Translational Validation Study to Examine KFO179-1 Biomarker Scores for the Prediction and Prognosis of Advanced Primary Resectable Rectal Cancer Stages UICC-II-IV, With a 5-Fluorouracil-based Standard Radiochemotherapy Followed by Total Mesorectal Excision.

Study Overview
=================
Brief Summary
-----------------
The objective of the TransValid-KFO179/GRCSG-Trial-A is the validation of potential biomarkers. These are predictive (Prediction of probability of response to a certain therapy) / prognostic (predicting long-term outcome) microarray-based gene expression signatures and immunohistochemically evaluated biomarkers. The evaluation was done within the KFO179 (www.kfo179.de) - the validation is implemented in this trial. Therefore tumor material of patients undergoing standard radiochemotherapy will be analyzed from pretreatment biopsies an residual tissue from the resection specimen after surgery. This validation and the biomaterial asservation will be incorporated into clinical routine in all participating centers as a model for the treatment of solid tumors. The obtained biomarkers with a predictive and prognostic power will be used to develop an algorithm to predict patients at high risk of local and distant cancer recurrence.

Detailed Description
-----------------
The objective of the TransValid-KFO179/GRCSG-Trial-A is to validate the predictive/prognostic microarray-based gene expression signatures and single gene biomarkers (including 5-Fluorouracil (FU) metabolism, apoptosis, Kirsten Rat Sarcoma (KRAS), CpGCpG island methylation phenotype (CIMP) and TGF-beta pathway), which have been established in patients treated with standard 5-FU based RCT in the GRCSG trials (e.g. the CAO/ARO/AIO-94-, CAO/ARO/AIO-04-phase III trials). This validation will be incorporated into clinical routine in all participating centers as a model for the treatment of solid tumors. If the KFO179 biomarkers are predictive at a satisfactory level in the validation set, we will propose a prediction algorithm to stratify the patient population into a high-risk and low-risk population to develop local and distant cancer recurrence.

Official Title
-----------------
Translational Validation Study to Examine KFO179-1 Biomarker Scores for the Prediction and Prognosis of Advanced Primary Resectable Rectal Cancer Stages UICC II-IV, With a 5-FU-based Standard Radiochemotherapy Followed by Total Mesorectal Excision.

Conditions
-----------------
Locally Advanced Rectal Cancer

Intervention / Treatment
-----------------
* Other: Translational Research and multimodal treatment


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Aged 18 to 85 years, inclusive Histologically confirmed advanced primary rectal cancer localized up to 12 cm above the anocutaneous line (determined with a rigid rectoscope), classified as T3/T4 or N+ carcinomas or with evidence for synchronous, but resectable distant metastases (liver or lung metastases) No specific tumor treatment except colostomy due to tumor stenosis with ileus World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) status ≤2 Adequate bone marrow function (WBC >3.0x10^9/L, neutrophils >1.5x10^9/L, thrombocytes >100x10^9/L, hemoglobin ≥10 g/dl) Adequate liver function (bilirubin ≤2.0 mg/dl, SGOT, SGPT, AP, gamma-GT < three point five fold of upper level of normal range serum creatinine < 1.5 mg/dl Written and signed informed consent indicating the understanding of the investigational nature and the study protocol. Exclusion Criteria: Pregnant or lactating women 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 Prolonged drug, medication or alcohol abuse Previous chemotherapy (up to 2 years before diagnosis of rectal cancer) Previous radiotherapy to the pelvic area Simultaneous therapy with other anti-cancer drugs Participation in a clinical trial in the period 30 days prior to inclusion Patients (man and woman) who are not able or willing to accept treatment and follow-up care according to trial protocol Patients (man and woman) with uncontrolled, serious physical or mental diseases, e.g.: instable cardiac disease in spite of medical treatment, myocardial infarction during the last 3 months prior to start of trial participation neurological or psychiatric dysfunction including dementia or seizure disorder Disseminated infection or sepsis Disseminated intravascular coagulopathy Symptomatic neuropathy (NCI CTC ≥2) Patients with secondary malignancies except basal cell carcinoma of the skin or carcinoma in situ of the cervix, which have been successfully treated. (The inclusion of patients with other tumors that were successfully treated and no recurrence within the last 3-5 years should be discussed before registration in the trial) Chronic diarrhea (>grade 1 according NCI CTCAE) Allergic reaction to platin-derivates or study medication Simultaneous treatment with sorivudine and analogous Known Dihydropyrimidine dehydrogenase deficiency

