Macroscopic and microscopic changes of a locally advanced rectal tumour during radiotherapy: assessment using anatomical, functional and cinematic MRI.

The standard of care for locally advanced rectal cancer (LARC) is 5 weeks
neo-adjuvant radiochemotherapy (RCT) followed by radical surgery 6-8 weeks
afterwards. Surgery is performed independent the response to RCT and is
attended with substantial morbidity such as the need for colostomy, faecal
incontinence, urinary incontinence, perineal pain and impaired bowel function
or sexuality.
A pathological complete response (pCR) rate ranging from 12-24 % is reported
after neo-adjuvant irradiation combined with capecitabine chemotherapy. This
response rate is dose dependent. The higher the delivered radiotherapy dose the
better the tumour response. Dose escalation therefore is attractive but
unfortunately limited because of toxicity due to irradiation of surrounding
healthy tissues.
Two dose escalation strategies are possible, sequential boost after completion
of elective field irradiation and boost dose delivery during irradiation of the
elective field. Safe dose escalation is only achievable when there are little
to no healthy tissues in the boost field but still assurance of full tumour
coverage. For boost field delivery during radiotherapy adaptation of the boost
field is needed to tumour shrinkage and tumour movement during therapy. For
sequential boost delivery adaptation is needed to tumour shrinkage and movement
during the week after RCT.
Development of a safe dose escalation strategy and so optimizing tumour
response is correlated with clinical outcome and could also be important in
medical decision making. A few retrospective studies compared clinical outcomes
in patients with clinical complete response (cCR) without surgery to clinical
outcomes in operated patients with pCR to RCT. The similar outcomes found in
these studies indicate the possibility to perform RCT as sole treatment in
patients with a good response. This approach is of obvious interest, but
unfortunately remains controversial because of the known dissociation between
clinically and pathologically assessed response.
To discriminate patients with a good response from patients with a poor
response to RCT, a reliable tool is needed. Anatomical MRI, which is an
accurate imaging modality for staging of LARC, has a low accuracy after RCT
because of improper discrimination between fibrosis and vital tumour.
Functional MRI imaging shows promising results in tissue discrimination because
it reflects tissue function and microanatomy, therefore it could be a more
reliable option for pathological response prediction.
With the combination of both tumour shrinkage and movement information during
therapy and reliable tumour pathological response prediction methods a first
step is made to safe dose escalation which leads to better response to RCT and
the possibility of personalised multimodality treatment in the heterogenic
group of LARC.

The purpose of this pilot study is twofold:
- evaluation of the tumour movement and regression during and short after long
course pre-operative therapy for locally advanced rectal cancer in order to
develop an integrated or sequential dose escalation strategy for rectal cancer;
- examination of feasibility to use repeated functional MRI imaging during
pre-operative treatment to predict pathological response after surgery.
With the combination of this knowledge a first step is made to safe dose
escalation which results in better response and the possibility of personalised
multimodality treatment in the heterogenic group of locally advanced rectal
tumours.

Prospective pilot study with weekly MRI during long course pre-operative RCT
and one MRI during the second week after RCT for LARC. The MRI protocol
consists of anatomical and cinematic MRI for assessment of movement
characteristics and tumour shrinkage and functional MRI for tumour response
assessment. The clinical tumour response will be correlated with pathological
tumour regression grade.

For study purposes patients will undergo six extra MRI scans. After proper
screening the use of MRI is free of any risks. Five scans will be scheduled in
combination with radiation treatment and one scan will be scheduled in the
second week after RCT. For this last scan patients will receive reimbursement
of travelling expenses.