018, The Lancet Oncology published the initial results from the PORTEC-3 trial.¹ PORTEC-3 was an open-label, multicenter, phase III randomized trial that compared adjuvant chemoradiotherapy versus radiotherapy alone for women with locally advanced and high-risk endometrial cancer. Women who received radiation alone were dosed to 48.6 Gy in 1.8-Gy fractions given over 5 weeks. Women who received chemoradiotherapy were treated with two cycles of cisplatin at 50 mg/m² during radiotherapy, followed by four cycles of carboplatin AUC = 5 and paclitaxel at 175 mg/m².

At a median follow-up of 60.2 months, the previously reported results showed a statistically significant benefit in failure-free survival at 5 years in the adjuvant chemoradiotherapy group, but no significant overall survival benefit. However, in a subgroup analysis, there was a statistically significant survival advantage among those with stage III disease and those with serous histology.

Leading with systemic chemotherapy may have the benefit of improving distant control while maintaining the benefits of local control achieved with subsequent radiation.

— Maureen E. Roberts, MD, and Christina S. Chu, MD

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Recently, de Boer et al published an ad hoc analysis—reviewed in this issue of The ASCO Post—that now shows a significant overall survival benefit for the cohort that received chemoradiation.² Failure-free survival remained statistically improved for those receiving chemoradiation (76.5% vs 69.1%, P = .016). At a median follow-up of 72.6 months, 5-year overall survival was 81.4% vs 76.1% in favor of chemoradiation (P = .034). This overall survival benefit was again most pronounced in patients with stage III disease and in those with serous tumors. The rates of distant metastases, isolated vaginal recurrence, and isolated pelvic recurrence were similar between the two groups. Unsurprisingly, at 5 years, grade 2 or worse adverse events, particularly sensory neuropathies, were statistically more common in the chemoradiotherapy group. As a result of the updated analyses showing statistically significant improvement in both failure-free and overall survival, the authors concluded that chemoradiation should be recommended, especially for women with stage III or serous cancers.

Survival Benefit Applicable to All Subgroups?

This trial has the strengths of being a large, randomized, international, phase III study conducted at multiple sites. More than 650 subjects were evaluable, with a median follow-up of over 6 years—more than 75% of participants reached 5 years of follow-up. However, because the inclusion criteria permitted a diverse group of patients of different stages and histologies (the study included patients with high-risk stage I endometrioid histology, stages II and III disease, and stages I to III serous and clear cell histologies), the question arises as to whether the survival benefit is applicable to all subgroups of patients. In subgroup analyses, it would appear that those with stage III or serous histology of any stage received the most benefit from combined therapy.

Remaining Questions and Future Directions

Despite the updated results of the PORTEC-3 trial, questions remain regarding the optimal schedule of combination radiation and chemotherapy. Although the chemoradiation arm of PORTEC-3 was based on the prospective phase II RTOG 9708 study,³ many have advocated for a “sandwich” approach, which starts with three cycles of chemotherapy, followed by radiation, then three additional cycles of chemotherapy. The sandwich approach has been noted to be both safe and effective in multiple studies.^4-7 With distant metastases being the most common site of failure in the PORTEC-3 study, leading with systemic chemotherapy may have the benefit of improving distant control while maintaining the benefits of local control achieved with subsequent radiation.

In recent years, research into the use of targeted therapies for endometrial cancer has increased considerably. Will future combinations of immunotherapy and/or targeted therapy play a role in upfront chemoradiation regimens, particularly in patients with mismatch repair–deficient disease? With the classification of endometrial cancer based on its genomic characteristics,⁸ investigative efforts have focused on the development of novel therapies targeting genetic and molecular alterations within the tumor. The clinical benefit of mTOR inhibitors in combination with hormonal therapy⁹ and new interest in checkpoint inhibitors¹⁰ in recurrent disease have led to discussion of the use of these therapies in upfront therapy.

