Preoperative Short-Course Radiation Therapy With PROtons Compared to Photons In High-Risk RECTal Cancer (PRORECT)

Official title

Preoperative Short-Course Radiation Therapy With PROtons Compared to Photons In High-Risk RECTal Cancer (PRORECT): A Prospective Randomized Swedish Phase II Trial

Overview

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.

Detailed description

The aim of this study is to investigate whether proton beam radiotherapy in locally advanced rectal cancer can offer meaningful reductions in acute gastrointestinal toxicity compared to standard treatment with photons which may improve patient's tolerability of neoadjuvant chemotherapy.

There are currently no published clinical reports evaluating the use of proton therapy in the upfront treatment of locally advanced rectal cancer. There are further no published randomized trials comparing radiotherapy with photon vs proton in locally advanced rectal cancer.

This is a prospective randomized trial, initially run at the limited number of centres but later expanded to other centres participating in the Skandion network. Patients will be treated with short course 5 x 5 Gy radiation scheme with either photons (standard arm) or protons (Skandion clinic) followed by four to six cycles of combination chemotherapy (capecitabine and oxaliplatin) and surgery. The rectal tumour will be removed by TME/PME surgery or more extensive surgery if required because of tumour extent.

All patients will receive at least 4 courses of CAPOX (Capecitabine b.i.d.1000 mg/m2 day 1-14 every 3 weeks, Oxaliplatin 130 mg/m2 day 1 every 3 weeks) week 3-14, followed by surgery at week 17-20.

Interventions

• Radiation Radiation therapy
  5 x 5 Gy external radiation therapy

Primary outcome measures

• Incidence of acute grade 2-5 gastrointestinal toxicity [Time frame: From start of radiotherapy to planned start of the third (3) CAPOX cycle (week 9-10 of the trial)]

Secondary outcome measures (5)

• Incidence of grade >2 hematologic and non-hematologic toxicity [Time frame: Baseline up to five years after treatment]
• Differences in patient reported outcomes (PRO) [Time frame: Baseline, Day 1-5, 2 and 3 weeks, 3, 6, 9, 12, 24, 36 and 60 months]
• Proportion of patients being able to undergo full dose neoadjuvant chemotherapy [Time frame: From week 3 until week 20 of the trial]
• Tumour regression grading (mrTRG) [Time frame: Baseline to response evaluation week 16-17 of the trial]
• Cost effectiveness analysis measured by QALY [Time frame: Time from randomization up to 5 years]

Eligibility criteria

Inclusion criteria

Inclusion Criteria - Primary tumour characteristics

• 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.
• Locally advanced tumour fulfilling at least one of the following criteria on pelvic MRI indicating high risk of failing locally and/or systemically:

• 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+).
• N2-status regarded as metastatic according to ESGAR consensus criteria
• Positive MRF, i.e. tumor or lymph node one mm or less from the mesorectal fascia.
• Metastatic lateral nodes (lat LN+) according to ESGAR consensus criteria

Inclusion Criteria - General

• Staging done within 6 weeks before start of radiotherapy. No contraindications to chemotherapy with CAPOX including adequate blood counts, (within 5 weeks prior to randomisation):

• white blood count ≥4.0 x 10\*9/L
• platelet count ≥100 x 10\*9/L
• clinically acceptable haemoglobin levels
• creatinine levels indicating renal clearance of ≥50 ml/min
• bilirubin ˂35 µmol/l.
• ECOG performance score ≤1
• Patient is considered to be mentally and physically fit for chemotherapy with CAPOX as judged by the oncologist.
• Age ≥18 years
• Written informed consent.
• Adequate potential for follow-up.

Exclusion criteria

• 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.
• Any contraindications to MRI (e.g. patients with pacemakers).
• Medical or psychiatric conditions that compromise the patient's ability to give informed consent.
• Concurrent uncontrolled medical conditions.
• Any investigational treatment for rectal cancer within the past month.
• Pregnancy or breast feeding.
• Patients with known malabsorption syndromes or a lack of physical integrity of the upper gastrointestinal tract.
• Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac dysrhythmia, e.g. atrial fibrillation, even if controlled with medication) or myocardial infarction within the past 12 months.
• Patients with symptoms of peripheral neuropathy.
• Patients with pacemaker or ICD
• Patients with bilateral hip protheses

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Sweden · 9 centers

• Karolinska University Hospital, Theme Cancer, Dept of Pelvic cancer — Stockholm
• Gävle Hospital — Gävle
• Sahlgrenska University Hospital — Gothenburg
• Linköping University Hospital — Linköping
• Skåne University Hospital — Lund
• Stockholm South General Hospital — Stockholm
• Sundsvall Hospital — Sundsvall
• University Hospital of Umeå — Umeå
• … and 1 more center

Publications

• Pedone C, Sorcini B, Staff C, Farlin J, Fokstuen T, Frodin JE, Nilsson PJ, Martling A, Valdman A. Preoperative short-course radiation therapy with PROtons compared to photons in high-risk RECTal cancer (PRORECT): Initial dosimetric experience. Clin Transl Radiat Oncol. 2022 Dec 17;39:100562. doi: 10.1016/j.ctro.2022.100562. eCollection 2023 Mar. PMID 36582423

Identifiers

NCT: NCT04525989 · PRORECT

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