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Blood and tissue samples during therapy<br>Collection of blood and tissue samples during preoperative multimodal treatment (Radiochemotherapy (RCTx) followed by total mesorectal excision (TME) and Chemotherapy (CT)) in rectal cancer. | Other: Translational Research and multimodal treatment<br>* Blood/biopsy samples (tumor & mucosa) are taken pretherapeutically. Blood samples (serum & plasma) are drawn at 11 time points during RCTx (e.g. for analysis of 5-FU metabolism, genomic DNA extraction). After pathohistological workup of the TME specimen, the formalin-fixed material will be transferred to the central biobank of KFO179. Blood samples (plasma & serum) will be drawn during 5y-follow-up. Treatment (based on CAO/ARO/AIO-94- and CAO/ARO/AIO-04-phase-III trials of the GRCSG): Preoperative RCT: 28x1.8 Gy (total: 50.4 Gy, 5 fractions per week on d1-d38) combined with 5-FU (1000 mg/m2/d) as 120 h civ during 1st and 5th week. TME-surgery is performed 6 weeks after RCTx. 4 to 8 weeks after surgery, patients receive either 4 cycles 5-FU (500 mg 5-FU/m2 iv, d1-5, repeat d 29-33) or 3 cycles (6 single appl.) of FOLFOX regimen [(400 mg FA/m2, 2-h civ, d 1; 100 mg oxaliplatin/m2, 2-h civ in 500 ml Glucose 5%, d 1; 2400 mg 5-FU/m2 as 46-h civ) on d1+d15, d30+d45 and d60+d75].<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with histopathologically confirmed complete remission (pCR) (ypT0N0 R0) after preoperative RCTx related to pretherapeutically determined gene expression signature predicting tumor response to RCTx. | The efficacy of the pretherapeutically determined response prediction using a reliable and robust panel of biomarkers (gene expression signature) is assessed by several clinicopathological parameters after preoperative RCTx and TME-surgery that indicate response and toxicity (ypN-status, pCR, tumor regression-grading, R-status, toxicity). Timepoint for measuring the gene expression signature is the time of diagnosis (pretreatment biopsy); several immunohistochemical biomarkers (Thymidylatesynthase, Survivin, HER-2) will be determined in the pretreatment biopsy as well as at the time of resection in the residual tumor tissue. | 1 year after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| R0-rate of resection | The resection status will be classified by the pathologists according to the established UICC-TNM-Classification (R0 vs R1 vs R2 resection status) | 30 days after surgery based on histopathological findings and reports | 
| post-operative 30-day mortality |  | 30 days after surgery | 
| post-operative morbidity (esp. rate of anastomotic insufficiencies) |  | 30 days after surgery | 
| post-operative late complications (defecation problems, anastomotic, stenoses, loss of sphincter function) |  | up to 5 years after surgery | 
| Quality of TME-surgery according to M.E.R.C.U.R.Y classification | The quality of total mesorectal excision (TME) will be classified by the surgeons (intraoperatively according to M.E.R.C.U.R.Y criteria: good vs moderat vs poor as published in national guidelines) and independently by the pathologists (on the resected specimen according to the well established M.E.R.C.U.R.Y criteria: good vs moderate vs poor). | 30 days after surgery based on surgical and histopathological findings/reports | 
| acute and late toxicity of the chemotherapy according to the CommonToxicity Criteria of the National Cancer Institute (CTC) (vs 4.0) |  | up to 5 years after therapy | 
| Disease free survival (DSF) after 2 and 3 years (local and/or distant recurrences) |  | up to 3 years after surgery | 
| Cumulative incidence of local relapses and distant metastases |  | up to 5 years after surgery | 
| Overall cancer specific survival (CSS) after 3 and 5 years |  | up to 5 years after surgery | 
| Quality of life (QL) according to the EORTC-Questionnaire QLQ-30 (3.0) | The EORTC-Questionnaire QLQ-30 (3.0) have to be completed at the following timepoints: before first treatment (baseline), at the end of treatment (30 days after last intervention or application) and during follow-up (12, 36 and 60 months after surgical intervention). The outcome measures at the end of treatment, 12,36,60 months after surgery will be compared to baseline. EORTC-Life Quality (LQ)-Questionnaire and Wexner Score-Questionnaire will be analysed separately. | up to 5 years after surgery | 
| Wexner-Score-Questionnaire | The Wexner-Score-Questionnaire have to be completed at the following timepoints: before first treatment (baseline), at the end of treatment (30 days after last intervention or application) and during follow-up (12, 36 and 60 months after surgical intervention). The outcome measures at the end of treatment, 12,36,60 months after surgery will be compared to baseline. EORTC-LQ-Questionnaire and Wexner Score-Questionnaire will be analysed separately. | up to 5 years after surgery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
locally advanced rectal cancer, translational research, Biomarker