Locally advanced rectal cancer (UICC stage II and III) MedDRA version: 21.0 Level: PT Classification code 10038050 Term: Rectal cancer stage III System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.0 Level: PT Classification code 10038049 Term: Rectal cancer stage II System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: 5-fluorouracil
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: FLUOROURACIL
Other descriptive name: FLUOROURACIL
Product Name: Oxaliplatin
Pharmaceutical Form: Concentra
Sponsors
University Hospital Frankfurt, Goethe University
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Male and female patients with histologically confirmed diagnosis of rectal adenocarcinoma localised 0 – 12 cm from the anocutaneous line as measured by rigid rectoscopy (i.e. lower and middle third of the rectum). • Staging requirements: High-resolution, thin-sliced (i.e. 3mm) magnetic resonance imaging (MRI) of the pelvis is the mandatory local staging procedure. • MRI-defined inclusion criteria: presence of at least one of the following high-risk conditions: o any cT3 if the distal extent of the tumor is cT3b), or o cT3 with clear cN+ based on strict MRI-criteria (see appendix) o cT4 tumors, or o Tany middle/low third of rectum with clear MRI criteria for N+ o mrCRM+ (= 1mm), or o Extramural venous invasion (EMVI+). • Transrectal endoscopic ultrasound (EUS) is additionally used when MRI is not definitive to exclude early cT1/T2 disease in the lower third of the rectum or early cT3a/b tumors in the middle third of the rectum. • 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: o Leukocytes = 3.000/mm3, ANC = 1.500/mm3, platelets = 100.000/mm3, Hb > 9 g/dl o Serum creatinine = 1.5 x upper limit of normal o Bilirubin = 2.0 mg/dl, SGOT-SGPT, and AP = 3 x upper limit of normal. • Informed consent of the patient Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 600 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 102
Exclusion criteria
Exclusion criteria: • Lower border of the tumor localised more than 12 cm from the anocutaneous line as measured by rigid rectoscopy. • 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 (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). • On-treatment participation in a clinical study in the period 30 days prior to inclusion. • Previous or current drug abuse. • 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 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 on study medication. • Known dihydropyrimidine dehydrogenase deficiency. • 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).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary endpoint of this trial, organ preservation, is defined as follows: survival with rectum intact, no major surgery, no stoma. Accordingly, the primary endpoint, organ preservation, will not be reached if any of the following occurs: (1) death, (2) any major surgery other than local excision (R0) performed after randomization, during TNT, at re-staging scheduled 22-24 weeks after start of TNT due to clinical non-complete response, or for any locoregional regrowth after initial clinical complete response requiring salvage-TME, (3) any locoregional regrowth not amenable to salvage surgery, or (4) any stoma (non-re-converted protective stoma within 6 months after completion of TNT, or any stoma needed for toxicity or poor function), whichever occurs first. We hypothesized that the 3-year organ preservation rate will improve from 30% in the control arm to 40% in the investigational arm (hazard ratio of 0.76). ;Secondary Objective: • Disease-free survival • Rate of clinical complete response after TNT • Rate of immediate TME after TNT • Cumulative incidence of locoregional regrowth after cCR • Rate of salvage surgery (LE/TME with or without APR/stoma) after locoregional regrowth • Cumulative incidence of local recurrence after (salvage) surgery • Postoperative complications of (salvage) surgery • Rate of sphincter-sparing (salvage) surgery • Pathological TNM-staging • R0 resection rate; negative circumferential resection rate • Tumor regression grading according to Dworak • Neoadjuvant rectal score • Quality of TME according to MERCURY • Acute and late toxicity assessment according to NCI CTCAE V.5.0) • Quality of life and functional outcome based on treatment arm and surgical procedures/organ preservation • Cumulative incidence of distant metastases • Overall survival ;Primary end point(s): The primary endpoint of this trial, organ preservation, is defined as follows: survival with rectum intact, no major surgery, no stoma. Accordingly, the | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Disease-free survival • Rate of clinical complete response after TNT • Rate of immediate TME after TNT • Cumulative incidence of locoregional regrowth after cCR • Rate of salvage surgery (LE/TME with or without APR/stoma) after locoregional regrowth • Cumulative incidence of local recurrence after (salvage) surgery • Postoperative complications of (salvage) surgery • Rate of sphincter-sparing (salvage) surgery • Pathological TNM-staging • R0 resection rate; negative circumferential resection rate • Tumor regression grading according to Dworak • Neoadjuvant rectal score • Quality of TME according to MERCURY • Acute and late toxicity assessment according to NCI CTCAE V.5.0) • Quality of life and functional outcome based on treatment arm and surgical procedures/organ preservation • Cumulative incidence of distant metastases • Overall survival • Translational / biomarker studies;Timepoint(s) of evaluation of this end point: after 3 year follow up | — |
Countries
Germany, Switzerland
Contacts
Public ContactAtefeh Nateghian
University Hospital Frankfurt, Goethe University
Outcome results
None listed