Patients with advanced but resectable rectal cancer (clinically staged as rectal cancers of the UICC stages II, III or IV)
Conditions
Interventions
Product Name: 5-Fluorouracil
Pharmaceutical Form:
INN or Proposed INN: 5-Fluorouracil
Other descriptive name: FLUOROURACIL
Product Name: Folinic acid
Pharmaceutical Form:
INN or Proposed INN: Folin
Sponsors
Universitätsmedizin Goettingen
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: -Histologically confirmed resectable advanced primary rectal cancer of the lower thirds of the rectum (localized within 0 to 12 cm above the anocutaneous verge as measured by rigid rectoscopy), clinically (c) classified as cT3/cT4 or cN+ carcinomas or with evidence for synchronous, but resectable distant metastases (liver metastases, cM+) Staging requirements: --Transrectal endoscopic ultrasound is the mandatory local staging procedure, --Additional high-resolution, thin-sliced (i.e. 3 mm) magnetic resonance imaging (MRI) of the pelvis to classify infiltration depth and/or cN+ status or extramural venous cancer invasion (based on MRI-criteria) --abdominal sonography and chest x-ray /or contrast-enhanced computed tomography scan of the thorax and abdomen (and pelvis, if EUS and/or MRI are not available) to complete UICC staging classification -Aged 18 to 80 years, inclusive -WHO/ECOG status =2 -Life expectancy =weeks -Adequate bone marrow function: WBC >3.0x109/L, neutrophils >1.5x109/L, thrombocytes >100x109/L, hemoglobin =10 g/dl -Adequate liver function: bilirubin =2.0 mg/dl, SGOT, SGPT, AP, gamma- GT 50ml/min, serum creatinine =1.5 mg/dl -Written and signed informed consent of competent 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 50 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 50
Exclusion criteria
Exclusion criteria: - Prior or concurrent malignancy (=3 years prior to enrolment in study) except non-melanoma skin cancer or cervical carcinoma FIGO stage 0 1 if the patient is continuously disease-free patients with other tumors that have been successfully treated and have not reappeared during the last 3 years, may be included at the principal investigator's discretion - Simultaneous therapy with other anti-cancer drugs - Major surgery at the pelvic region 2-3 weeks prior to inclusion - Previous multimodal treatment of rectal cancer - Chronic colonic diseases - Chronic diarrhea (>grade 1 according NCI CTCAE) - Allergic reaction to platin-derivates or study medication - Symptomatic neuropathia (NCI CTC =2) - Simultaneous treatment with sorivudin and analogous - Known Dihydropyrimidine dehydrogenase deficiency - Cardiac infarction/failure within 3 months before start of multimodal therapy - Disseminated infection or sepsis - Activated disseminated intravasal coagulopathia - Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment - Men and women unwilling or unable 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) - Participation in an AMG-clinical trial in the period 30 days prior to inclusion - Current drug abuse - 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) - Insufficient compliance of the patient
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The aim of this study is to establish the feasibility and to receive first data on the efficacy of an innovative sequential combination of established pre-operative intensified RCT (5-FU+Oxaliplatin) with consecutively intensive but shortened preoperative FOLFOXchemotherapy (5-FU+Oxaliplatin) followed by TME-surgery. Primary Objectives: - The primary objectives for this evaluation will be toxicity and histopathologically confirmed complete tumor remission (pCR). - The data will be compared exploratively to the separate TransValid- KFO179/GRCSG-Trial-A (validation study, n=200 patients) and to expectations derived from historical data (e.g. the large CAO/AIO/ARO- 94 as well as -04 trial of the German Rectal Cancer Study Group [GRCSG] and others).;Secondary Objective: -R0-rate of resection, CRM, resection status -Rate of sphincter-sparing surgery -Clinical response after each treatment step -TRG -residual tumor infiltration depth -residual lymph node status incl. residual metastases in mesorectal lymph nodes -post-operative 30-day mortality, morbidity and late complications -quality of TME-surgery -acute and late toxicity of the RCT and CTx according to the CTC/ NCI -DFS after 2 and 3 ys -cumulative incidence of local relapses and/or distant metastases -overall cancer-specific survival (CSS) after 3 and 5 ys -Quality of life -Translational/biomarker trial: Re-evaluate the prognostic relevance of the KFO179 scores [A predictive microarray-based gene expression signatures and single gene biomarkers in patients treated with 5-FU based RCT] + primary clinicopathological parameters/biomarkers in a follow-up. Developing an improved 5-FU dose adjustment by measuring 5-FU blood levels during preoperative RCT and CTx.;Primary end point(s): 1) toxicity 2) histopathologically confirmed complete remission (pCR) These data will be compared exploratively to the TransValid-KFO179/ GRCSG-A-Trial (validation study, n=200 patients), conducted in parallel, and to expecta | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1) R0-rate of resection, circumferential resection margin, resection status 2) tumor regression grading 3) residual tumor infiltration depth (ypT-status) 4) residual lymph node status (ypN-status) 5) post-operative 30-day mortality 6) post-operative morbidity (esp. rate of anastomotic insufficiencies) 7) post-operative late complications (defecation problems, anastomotic, stenoses, loss of sphincter function) 8) quality of TME-surgery 9) acute and late toxicity of the chemotherapy according to the Common Toxicity Criteria of the National Cancer Institute (vs 4.0) 10) Disease-fee survival (DFS) after 2 and 3 years (local and/or distant recurrences) 11) cumulative incidence of local relapses and distant metastases 12) overall cancer-specific survival (CSS) after 3 and 5 years 13) quality of life according to the EORTC-Questionnaire QLQ-30 (3.0) and Wexner-Score 14) Translational / biomarker studies: 14a) to re-evaluate the prognostic relevance of the KFO179 scores identified during the KFO179-1 funding period (as predictive/prognostic microarray-based gene expression signatures and single gene biomarkers [see KFO 179-2 application, pp 32-228, Appendix 21]). The identified biomarkers will be compared with results from patients treated with standard 5-FU based RCT in the CAO/ARO/AIO-94- and CAO/ARO/AIO-04-trials of the GRCSG, in the TransValid- KFO179/GRCSG-A-Trial (validation study, n=200 patients)], and with primary clinicopathological parameters/biomarkers in long term followup by recording the data (i.e. disease free and/or overall survival, occurrence of local and distant metastases, long-term [chronic] toxicity) of all patients in the trial. 14b) to evaluate a proof-of-concept multimodal treatment selection by risk stratification on the basis of the KFO179 biomarkers (as re-validated within the TransValid-KFO179/GRCSG-A-Trial (validation study). 14c) to develop an improved 5-FU dose adjustment by measuring | — |
Countries
Germany
Contacts
Public ContactTrial Office
Universitätsmedizin Göttingen
Outcome results
None listed