Clinical trial NCT02363374: Induction Chemotherapy Before or After Preoperative Chemoradiotherapy and Surgery for Locally Advanced Rectal Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Rectal Neoplasms
Rectal Cancer Stage II
Rectal Cancer Stage III
Keywords: Rectal cancer stage II
Rectal cancer stage III
Multimodality treatment of locally advanced rectal cancer
Lead sponsor: Goethe University
Sponsor class: OTHER
Collaborators: name: Johann Wolfgang Goethe University Hospital
name: Deutsche Krebshilfe e.V., Bonn (Germany)
First posted: 2015-02-16
Enrollment: 311
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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


Eligibility criteria: 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)

Primary outcomes:
measure: Number of patients with pathological complete response (pCR), i.e. ypT0N0.
timeFrame: 123 +30 days
Secondary outcomes:
measure: Safety of the respective combination sequences by Toxicity assessment according to NCI CTCAE V.4.0
timeFrame: 5 years
measure: Surgical morbidity
timeFrame: 123 +30 days
measure: Surgical complications
timeFrame: 123 +30 days
measure: Pathological staging
timeFrame: 123 +14 days
measure: Tumor downstaging assessed by ypTNM (neoadjuvant pathological staging tumor nodes metastasis) findings in relation to initial cTNM (clinical stage tumor nodes metastasis)
timeFrame: 123 +14 days
measure: Tumor regression grading according to Dworak
timeFrame: 123 +14 days
measure: R0 resection rate; negative circumferential resection rate
timeFrame: 123 +14 days
measure: Rate of sphincter-sparing surgery
timeFrame: 123 +14 days
measure: Relapse-free survival (local / distant / overall)
timeFrame: 5 years
measure: Overall survival
timeFrame: 5 years
Other outcomes:
Locations:
city: Erlangen
country: Germany
facility: University Clinic
state: Bavaria
city: Aachen
country: Germany
facility: RWTH Aachen
city: Bochum
country: Germany
facility: University Clinic
city: Chemnitz
country: Germany
facility: Clinic for Radiotherapy
city: Coburg
country: Germany
facility: Diacura Clinic for Radiotherapy
city: Dresden
country: Germany
facility: Internist Practice
city: Dresden
country: Germany
facility: University Clinic
city: Esslingen
country: Germany
facility: University Clinic
city: Frankfurt
country: Germany
facility: University Hospital Frankfurt Goethe University
city: Freiburg
country: Germany
facility: University Clinic
city: Leipzig
country: Germany
facility: HELIOS Park-Klinikum Leipzig
city: Leipzig
country: Germany
facility: University Clinic
city: Mannheim
country: Germany
facility: University Clinic
city: Moenchengladbach
country: Germany
facility: Hospital Miria Hilf
city: Oldenburg
country: Germany
facility: Pius Hospital Oldenburg
city: Oldenburg
country: Germany
facility: University Clinic
city: Regensburg
country: Germany
facility: Hospital Barmherziger Brueder
city: Regensburg
country: Germany
facility: University Clinic
city: Rostock
country: Germany
facility: University Clinic
city: Wuerzburg
country: Germany
facility: University Clinic
Study officials:
affiliation: Head of Department of Radiation therapy and Oncology, Johann Wolfgang Goethe University Hospital
name: Claus Rödel, Prof., MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
citation: 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.
citation: Fokas E, Schlenska-Lange A, Polat B, Klautke G, Grabenbauer GG, Fietkau R, Kuhnt T, Staib L, Brunner T, Grosu AL, Kirste S, Jacobasch L, Allgauer M, Flentje M, Germer CT, Grutzmann R, Hildebrandt G, Schwarzbach M, Bechstein WO, Sulberg H, Friede T, Gaedcke J, Ghadimi M, Hofheinz RD, Rodel C; German Rectal Cancer Study Group. Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer: Long-term Results of the CAO/ARO/AIO-12 Randomized Clinical Trial. JAMA Oncol. 2022 Jan 1;8(1):e215445. doi: 10.1001/jamaoncol.2021.5445. Epub 2022 Jan 20.