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

  • STATUS
    Recruiting
  • End date
    Aug 20, 2030
  • participants needed
    818
  • sponsor
    Ralf Hofheinz
Updated on 20 August 2022
oxaliplatin
capecitabine
folfox regimen
adenocarcinoma
xelox

Summary

This is a multicenter, prospective, randomized, stratified, controlled, open-label study comparing preoperative FOLFOX versus postoperative risk-adapted chemotherapy in patients with locally advanced rectal cancer and low risk for local failure

Description

Patients with locally advanced rectal cancer are generally treated with preoperative 5-FU- or capecitabine-based chemo-radiotherapy (CRT) and total mesorectal excision (TME) surgery in order to decrease the rate of local failure. In patients with low risk for local failure in the middle third of the rectum (cT3a/b, N-) as determined with quality controlled MRI, the German S3 guidelines and the ESMO clinical practice guidelines state that neoadjuvant radiotherapy may be omitted. However, distant failure rate is still substantial in the range of 20-25% in these patients highlighting the need for more effective systemic treatment.

The hereby proposed ACO/ARO/AIO-18.2 randomized trial incorporates three novel aspects: (1) patient selection relies on strict and quality controlled MRI features and therefore identifies a cohort without imminent need for radiotherapy, (2) the sequence of chemotherapy and surgery is changed in a way that chemotherapy is administered preoperatively to increase the rate of patients treated with chemotherapy, and (3) three months of neoadjuvant FOLFOX or XELOX (instead of up to 6 months adjuvant chemotherapy) are used as a sole perioperative treatment in order to administer effective doses of the presumably most effective perioperative treatment at an early time point during the course of disease.

Thus, patients with locally advanced rectal cancer but low risk for local failure (cT1/2N+ in all thirds of the rectum, cT3a/b N- in the middle third, and cT3-4 Nany in the upper third) will be included and randomized between three months of neoadjuvant FOLFOX/XELOX in Arm A and primary resection of the tumor followed by risk (i.e. stage) adapted chemotherapy in Arm B.

Details
Condition Rectal Cancer
Treatment mFOLFOX (neoadjuvant), XELOX (neoadjuvant), mFOLFOX (adjuvant), XELOX (adjuvant), Capecitabine (adjuvant), infusional 5-FU/FA "AIO" regimen (adjuvant), infusional 5-FU/FA "de Gramont" (adjuvant)
Clinical Study IdentifierNCT04495088
SponsorRalf Hofheinz
Last Modified on20 August 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

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)
Staging requirements: High-resolution magnetic resonance imaging (MRI) of the pelvis is the mandatory local staging procedure
Transrectal endoscopic ultrasound (EUS) is used to help discriminate between T1/2 and early T3 tumors
MRI-defined inclusion criteria
Lower third (0-6 cm): cT1/2 with clear cN+ based on MRI-criteria (see SOP in chapter 13.3 of the appendix), provided CRM- and EMVI- (defined as MRI-EMVI score 0-3; see SOP in chapter 13.3 of the appendix)
Middle third (≥ 6-12 cm): cT1/2 with clear cN+ provided CRM- and EMVI-; cT3a/b, i.e. evidence of extramural tumor spread into the mesorectal fat of ≤ 5 mm provided N-, CRM-, and EMVI-
Upper third (≥ 12-16 cm): cT1/2 with clear cN+ provided CRM- and EMVI-; any cT3-4 irrespective of nodal status
Spiral-CT of the abdomen and chest to exclude distant metastases
Aged at least 18 years. No upper age limit
WHO/ECOG Performance Status ≤1
Adequate haematological, hepatic, renal and metabolic function parameters
Leukocytes ≥ 3.000/mm³, ANC ≥ 2.000/mm³, platelets ≥ 100.000/mm³, Hb > 9 g/dl
Serum creatinine ≤ 1.5 x upper limit of normal
Bilirubin ≤ 2.0 mg/dl, SGOT-SGPT, and AP ≤ 3 x upper limit of normal
QTc interval (Bazett) ≤ 440 ms
Informed consent of the patient
Formula for QTc interval calculation (Bazett): QTc= ((QT) ̅" (ms)" )/√(RR (sec))=
((QT) ̅" (ms)" )/√(60/(frequency (1/min)))

Exclusion Criteria

Distant metastases (to be excluded by CT scan of the thorax and abdomen)
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 breast feeding, 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 during treatment and for 6 months (male or female) after the end of
Previous or current drug abuse
treatment Male patients treated with Oxaliplatin should take legal advice concerning
Other concomitant antineoplastic therapy
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
Chronic diarrhea (> grade 1 according NCI CTCAE)
appropriate contraceptive measure
On-treatment participation in a clinical study in the period 30 days prior to
inclusion
Severe kidney dysfunction (creatinine clearance < 30 ml/min)
Serious concurrent diseases, including neurologic or psychiatric disorders (incl
Recent or concurrent treatment with brivudine
Pernicious or other megaloblastic anaemia caused by vitamin B12 deficiency
dementia and uncontrolled seizures), active, uncontrolled infections, active
Known dihydropyrimidine dehydrogenase deficiency
disseminated coagulation disorder
Clinically significant cardiovascular disease in (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 or hypersensitivity on study medication or to any of the
associated with the study treatments)
other excipients
Evidence of peripheral sensory neuropathy > grade 1 according to CTCAE version 5.0
(see appendix)
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
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