Induction Chemotherapy Before or After Preoperative Chemoradiotherapy and Surgery for Locally Advanced Rectal Cancer

Rectal Neoplasms Clinical Trial

— CAOAROAIO-12  

Official title:

Induction Chemotherapy Before or After Preoperative Chemoradiotherapy and Surgery for Locally Advanced Rectal Cancer: A Randomized Phase II Trial of the German Rectal Cancer Study Group

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02363374
• Other study ID #: CAOAROAIO-12
• Status: Completed
• Phase: Phase 2
• Start date: March 25, 2015
• Est. completion date: June 16, 2023

Study information

• Verified date: November 2023
• Source: Goethe University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Preoperative 5-FU-based (5-fluorouracil) chemoradiotherapy (CRT), total mesorectal excision surgery, and 4 cycles of adjuvant 5-FU - as established by CAO/ARO/AIO-94 - is at present a standard of care for patients with locally advanced rectal cancer (UICC stage II and III). The phase III German CAO/ARO/AIO-04 trial showed, that the addition of oxaliplatin increased treatment efficacy in terms of early secondary efficacy endpoints (e.g. the pCR-rate). With a median follow-up of 50 months, the primary endpoint of this trial - disease free survival - was significantly improved in the oxaliplatin-containing treatment arm (3-year disease-free survival (DFS) 71.2% versus 75.9%, hazard ratio (HR) 0.79, 95% confidence interval (CI) 0.64-0.98, p=0.03). The hereby proposed randomized phase II trial CAO/ARO/AIO-12 aims at finding novel and innovative aspects of rectal cancer treatment, and will thus provide important information for defining the experimental arm in the upcoming large scale trial of the group. Compared to the current standard, in both study arms, the sequence of the three treatment modalities is modified, placing the chemotherapy block before surgery. The pre-operative sequence of chemotherapy -> chemoradiotherapy (arm A) has been shown to be feasible with no early tumor progression prior to definitive surgical resection in a small randomized phase II study from Spain. The sequence chemoradiotherapy -> chemotherapy (arm B) may be beneficial according to response kinetics considerations, and by maintaining a highly effective local treatment in the first place. Both approaches could avoid the problem of major compliance problems with post-operative adjuvant chemotherapy. CAO/ARO/AIO: German Rectal Cancer Study Group

Recruitment information / eligibility

• Status: Completed
• Enrollment: 311
• Est. completion date: June 16, 2023
• Est. primary completion date: September 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Male and female patients with histologically confirmed diagnosis of rectal cancer 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: any cT3 (clinical stage tumor-3) if the distal extent of the tumor is < 6 cm from anocutaneous line or cT3 in the middle third of the rectum (= 6-12 cm) with MRI evidence of extramural tumor spread into the mesorectal fat of more than 5 mm (>cT3b), or resectable cT4 tumors, or any clear cN+ (clinical staging nodes) based on MRI-criteria
• Trans-rectal 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 (World Health Organisation/Eastern Cooperative Oncology Group) Performance Status = 1
• Adequate haematological, hepatic, renal and metabolic function parameters: Leukocytes = 3.000/mm^3, absolute neutrophil count (ANC) = 1.500/mm^3, platelets =100.000/mm^3, Hb > 9 g/dl; Serum creatinine = 1.5 x upper limit of normal; Bilirubin = 2.0 mg/dl, serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT), and alkaline phosphatase (AP) = 3 x upper limit of normal
• 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
• 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
• Concomitant other 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
• Chronic diarrhea (> grade 1 according NCI CTCAE)
• Prior or concurrent malignancy = 3 years prior to enrolment in study (Exception:

non-melanoma skin cancer or cervical carcinoma FIGO (International Federation of Gynecology and Obstetrics) 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)

Related Conditions & MeSH terms

• Rectal Cancer Stage II
• Rectal Cancer Stage III
• Rectal Neoplasms

Intervention

Drug:
• Induction Chemotherapy arm A
Patients receive three induction chemotherapy cycles, starting on day 1, 15 and 29, consisting of: Folinic acid: 400 mg/sqm, 2h-iv; Oxaliplatin: 100 mg/sqm, 2h-iv; 5-FU: 2400 mg/sqm, 46h-iv After a break of two weeks, radiotherapy starts combined with: 5-FU: 250 mg/sqm per day, iv, on day 43-57, day 64-77 Oxaliplatin: 50 mg/sqm, day 43, 50, 64, and 71