The combination of radiation and chemotherapy, particularly for those with stage III disease or serous histology, should merit serious consideration as the current standard of care.

— Maureen E. Roberts, MD, and Christina S. Chu, MD

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Currently recruiting, PORTEC-4a seeks to further elucidate the role of molecular profiling in high-intermediate–risk endometrial cancer to better direct adjuvant therapy.¹¹ Radiotherapy has been shown to enhance the T-cell antitumor response, supporting the combination of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors with radiation therapy.

Several clinical trials are currently in progress across diverse tumor types to evaluate this strategy in gynecologic malignancies. In particular, trials of pembrolizumab or nivolumab in combination with chemoradiation for cervical cancer (ClinicalTrials.gov identifiers NCT02635360 and NCT03298893, respectively) are currently recruiting. Another study of TSR-042 (a PD-1 inhibitor) as maintenance after chemoradiation for cervical cancer is also in progress (ATOMICC trial, NCT03833479). For endometrial cancer, a phase I trial of TSR-042 in addition to definitive standard-of-care radiation for advanced-stage disease is expected to open to accrual soon.

The PORTEC group is to be commended for the completion of this study and its progress in treating women with locally advanced and high-risk disease. It appears that the combination of radiation and chemotherapy, particularly for those with stage III disease or serous histology, should merit serious consideration as the current standard of care. However, progress still needs to be made in determining the most appropriate treatments, schedules, and combinations for various subtypes of patients with endometrial cancer. ■

Drs. Roberts and Chu practice in the Division of Gynecologic Oncology, Department of Surgical Oncology, Fox Chase Cancer Center/Temple University Hospital, Philadelphia.

DISCLOSURE: Drs. Roberts and Chu reported no conflicts of interest.

REFERENCES

1. de Boer SM, Powell ME, Mileshkin L, et al: 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 19:295-309, 2018.

2. de Boer SM, Powell ME, Mileshkin L, et al: Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): Patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol 20:1273-1285, 2019.

3. Greven K, Winter K, Underhill K, et al: Final analysis of RTOG 9708: Adjuvant postoperative irradiation combined with cisplatin/paclitaxel chemotherapy following surgery for patients with high-risk endometrial cancer. Gynecol Oncol 103:155-159, 2006.

4. Alvarez Secord A, Havrilesky LJ, Bae-Jump V, et al: The role of multi-modality adjuvant chemotherapy and radiation in women with advanced stage endometrial cancer. Gynecol Oncol 107:285-291, 2007.

5. Geller MA, Ivy J, Dusenbery KE, et al: A single institution experience using sequential multi-modality adjuvant chemotherapy and radiation in the “sandwich” method for high risk endometrial carcinoma. Gynecol Oncol 118:19-23, 2010.

6. Geller MA, Ivy JJ, Ghebre R, et al: A phase II trial of carboplatin and docetaxel followed by radiotherapy given in a “Sandwich” method for stage III, IV, and recurrent endometrial cancer. Gynecol Oncol 121:112-117, 2011.

7. Lupe K, et al: Adjuvant carboplatin and paclitaxel chemotherapy interposed with involved field radiation for advanced endometrial cancer. Gynecol Oncol 114:94-98, 2009.

8. Cancer Genome Atlas Research Network, Kandoth C, Schultz N, et al: Integrated genomic characterization of endometrial carcinoma. Nature 497:67-73, 2013.

9. Slomovitz BM, Jiang Y, Yates MS, et al: Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. J Clin Oncol 33:930-936, 2015.

10. Ott PA, Bang YJ, Berton-Rigaud D, et al: Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1-positive endometrial cancer: Results from the KEYNOTE-028 study. J Clin Oncol 35:2535-2541, 2017.

11. Wortman BG, Bosse T, Nout RA, et al: Molecular-integrated risk profile to determine adjuvant radiotherapy in endometrial cancer: Evaluation of the pilot phase of the PORTEC-4a trial. Gynecol Oncol 151:69-75, 2018.