To investigate a potential toxicity benefit of preoperative radiation therapy with protons compared to conventional photon beam radiation therapy in patients with locally advanced rectal cancer.
Biopsy-proven, newly diagnosed primary rectal adenocarcinoma, i.e. with the lowest part of the tumour less than 16 cm from the anal verge detected using a rigid rectoscope.
Clinical stage (c) T4b, i.e. infiltration of an adjacent organ or structure like the prostate, urinary bladder, uterus, sacrum, pelvic floor or side-wall (according to TNM version 8).
cT4a, i.e. peritoneal involvement.
Extramural vascular invasion (EMVI+).
Extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is seen.
Presence of metastatic disease or recurrent rectal tumour. Familial Adenomatosis Polyposis coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn's disease or active ulcerative Colitis.
Concomitant malignancies, except for adequately treated basocellular carcinoma of the skin or in situ carcinoma of the cervix uteri. Subjects with prior malignancies must be disease-free for at least 5 years.
Known DPD deficiency.
Parallel
Radiation therapy
Radiation5 x 5 Gy external radiation therapy
Incidence of acute grade 2-5 gastrointestinal toxicity
The incidence of acute preoperative grade 2-5 gastrointestinal toxicity according to CTCAE v5.0 associated with proton vs. photon radiotherapy
Incidence of grade >2 hematologic and non-hematologic toxicity
The incidence of grade \>2 hematologic (blood count, febrile neutropenia) and non-hematologic toxicity (general, genitourinary, gastrointestinal, skin) associated with protocol treatment, assessed by CTCAE v5.0 in the preoperative period, the postoperative period, and overall. Patient reported side-effects will be assessed by European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire, the QLQ-C30, version 3. The QLQ-C30 will be supplemented with the disease specific module (rectal-cancer) QLQ-CR29. During radiotherapy, daily reported symptoms will be investigated by a newly developed symptom scale, Radiotherapy related symptom assessment scale (RSAS). The questionnaire includes 13 items specific for current diagnose. The RSAS is a validated instrument for assessing symptom intensity and distress in patients with different cancer disease undergoing radiotherapy, with psychometric properties within the expected range.
Differences in patient reported outcomes (PRO)
Differences in patient reported outcomes (PRO) between treatment arms in the preoperative period, the postoperative period, and overall
Proportion of patients being able to undergo full dose neoadjuvant chemotherapy
Differences between treatment arms in proportion of patients being able to undergo full dose neoadjuvant chemotherapy i.e. at least 4 cycles of CAPOX or 6 cycles of FOLFOX
Tumour regression grading (mrTRG)
Radiological assessment and comparison of tumour regression grading (mrTRG) between treatment arms
Disease free survival
Disease free survival after proton vs. photon treatment
Overall survival
Overall survival after proton vs. photon treatment
Quality of Life (QLQ-C30)
Quality of life after proton vs. photon treatment (QLQ-C30)
Difference in postoperative complications
Difference in postoperative complications between study arms measured by LARS score
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Alexander Valdman
Lead sponsor
Karolinska University Hospital
Sponsor institution