Radiation:
• Radiation arm A
Radiotherapy: 28 x 1.8 Gy (total: 50.4 Gy), 5 fractions per week on day 43 -80
• Radiation arm B
Radiotherapy: 28 x 1.8 Gy (total: 50.4 Gy), 5 fractions per week on day 1- 38

Drug:
• Chemotherapy arm B
chemoradiotherapy is started according to the following schedule: 5-FU: 250 mg/sqm per day, iv, on day 1-14, day 22-35; Oxaliplatin: 50 mg/sqm, day 1, 8, 22, and 29. After a break of two and a half weeks, patients receive three chemotherapy cycles, starting on day 57, 71 and 85, consisting of: Folinic acid: 400 mg/sqm, 2h-iv; Oxaliplatin: 100 mg/sqm, 2h-iv; 5-FU: 2400 mg/sqm, 46h-iv

Procedure:
• Surgery
Surgery should be performed about 5 (arm B) or 6 (arm A) weeks after the last radiation or chemotherapy, i.e. around day 123

Locations

Country	Name	City	State
Germany	RWTH Aachen	Aachen
Germany	University Clinic	Bochum
Germany	Clinic for Radiotherapy	Chemnitz
Germany	Diacura Clinic for Radiotherapy	Coburg
Germany	Internist Practice	Dresden
Germany	University Clinic	Dresden
Germany	University Clinic	Erlangen	Bavaria
Germany	University Clinic	Esslingen
Germany	University Hospital Frankfurt Goethe University	Frankfurt
Germany	University Clinic	Freiburg
Germany	HELIOS Park-Klinikum Leipzig	Leipzig
Germany	University Clinic	Leipzig
Germany	University Clinic	Mannheim
Germany	Hospital Miria Hilf	Moenchengladbach
Germany	Pius Hospital Oldenburg	Oldenburg
Germany	University Clinic	Oldenburg
Germany	Hospital Barmherziger Brueder	Regensburg
Germany	University Clinic	Regensburg
Germany	University Clinic	Rostock
Germany	University Clinic	Wuerzburg

Sponsors (3)

Lead Sponsor	Collaborator
Prof. Dr. med. Claus Rödel	Deutsche Krebshilfe e.V., Bonn (Germany), Johann Wolfgang Goethe University Hospital

Country where clinical trial is conducted

Germany, 

References & Publications (3)

Rodel C, Liersch T, Becker H, Fietkau R, Hohenberger W, Hothorn T, Graeven U, Arnold D, Lang-Welzenbach M, Raab HR, Sulberg H, Wittekind C, Potapov S, Staib L, Hess C, Weigang-Kohler K, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R; German Rectal Cancer Study Group. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol. 2012 Jul;13(7):679-87. doi: 10.1016/S1470-2045(12)70187-0. Epub 2012 May 23. — View Citation

Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens JH, Liersch T, Schmidberger H, Raab R; German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004 Oct 21;351(17):1731-40. doi: 10.1056/NEJMoa040694. — View Citation

Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, Becker H, Raab HR, Villanueva MT, Witzigmann H, Wittekind C, Beissbarth T, Rodel C. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012 Jun 1;30(16):1926-33. doi: 10.1200/JCO.2011.40.1836. Epub 2012 Apr 23. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of patients with pathological complete response (pCR), i.e. ypT0N0.	Efficacy (pCR) of induction chemotherapy followed by chemoradiotherapy, or the other way round, before surgery in patients with locally advanced rectal cancer.	123 +30 days
Secondary	Safety of the respective combination sequences by Toxicity assessment according to NCI CTCAE V.4.0		5 years
Secondary	Surgical morbidity		123 +30 days
Secondary	Surgical complications		123 +30 days
Secondary	Pathological staging		123 +14 days
Secondary	Tumor downstaging assessed by ypTNM (neoadjuvant pathological staging tumor nodes metastasis) findings in relation to initial cTNM (clinical stage tumor nodes metastasis)		123 +14 days
Secondary	Tumor regression grading according to Dworak		123 +14 days
Secondary	R0 resection rate; negative circumferential resection rate		123 +14 days
Secondary	Rate of sphincter-sparing surgery		123 +14 days
Secondary	Relapse-free survival (local / distant / overall)		5 years
Secondary	Overall survival		5 years

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