The goal of this clinical trial is to evaluate the efficacy of deep regional hyperthermia in the context of radiochemotherapy followed by consolidation chemotherapy in locally advanced rectal cancer.

Questions it aims to answer are:

• Can surgery be avoided if the tumor completely regresses?
• How high is the Local re-growth rate
• Is the treatment safe?
• Assessment of the Quality of life
• Rate of sphincter-sparing surgery
• Pathological staging, tumor downstaging
• Assessment of continence during the course of therapy

Participants will:

Undergo radiochemotherapy with or without addition of hyperthermia (50:50 randomisation) followed by standard consolidation chemotherapy. After treatment response evaluation surgery or non-operative management takes place.

In this prospective, randomized phase III trial "Radiochemotherapy with concomitant deep regional hyperthermia in locally advanced rectal cancer" trial it is hypothesized that with the addition of hyperthermia complete response rates can be further increased resulting in a higher number of patients who can omit surgery in favor of organ preservation and a surveillance protocol. Patients receive radiochemotherapy with 5-FU or capecitabine followed by standard consolidation chemotherapy with 5-FU/folinic acid/oxaliplatin or CAPOX. Hyperthermia will take place based on a 1:1 randomisation. After evaluation of treatment response in week 22 patients will either undergo surgical resection in case of residual tumor or non-operative management when a clinical complete response is seen or repeat evaluation after another 3 months in case of a near clinical complete response. In selected cases endoscopic procedures can be considered as an alternative to radical surgery.The primary objective of the study is to evaluate the efficacy of deep regional hyperthermia in the context of radiochemotherapy followed by consolidation chemotherapy in locally advanced rectal cancer. As the primary endpoint TME-free survival will be used (TMEFS).

Inclusion Criteria:

• Male and female patients with histologically confirmed diagnosis of rectal cancer localized 0-12 cm from the anocutaneous line (i.e. lower and middle third of the rectum)

• Indication for total neoadjuvant therapy irrespective of participation in the current study.

• Any MRI staged rectal cancer with one of the following high-risk features:

  • cT4
  • cN2 (see Appendix)
  • Distance to mesorectal fascia 1mm or less.
  • Involved Lateral pelvic lymph nodes
  • EMVI (extramural venous invasion) positivity

• Staging requirements: High-resolution, thin-sliced (i.e. 3mm) magnetic resonance imaging (MRI) of the pelvis is the mandatory local staging procedure.

• Cross-sectional imaging of the abdomen and chest to exclude distant metastases.

• Aged at least 18 years. No upper age limit.

• WHO/ECOG Performance Status ≤ 1

• Adequate hematological, hepatic, renal and metabolic function parameters

• Informed consent of the patient

Exclusion Criteria:

• Lower border of the tumor localised more than 12 cm from the anocutaneous line as measured by rigid rectoscopy
• Tumors with microsatellite instability ("MSI-High Tumors") and the possibility for treatment with immune checkpoint inhibition.
• Contraindication for hyperthermia such as metal implants or pacemakers
• Distant metastases (to be excluded by CT scan of the thorax and abdomen)
• Preexisting fecal incontinence for solid stool
• Prior antineoplastic therapy for rectal cancer
• Prior radiotherapy of the pelvic region
• Major surgery within the last 4 weeks prior to inclusion
• Subject pregnant or breastfeeding, or planning to become pregnant within 6 months after the end of treatment
• Subject (male or female) is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for 6 months (male or female) after the end of treatment (adequate: oral contraceptives, intrauterine device or barrier method in conjunction with spermicidal jelly)
• Other concomitant antineoplastic therapy
• Serious concurrent diseases, including neurologic or psychiatric disorders (incl. dementia and uncontrolled seizures), active, uncontrolled infections, active, disseminated coagulation disorder
• Clinically significant cardiovascular disease (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 6 months before enrolment
• Prior or concurrent malignancy ≤ 3 years prior to enrolment in study (Exception: non-melanoma skin cancer or cervical carcinoma FIGO stage 0-1), if the patient is continuously disease-free
• Known allergic reactions on study medication
• Known dihydropyrimidine dehydrogenase deficiency
• Psychological, familial, sociological or geographical conditions potentially hampering compliance with the study protocol and follow-up schedule (these conditions should be discussed with the patient before registration in the trial)