Organ preservation in patients with a good clinical response after neoadjuvant (chemo)radiation for rectal cancer: optimization of treatment strategies and defining the role of additional contact x-ray brachytherapy versus extending the waiting interval and local excision.

The organ preservation approach for rectal cancer has been explored
increasingly, aiming at improving quality of life by prevention of total
mesorectal excision (TME-surgery). In patients with intermediate rectal cancer
(IRC) and locally advanced rectal cancer (LARC) who receive neoadjuvant
(chemo)radiotherapy (in general a short-course radiotherapy or a long-course
chemoradiation, respectively) subsequent TME-surgery is still standard of care.
In patients with a good clinical response after neoadjuvant (chemo)radiation,
organ preservation may be considered, depending on the extent of the response
monitored by radiological and endoscopic assessment. Some patients show a
clinical complete response and can be monitored closely in a watch-and-wait
approach. In case of a good, but not complete response, it remains unclear
which patients may benefit from extension of the observation period after
(chemo)radiation in order to achieve a complete clinical response over time, or
in whom additional local treatment options (such as contact x-ray brachytherapy
or local excision) are beneficial in obtaining organ preservation eventually.

The aim of this study is to investigate which rate of organ preservation can be
achieved in patients with rectal cancer treated with neoadjuvant
(chemo)radiotherapy with a good clinical response, and to optimize the
different treatment strategies (Figure 1). In patients with a near-complete
response or with a small residual tumour mass, participation is offered in a
phase II feasibility trial, in which two potential organ preservation treatment
strategies are evaluated: contact x-ray brachytherapy or extension of the
waiting interval with or without additional local excision in case of residual
disease.

This is a prospective study with a mixed design. It concerns a phase II
feasibility study for patients in whom a good, but not complete response has
been achieved after (chemo)radiation (OPAXX study): two parallel single
study-arms evaluate the efficacy of experimental organ preservation approaches.
To allow for a better comparison of secondary parameters (toxicity and
morbidity of both additional local treatments) eligible patients will be
randomized between two experimental arms. Furthermore, an observational cohort
study is established to register rectal cancer patients with a good but not
complete clinical response after (chemo)radiation who are not eligible for
randomisation in the OPAXX study (OPAXX registration study).

Arm 1: Contact x-ray brachytherapy will be given applied after randomisation
with a maximum interval of 14 weeks after finishing the neoadjuvant
(chemo)radiation. Contact x-ray brachytherapy consists of three fractions of
30Gy per fraction applied to the tumour, with a 2 week interval between each
boost. Response evaluation takes place every 3 months thereafter. Patients in
whom a clinical complete response is detected during follow-up are offered a
watch-and-wait approach; patients in whom an incomplete response or disease
progression is noted, completion or salvage TME-surgery is advised.
Arm 2: The waiting interval will be extended with 6-8 more weeks after the
first response evaluation, followed by a second (or third in case of ongoing
response) re-assessment. Patients with a clinical complete response at the time
of the second (or third) response evaluation will be offered a watch-and-wait
approach without any surgical treatment. Patients with a remaining small lesion
will be offered transanal local excision. Depending on the final pathological
staging after local excision, patients are categorized as low-risk or
high-risk, and will be offered a watch-and-wait strategy or completion
TME-surgery, respectively.

Standard treatment of IRC and LAR consists of neoadjuvant short-course or
long-course (chemo)radiotherapy followed by TME-surgery. If a clinical complete
response is seen at response evaluation, a watch-and-wait approach is currently
considered a valid strategy in selected patients according to the Dutch
national guidelines. In the ongoing Dutch national prospective registry
patients with a near-complete response are currently offered an extension of
the observation period rather than TME-surgery, and, subsequently, a
watch-and-wait policy when a clinical complete response is noted over time. On
the other hand, all patients with a persistent residual lesion will proceed to
TME-surgery.
In the current study, two experimental approaches are introduced that could
increase organ preservation rates in patients with a good, but not-complete
response at the first response evaluation: additional endoluminal contact x-ray
brachytherapy and local excision of the tumour remnant.
Prior to randomisation, eligible patients are well informed about the risks of
the two experimental treatment strategies (i.e. unclear long-term oncological
outcome), and are offered standard-of-care TME-surgery. Moreover, patients will
be informed that additional treatment with contact x-ray brachytherapy or local
excision might increase the morbidity rates in case completion or salvage
TME-surgery is required.
Finally, in both arms of this phase II study an intensive surveillance program
has been established, in order to detect treatment failure, tumour regrowth or
disease recurrence at an early stage, in order to proceed to completion or
salvage TME-surgery when needed and when possible.