Randomised Phase Ill Trial of molecular profile-based versus standard recommendations for adjuvant radiotherapy for women with early stage endometrial cancer: PORTEC-4a

Endometrial cancer (EC) is the most common gynaecological cancer. Surgery
(hysterectomy and oophorectomy) is the primary treatment. Previous randomized
trials including the Dutch PORTEC-1 trial have shown that postoperative
radiation therapy (RT) significantly reduces the risk of vaginal and pelvic
recurrence, but without difference in overall survival. Most (75%) recurrences
occur locally in the vaginal vault, and can effectively be treated with RT at
the time of recurrence. The indication for RT has since been 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 fewer side effects and better quality of life than external
beam RT. However, standard vaginal brachytherapy for all patients with risk
factors is still significant overtreatment, as 85% of women will not have local
recurrence. In a patient preference study it has been shown that women strongly
prefer a treatment to avoid recurrence over a watchful waiting policy,
especially when this involves a short treatment with few side effects. More
precise individual risk prediction could avoid both over- and undertreatment.
In recent years molecular-genetic characterisation of endometrial cancer has
been done in The Cancer Genome Atlas project, and four prognostic groups have
been defined which have been confirmed and validated in analysis of tissue
samples of the PORTEC-1 and -2 trial cohorts on paraffin embedded tissue. With
additional validated risk factors an integrated molecular profile has been
developed with which an individual risk assessment (favourable, intermediate,
unfavourable) can be given to patients previously all included in the group
with early stage endometrial carcinoma with classic high-intermediate risk
features. .

To determine if individual tailored treatment recommendation based on the
integrated molecular risk profile will (strongly) reduce the number of women
that will unnecessarily receive vaginal brachytherapy, with comparable local
control and recurrence-free survival compared to standard treatment, to reduce
overtreatment with related symptoms; retain best quality of life and save
health care costs.

Randomised multicenter phase Ill trial in which 550 patients with endometrioid
type EC with risk features will be randomised (1:2) to vaginal brachytherapy
(standard arm) or to molecular profile-based treatment recommendations for
observation (favourable group, about 55%), vaginal brachytherapy (intermediate
group, 40%) or E8RT (unfavorable group, 5%), the experimental arm.
Primary study endpoint is vaginal relapse. Secondary objectives are adverse
events and quality of life; recurrence-free and overall survival;
pelvic and distant recurrence; 5-year vaginal control (including treatment for
relapse if applicable); and EC-related health care costs.
The first 50 patients will be included in a pilot phase to confirm the
logistics and patient acceptance of the molecular profile; if positive this
trial will continue to a total of 550 evaluable patients (including 22 patients
already included in the previous PORTEC4 design).

Patients in the standard arm will be treated with vaginal brachytherapy (21 Gy
HDR in 3 fractions of 7 Gy each, specified at 5 mm from the applicator surface
and top, within overall time of 2 weeks).
Patients in the experimental arm will, based on the integrated molecular
profile, be either observed after surgery (55%), or will receive vaginal
brachytherapy as above (40%). The 5% who will be recommended pelvic external
beam radiotherapy will received a dose of 45-48.6 Gy in 1.8-2 Gy fractions
according to the centre's policy and technique.

Burden and risks of the study:
- potential distress and/of feelings of doubt and insecurity during the
decision making process;
- in the standard treatment group: psychological and practical burden 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
- in the experimental treatment group: psychological burden of the results of
the molecular profile: 'favourable', 'intermediate', or 'unfavourable'. In the
'favourable' group (about 55%) on the one hand reassurance of 'favourable'
profile, but on the other hand psychological distress and/or anxiety of no
treatment and feeling of 'waiting', even if the risk of recurrence is very low.
In the 'intermediate' group (about 40%) the situation and burden are the same
as for the standard arm described above. In the 'unfavourable' group (about 5%)
the psychological burden of 'unfavourable' results, and the burden of external
beam radiation treatments daily (working days) for 5 weeks with more side
effects such as bowel frequency, cramps and diarrhea and also bladder frequency
and fatigue which will continue for at least 1-2 weeks after completion of
therapy.
- no extra risks as to survival as this will be similar in both groups; aim is
reduction of overtreatment with similar overall outcomes
- low (3-5%) risk of result of possible lynch syndrome in both groups, with
referral to a clinical geneticist for information and analysis, with related
distress but potential advantages of adequate information and screening ..
- 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 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.