Despite the paucity of strong data showing benefit of chemotherapy + radiotherapy in patients with stage I-II high risk histology endometrial cancer, if you recommend treatment with both modalities, how do you determine treatment schedule?

For the purpose of this answer, I'll define high risk as serous, carcinosarcoma, undifferentiated, and dedifferentiated. Clear cell carcinoma can be considered and likely treated more by its molecular profile. As you indicate, there is little data to support the routine use of chemotherapy for FIGO stage I-II adverse histology though we know the prognosis is relatively poor, and patients have a high risk of distant progression. The PORTEC-3 data supports chemotherapy in addition to EBRT for serous patients and for p53 abnormal patients (on secondary analysis). There is some evidence supporting chemotherapy in carcinosarcoma patients as well, including stage I-II. So for patients with high risk histologies with deeply invasive FIGO stage I-I...

It is difficult to conduct a study with enough power to adequately evaluate the benefits of adjuvant therapy in early stage, high risk uterine cancer subtypes. I, therefore, base my utility of adjuvant therapy on their well-known aggressive behavior. If the patient is fully staged, I would typically give adjuvant platinum-based chemotherapy followed by brachytherapy. I offer external beam radiotherapy to patients with stage II disease who have not had preoperative radiotherapy nor radical hysterectomy.

To date, chemotherapy and radiation sequencing for endometrial cancer has not been evaluated in any prospective randomized trials. The regimens with the most data include chemoradiation followed by chemotherapy as in RTOG-9708 (Phase 2) and in the Phase 3 PORTEC-3 and GOG 258 trials. However, GOG 249 showed that vaginal brachytherapy followed by three cycles of carboplatin and paclitaxel is safe and there was no difference in recurrence-free or OS (compared to pelvic radiotherapy)¹. The “sandwich” approach has not been included in any of the phase 3 trials and data supporting this regimen is based on a small phase 2 study and retrospective studies. While it appears to be well tolerated, some of the concerns include questions surrounding the...

Chemotherapy followed by local RT.