Clinical trial NCT04525989: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Rectal Cancer
Keywords: Proton therapy
Preoperative radiation
Short-course
Primary adenocarcinoma
Lead sponsor: Karolinska University Hospital
Sponsor class: OTHER
First posted: 2020-08-25
Enrollment: 254
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective randomized
Primary purpose: TREATMENT

Brief summary: 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.

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

Primary outcomes:
measure: Incidence of acute grade 2-5 gastrointestinal toxicity
timeFrame: From start of radiotherapy to planned start of the third (3) CAPOX cycle (week 9-10 of the trial)
Secondary outcomes:
measure: Incidence of grade >2 hematologic and non-hematologic toxicity
timeFrame: Baseline up to five years after treatment
measure: Differences in patient reported outcomes (PRO)
timeFrame: Baseline, Day 1-5, 2 and 3 weeks, 3, 6, 9, 12, 24, 36 and 60 months
measure: Proportion of patients being able to undergo full dose neoadjuvant chemotherapy
timeFrame: From week 3 until week 20 of the trial
measure: Tumour regression grading (mrTRG)
timeFrame: Baseline to response evaluation week 16-17 of the trial
measure: Cost effectiveness analysis measured by QALY
timeFrame: Time from randomization up to 5 years
Other outcomes:
measure: Disease free survival
timeFrame: Time from randomization until first recurrence, local/regional/systemic or death
measure: Overall survival
timeFrame: Time from randomization until death
measure: Quality of Life (QLQ-C30)
timeFrame: Baseline, 3 weeks, 3, 6, 9, 12, 24, 36 and 60 months
measure: Difference in postoperative complications
timeFrame: From week 17-20 of the trial up to 5 years
measure: Clinical complete remission (cCR)
timeFrame: From start of treatment up to 1 year
measure: Incidence of acute lumbar plexus neuralgia
timeFrame: From baseline until week 4 of the trial
measure: Exploratory: Concentrations of CD8+ and FOXP3 + tumour-infiltrating T cells
timeFrame: Postoperative pathology from week 17 until week 24 of the trial
measure: Exploratory: Difference in concentrations of CEA (carcinoembryonic antigen) between treatment arms
timeFrame: CEA measurements at baseline, week 3, 6, 9 and 12 of the trial
Locations:
city: Stockholm
country: Sweden
facility: Karolinska University Hospital, Theme Cancer, Dept of Pelvic cancer
state: Solna
Study officials:
affiliation: Department of Radiotherapy, Karolinska University Hospital, Stockholm, Sweden
name: Alexander Valdman, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: