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.

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.

Sex

All

Minimum age

18 Years

Maximum age

85 Years

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

• BACKGROUNDSauer 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. PMID 15496622
• BACKGROUNDJakob C, Aust DE, Meyer W, Baretton GB, Schwabe W, Hausler P, Becker H, Liersch T. Thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase expression, and histological tumour regression after 5-FU-based neo-adjuvant chemoradiotherapy in rectal cancer. J Pathol. 2004 Dec;204(5):562-8. doi: 10.1002/path.1663. PMID 15538739
• BACKGROUNDGhadimi BM, Grade M, Difilippantonio MJ, Varma S, Simon R, Montagna C, Fuzesi L, Langer C, Becker H, Liersch T, Ried T. Effectiveness of gene expression profiling for response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. J Clin Oncol. 2005 Mar 20;23(9):1826-38. doi: 10.1200/JCO.2005.00.406. PMID 15774776
• BACKGROUNDJakob C, Liersch T, Meyer W, Baretton GB, Hausler P, Schwabe W, Becker H, Aust DE. Immunohistochemical analysis of thymidylate synthase, thymidine phosphorylase, and dihydropyrimidine dehydrogenase in rectal cancer (cUICC II/III): correlation with histopathologic tumor regression after 5-fluorouracil-based long-term neoadjuvant chemoradiotherapy. Am J Surg Pathol. 2005 Oct;29(10):1304-9. doi: 10.1097/01.pas.0000170346.55304.88. PMID 16160472
• BACKGROUNDLiersch T, Meller J, Kulle B, Behr TM, Markus P, