PORTEC-4: Randomised trial investigating the role and optimal dose of vaginal brachytherapy for endometrial cancer.

Background:

Endometrial cancer (EC) is the most common gynaecological cancer. Surgery (hysterectomy and oophorectomy) is the primary treatment. Previous randomized trials, among which the PORTEC-1 trial, have shown that postoperative radiation therapy (RT) significantly reduces the risk of vaginal and pelvic recurrence from 14 to 4%, but without difference in overall survival. Most (75%) local recurrences are located in the proximal vagina, and can effectively be treated with RT at the time of recurrence. After completion of the PORTEC-1 trial, the indication for RT has become limited to patients with risk factors. The PORTEC-2 trial has shown that for these patients, vaginal brachytherapy alone is highly effective in preventing vaginal recurrence, with less side effects and better quality of life than external beam pelvic radiotherapy. However, treating all patients with risk factors with brachytherapy is still significant overtreatment. If a watchful waiting policy would be adopted, with prompt treatment in case of vaginal relapse, the eventual local control (including treatment for relapse) might be very similar to the local control after adjuvant brachytherapy. A range of published brachytherapy dose schedules has equal efficacy, and the rate of vaginal atrophy changes in PORTEC-2 suggests that the standard dose schedule of 21 Gy in 3 fractions of 7 Gy could be compared to a lower dose schedule.



Objectives and Design:

In this multicenter trial, patients with endometrioid type endometrial adenocarcinoma with high-intermediate risk features were randomised (2:1) to vaginal brachytherapy (standard arm) and observation (experimental arm). Patients in the vaginal brachytherapy arm were 1:1 randomized to brachytherapy dose 21 Gy HDR in 3 fractions of 7 Gy each (standard dose) and brachytherapy dose 15 Gy HDR at 5 mm depth, in 3 fractions of 5 Gy (lower dose).

However, the study was stopped in this design from 20 September 2015 onwards, and continued after a major design change in June 2016 as PORTEC-4a with a new design, with new METC number and approval - see the PORTEC-4a trial record NL5602 (NTR5841)

Although vaginal brachytherapy reduces vaginal recurrence compared to observation after surgery for endometrial cancers with high-intermediate risk features, ultimate 5-year vaginal control including treatment for relapse will be similar, and a lower dose of vaginal brachytherapy (15 Gy vs 21 Gy in 3 fractions) has similar efficiacy with reduced vaginal side effects.

5-year rates of recurrence, vaginal control, survival, quality of life, vaginal toxicity.

Evaluation at 6-months invervals.

Patients are randomised (2:1) to receive vaginal brachytherapy (standard arm), or observation after surgery (experimental arm); patients in the vaginal brachytherapy group are randomized 1:1 to standard dose (21 Gy in 3 Gy fractions), or reduced dose (15 Gy in 3 fractions).