Preoperative FOLFOX Versus Postoperative Risk-adapted Chemotherapy in Patients With Locally Advanced 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 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

Study Overview

• Status: Recruiting
• Conditions: Rectal Cancer
• Intervention / Treatment: Drug: mFOLFOX (neoadjuvant); Drug: XELOX (neoadjuvant); Drug: mFOLFOX (adjuvant); Drug: XELOX (adjuvant); Drug: Capecitabine (adjuvant); Drug: infusional 5-FU/FA "AIO" regimen (adjuvant); Drug: infusional 5-FU/FA "de Gramont" (adjuvant)

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 818
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Ralf-Dieter Hofheinz, Prof. Dr.; Phone Number: 2855 +49 621 383; Email: ralf.hofheinz@umm.de
• Study Contact Backup: Name: Benedict Atzler; Phone Number: 7052 +49 69 7601; Email: atzler.benedict@ikf-khnw.de

Study Locations

• Germany
  • Mannheim, Germany, 68167
    • Recruiting
    • Unversity Hospital Mannheim
    • Contact: Ralf Hofheinz, Prof.; Phone Number: +49 621 383 2855; Email: Ralf.Hofheinz@umm.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

   • 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.
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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A (experimental arm); The experimental arm A starts with 6 cycles of mFOLFOX or 4 cycles of XELOX. Surgery is scheduled four or six weeks after day 1 of the last mFOLFOX or XELOX cycle, respectively. No postoperative chemotherapy is planned	Drug: mFOLFOX (neoadjuvant); neoadjuvant application Folinic acid: 400 mg/m2, 2h i.v., on day 1 Oxaliplatin: 85 mg/m2, 2-6h i.v., on day 1 5-FU: 2400 mg/m2, 46-48h i.v., on day 1. Cycles are repeated on day 15. A total of 6 cycles are administered.; Other Names: Folinic acid, Oxaliplatin, 5-FU; Drug: XELOX (neoadjuvant); neoadjuvant application Capecitabine: 1,000 mg/m2 bid, po, on days 1-14 Oxaliplatin: 130 mg/m2, 2-6h i.v. day 1 Cycles are repeated on day 22. A total of 4 cycles are administered.; Other Names: Capecitabine, Oxaliplatin
Active Comparator: B (control arm); In the standard arm B, patients undergo surgical resection of the primary tumor followed by stage- (risk-)adapted adjuvant chemotherapy 4-8 weeks after surgery according to recommendations of the S3 guidelines in analogy to colon cancer. Details of the recommended protocols are provided in the protocol.	Drug: mFOLFOX (adjuvant); adjuvant application Folinic acid: 400 mg/m2, 2h i.v., on day 1 Oxaliplatin: 85 mg/m2, 2-6h i.v., on day 1 5-FU: 2400 mg/m2, 46-48h i.v., on day 1. Cycles are repeated on day 15. A total of 6 cycles are administered.; Other Names: Folinic acid, Oxaliplatin, 5-FU; Drug: XELOX (adjuvant); adjuvant application Capecitabine: 1,000 mg/m2 bid, po, on days 1-14 Oxaliplatin: 130 mg/m2, 2-6h i.v. day 1 Cycles are repeated on day 22. A total of 4 cycles are administered.; Other Names: Capecitabine, Oxaliplatin; Drug: Capecitabine (adjuvant); adjuvant application Capecitabine: 1,250 mg/m2 bid, po, on days 1-14 Cycles are repeated on day 22. A total of 8 cycles are administered.; Other Names: Capecitabine; Drug: infusional 5-FU/FA "AIO" regimen (adjuvant); adjuvant application Folinic acid 2h i.v. 500 mg/m² 5-FU 2,600mg/m² (24h infusion) Days 1, 8, 15, 22, 29, 36; cycle is repeated day 57 (representing one cycle); a total of 3 cycles should be administered.; Other Names: 5-FU, Folinic acid; Drug: infusional 5-FU/FA "de Gramont" (adjuvant); adjuvant application Folinic acid 2h i.v. 200 mg/m² days 1 and 2 5-FU 400mg/m² bolus followed by 600mg/m² 22h infusion days 1 and 2 The cycle is repeated day 15; a total of 12 cycles should be administered.; Other Names: 5-FU, Folinic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
disease-free survival	time from randomisation to one of the following events: no surgery or non-radical (R2) surgery of the primary tumour, locoregional recurrence after R0/1 resection of the primary tumour, second primary colorectal or other cancer, metastatic disease or progression, or death from any cause, whichever occurred first.	up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute and late toxicity	assessment of acute and late toxicity according to NCI CTCAE version 5.0	From date of informed consent until the End of Treatment or 30 days after the last dose of study treatment
