Comparing preoperative and postoperative chemotherapy for rectal cancer

Preoperative FOLFOX Versus Postoperative Risk-adapted Chemotherapy in Patients With Locally Advanced Rectal Cancer and Low Risk for Local Failure: A Randomized Phase III Trial of the German Rectal Cancer Study Group

This study is testing whether giving chemotherapy before surgery is better than giving it after surgery for people with locally advanced rectal cancer who are at low risk for complications.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 550 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Universitätsmedizin Mannheim (Academic / other)
• Drugs / interventions: chemotherapy
• Locations: 1 site (Mannheim)
• Trial ID: NCT04495088 on ClinicalTrials.gov

What this trial studies

This multicenter, randomized trial evaluates the effectiveness of preoperative FOLFOX chemotherapy versus postoperative risk-adapted chemotherapy in patients with locally advanced rectal cancer who are at low risk for local failure. The study utilizes high-quality MRI for patient selection, aiming to identify those who may not require radiotherapy. Participants will receive three months of neoadjuvant chemotherapy, which is expected to enhance treatment efficacy by administering it earlier in the disease course. The trial seeks to improve outcomes by optimizing the sequence and timing of chemotherapy and surgery.

Who should consider this trial

Good fit: Ideal candidates include patients with histologically confirmed rectal adenocarcinoma localized within 0-16 cm from the anocutaneous line and classified as low risk for local failure based on MRI criteria.

Not a fit: Patients with high-risk features for local failure or those who do not meet the MRI-defined inclusion criteria may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could lead to improved survival rates and reduced recurrence in patients with locally advanced rectal cancer.

How similar studies have performed: Other studies have shown promise with similar neoadjuvant chemotherapy approaches, indicating potential for success in this trial.

Eligibility criteria

Inclusion Criteria:

1. Male and female patients with histologically confirmed diagnosis of rectal adenocarcinoma localised 0 - 16 cm from the anocutaneous line as measured by rigid rectoscopy (i.e. lower, middle and upper third of the rectum), depending on MRI-defined inclusion criteria (see below).
2. Staging requirements: High-resolution magnetic resonance imaging (MRI) of the pelvis is the mandatory local staging procedure.
3. Transrectal endoscopic ultrasound (EUS) is used to help discriminate between T1/2 and early T3 tumors.
4. MRI-defined inclusion criteria:

   i. Lower third (0-6 cm):
   * cT1/2 with clear cN+ based on defined MRI criteria or T3a-b (i.e. maximum infiltration into the perirectal fat of 5mm), provided CRM \> 2mm and EMVI-\*\* ii. Middle third (≥ 6-12 cm):
   * cT1/2 with clear cN+ provided CRM- and EMVI-\*\*
   * cT3 irrespective of the depth of invasion into the perirectal fat, provided no evidence that tumor is adjacent to (defined as within 2 mm of) the mesorectal fascia on MRI (i.e. CRM \> 2 mm), N0 or N1, EMVI-\*\* iii. Upper third (≥ 12-16 cm):
   * cT1/2 with clear cN+, irrespective of CRM and EMVI
   * any cT3-4 irrespective of nodal status, CRM and EMVI.
5. Spiral-CT of the abdomen and chest to exclude distant metastases.
6. Aged at least 18 years. No upper age limit.
7. WHO/ECOG Performance Status ≤1.
8. Adequate haematological, hepatic, renal and metabolic function parameters:
9. Leukocytes ≥ 3.000/mm³, ANC ≥ 2.000/mm³, platelets ≥ 100.000/mm³, Hb \> 9 g/dl
10. Serum creatinine ≤ 1.5 x upper limit of normal
11. Bilirubin ≤ 2.0 mg/dl, SGOT-SGPT, and AP ≤ 3 x upper limit of normal.
12. QTc interval (Bazett\*\*) ≤ 440 ms
13. Informed consent of the patient.

"\*\*" Formula for QTc interval calculation (Bazett): QTc= ((QT) ̅" (ms)" )/√(RR (sec))= ((QT) ̅" (ms)" )/√(60/(frequency (1/min)))

Exclusion Criteria:

1. Distant metastases (to be excluded by CT scan of the thorax and abdomen).
2. Prior antineoplastic therapy for rectal cancer.
3. Prior radiotherapy of the pelvic region.
4. Major surgery within the last 4 weeks prior to inclusion.
5. Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment.
6. Subject (male or female) is not willing to use highly effective\*\*\* methods of contraception during treatment and for 6 months (male or female) after the end of treatment Male patients treated with Oxaliplatin should take legal advice concerning sperm conservation before start of therapy and should additionally use a condom during treatment period. Their female partner of childbearing potential should also use an appropriate contraceptive measure.
7. On-treatment participation in a clinical study in the period 30 days prior to inclusion.
8. Previous or current drug abuse.
9. Other concomitant antineoplastic therapy.
10. Serious concurrent diseases, including neurologic or psychiatric disorders (incl. dementia and uncontrolled seizures), active, uncontrolled infections, active, disseminated coagulation disorder.
11. Clinically significant cardiovascular disease in (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 6 months before enrolment.
12. Chronic diarrhea (\> grade 1 according NCI CTCAE).
13. 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.
14. Known allergic reactions or hypersensitivity on study medication or to any of the other excipients.
15. Evidence of peripheral sensory neuropathy \> grade 1 according to CTCAE version 5.0 (see appendix).
16. Severe kidney dysfunction (creatinine clearance \< 30 ml/min).
17. Recent or concurrent treatment with brivudine.
18. Pernicious or other megaloblastic anaemia caused by vitamin B12 deficiency.
19. Known dihydropyrimidine dehydrogenase deficiency.
20. Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule (these conditions should be discussed with the patient before registration in the trial).

"\*\*\*"highly effective (i.e. failure rate of \<1% per year when used consistently and correctly) methods: intravaginal and transdermal combined (estrogen and progestogen containing) hormonal contraception; injectable and implantable progestogen-only hormonal contraception; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner; sexual abstinence (complete abstinence is defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments).

Where this trial is running

Mannheim

• Unversity Hospital Mannheim — Mannheim, Germany (Recruiting)

Study contacts

• Principal investigator: Ralf-Dieter Hofheinz, Prof. Dr. — Universitätsmedizin Mannheim
• Study coordinator: Ralf-Dieter Hofheinz, Prof. Dr.

Conditions Rectal Cancer