RandomizEd Controlled Trial for pre-operAtive dose-escaLation BOOST in locally advanced rectal cancer.

The current treatment for locally advanced rectal cancer consists of
pre-operative chemoradiation treatment (CRT) (50 Gy in 25 fractions) followed
by surgical resection. After this neo-adjuvant treatment approximately 15% of
patients show pathological complete response (pCR), i.e. no residual tumor in
the resected specimen on pathologic examination. Patients with pCR have a lower
risk of local and distant recurrences and significantly longer disease-free
and overall survival. Furthermore, in these patients surgery could possibly
have been omitted. Selected patients with a clinical complete response (cCR),
defined prior to surgery by rectoscopy, rectal examination and MRI, may opt for
an organ-preserving therapy, a so called wait and see approach.
Response to chemoradiation occurs in a dose dependent fashion. Therefore,
recent trials aimed to improve prognosis by radiation dose-escalation that
resulted in improved pCR rates. Toxicity rates associated with radiation doses
above 60 Gy are manageable and differ between studies; from increased to
comparable or even lower toxicity. Moreover, dose escalation may increase the
proportion of patients eligible for organ-preserving therapy.

We study whether addition of a radiation boost to standard chemoradiation in
patients with locally advanced rectal cancer increases the complete response
rate defined as pathological complete response in those who undergo surgery, or
2-years local recurrence-free survival (2y-LRFS), in those who opted for a wait
and see approach. Secondary objectives are adverse events due to chemoradiation
(acute, perioperative and late toxicity), tumor response assessed with MRI, the
impact of the boost on local and distant recurrence and survival as well as
patient-reported quality of life and workability.

Multicenter Randomized Controlled Trial, nested within a prospective cohort
according to the *cohort multiple randomized controlled trial* (cmRCT) design.

An irradiation boost of 15 Gy delivered to the gross tumor volume (GTV) in 5
fractions in addition to the standard chemoradiation treatment of 50 Gy.
Thereby increasing the total GTV dose to 65 Gy.

The study will be conducted according to the cohort multiple Randomized
Controlled Trial (cmRCT) design. Within our cohort (PLCRC Project), we will
identify all patients who are eligible for inclusion in the current study and
who have given informed consent to be invited for future experimental
interventions. From this subcohort, we offer the boost to a randomly selected
group of sixty patients. Randomly selected patients who refuse to undergo the
additional boost, will receive standard treatment. Eligible patients who were
not randomly selected will undergo standard treatment without further
notification.
Patients who accept the experimental intervention will receive an additional
five radiation fractions of a total of 15 Gy on the tumor (GTV) in addition to
the standard treatment. This requires five additional hospital visits. Patients
who participate in the intervention or control group are temporarily excluded
from other studies within the PLCRC project that use the same endpoint, of
which they are informed in the (initial PLCRC) patient-information letter.
Risks for patients in the intervention arm include higher toxicity, which,
based on previous studies, is rather unlikely. Benefits for patients in the
intervention arm may include higher probability of complete tumor response and
reduced risk of recurrent disease.
Patients in the experimental arm who receive chemoradiation in the UMC Utrecht
will undergo one additional MRI to assess tumor response, which will take place
during one of the standard radiotherapy visits. Patients in the experimental
arm who receive treatment in the MAASTRO clinic will undergo a PET-CT for
treatment planning. Both imaging procedures include minimal risks.
Since these patients are participants in the PLCRC cohort, and have also
already given informed consent to fill out questionnaires on Patient Reported
Outcomes, this is not an additional burden to the patient.