Compliance (completion rate) of chemotherapy	Rate of completion of administered chemotherapy	From date of randomization until end of chemotherapy, approx. 12 (arm A) respectively up to 34 (arm B) weeks after randomization
Surgical morbidity and complications	Surgical morbidity and complications if surgery is performed and events occur	After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
Pathological UICC-staging, including pCR (ypT0N0) rate	Pathological staging according UICC criteria, including detailed information about pathologically assessed complete response rate (ypT0N0)	After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
R0 resection rate, Negative circumferential resection rate (CRM > 1mm)	defined as microscopically margin negative resection with no gross or microscopic tumor remains in the area of the primary tumor and/or samples regional lymph nodes based on evaluation by the local pathologist	After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
Tumor regression grading according to Dworak in the experimental arm	Grading of tumor regression according to Dworak in the experimental arm	After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
Rate of sphincter-sparing surgery	Rate of sphincter-sparing surgery if surgery is performed	After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization
Rate of W&W with or without local regrowth	Number of performed watch&wait approaches with or without local regrowth compared to planned and performed surgery	Up to 5 years after end of treatment
Cumulative incidence of local and distant recurrences	Total number of local and distant recurrences, if they occur	Up to 5 years after end of treatment
Overall survival	Overall survival is defined as the time interval between the date of randomization and the date of death of any cause. Patients who are still alive when last traced will be censored at the date of last follow-up	Up to at least 3 years and until 5 years
Patient reported outcome: Quality of life according to questionnaire EORTC-QLQ-C30	Quality of life scores according to validated questionnaires EORTC-QLQ-C30, based on treatment arm, and surgical procedures. 30 questions; score values from 1 (not at all) to 4 (very much) respectively from 1 (very poor) to 7 (excellent). Score outcome depends on score type.	From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months
Patient reported outcome: Quality of life according to questionnaire EORTC-QLQ-CR29	Quality of life scores according to validated questionnaires EORTC-QLQ-CR29, based on treatment arm, and surgical procedures. 29 questions; score values from 1 (not at all) to 4 (very much). Score outcome depends on score type.	From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months
Patient reported outcome: Functional outcome according to Wexner score	Functional score according to validated Wexner score, based on treatment arm, and surgical procedures. 5 questions; five score values from "never" to "1 per day or more often". The more often the worse the outcome.	From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months

Collaborators and Investigators

• Sponsor: Ralf Hofheinz
• Collaborators: Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest; Deutsche Krebshilfe e.V., Bonn (Germany); German Rectal Cancer Study Group
• Investigators: Principal Investigator: Ralf-Dieter Hofheinz, Prof. Dr., Universitätsmedizin Mannheim

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2020
• Primary Completion (Estimated): August 1, 2030
• Study Completion (Estimated): August 1, 2030

Study Registration Dates

• First Submitted: July 28, 2020
• First Submitted That Met QC Criteria: July 28, 2020
• First Posted (Actual): July 31, 2020

Study Record Updates

• Last Update Posted (Estimated): November 20, 2023
• Last Update Submitted That Met QC Criteria: November 16, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Rectal Cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Hematinics; Fluorouracil; Capecitabine; Oxaliplatin; Leucovorin; Levoleucovorin; Folic Acid
• Other Study ID Numbers: ACO/ARO/AIO-18.2; 2018-001356-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No