PORTEC-4: Randomised Phase III Trial Comparing Vaginal Brachytherapy (two doses schedules: 21 or 15 Gy HDR in 3 fractions) and Observation after Surgery in patients with Endometrial Carcinoma with High-Intermediate Risk Features

Endometrial cancer 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 radiation therapy (external beam radiation followed by brachytherapy) at
the time of recurrence. After completion of the PORTEC-1 trial, the indication
for RT has become limited to patients with high-intermediate risk factors. The
PORTEC-2 trial has shown that for these patients, vaginal brachytherapy alone
is highly effective in preventing vaginal recurrence, with fewer side effects
and better quality of life than external beam pelvic radiotherapy. Patients
treated with vaginal brachytherapy had higher rates of vaginal atrophy
(recorded at pelvic examination), although without measurable effects on
general or sexual quality of life of functioning. 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.

The primary objective of this study is to establish and compare the rates of
vaginal relapse in patients with high-intermediate risk endometrial carcinoma
treated with vaginal brachytherapy (standard versus reduced brachytherapy dose
schedule of 21 vs 15 Gy HDR in 3 fractions, respectively), versus no additional
treatment after surgery. Second primary objective is to establish overall
vaginal control, including salvage treatment for patients with vaginal relapse,
at 5 years.
Secondary objectives are to establish and compare the rates of pelvic nodal
recurrence; overall and failure-free survival; vaginal toxicity; and quality of
life. The objective of the brachytherapy dose comparison is to estimate the
differences in vaginal relapse, toxicity and quality of life (with emphasis on
sexual symptoms and functioning) between the two dose levels with sufficient
precision.

In this prospective multicenter randomized Phase III trial, 500 patients with
endometrioid type endometrial adenocarcinoma with high-intermediate risk
features will be randomised in 2:1 distribution to one of the following arms:
1. vaginal brachytherapy (standard arm), 1:1 randomized to
a. brachytherapy dose 21 Gy HDR in 3 fractions of 7 Gy each (standard dose)
b. brachytherapy dose 15 Gy HDR at 5 mm depth, in 3 fractions of 5 Gy
(reduced dose).
2. observation (experimental arm).

Stratification will be done for:
1. participating centre
2. grade (1 vs 2 vs 3)
3. type of surgery (laparoscopic vs abdominal hysterectomy; lymphadenectomy
yes/no)

Patients will be followed closely and prospectively evaluated for outcome
(vaginal control; local, pelvic or distant recurrence, survival) after primary
treatment (and, if applicable, after treatment for recurrence), for vaginal
changes, atrophy and symptoms, and general and site-specific quality of life.

Postoperative vaginal brachytherapy, dose 21 Gy in 3 fractions of 7 Gy each,
using high-dose-rate (HDR) equipment in outpatient setting, within 2 weeks
(standard treatment)
Postoperative vaginal brachytherapy, dose 15 Gy in 3 fractions of 5 Gy each,
using high-dose-rate (HDR) equipment in outpatient setting, within 2 weeks
(vaginal brachytherapy - reduced dose)
No further treatment, close follow-up, and prompt treatment in case of
recurrence (experimental arm, no further treatment)

Burden and risks of the study:
- potential distress and/of feelings of doubt and insecurity during the
decision making process;
- psychological distress and/or anxiety of no treatment and during the
'watchful waiting' period for the patients randomized to no furhter treatment
- psychological and practical burnden of 3 hospital visits for vaginal
brachytherapy (outpatient procedure, duration of 1 hour at 1st session, and
0.5-1 hr at 2nd and 3rd session) - this is the standard treatment and is also
applicable outside the scope of this trial
- completing quality of life questionnaires - these are standard validated
EORTC questionnaires (QLQ C-30 core questionnaire and EN24 module specific for
endometrial cancer), with 2 additional questions regarding sexual activity
(partner yes/no and if not active, reason). Duration of completing the
questionnaires: 10-15 min. Our experience with similar questionnaires in
previous PORTEC-trials shows that patients gererally feel positive about
quality of life questionnaires, which shows that their feedback is valued and
may influence future treatments, and that the response rates are high, also at
long term (70-80%)
The questionnaires before and after treatment are distributed by their own
doctor or research nurse, and IF the patient gives separate consent and submits
an address form, the questionnaires are sent directly to their home address at
6, 12, 24, 36 and 60 months and after 7 and 10 years. With each questionnaire
an accompanying letter is sent stating that the patient is free to decide not
to complete the questionnaire, and in that case is asked to sent back the blank
questionnaire in order to stop further sending. The database with address forms
is kept SEPARATELY from the general trial base and documents, and is managed by
a datacenter secretarial employee who does not have any other relation to the
trial.
- hospital visits to the radiation oncologist and gynaecologist, and procedures
and tests such as general and pelvic examination are identical to those for
patients who do not participate in the trial, with the only exception that
during standard pelvic examination, vaginal length and width are measured using
standard smooth perspex cilinders, at baseline and once annually thereafter, up
to a maximum of 5 years.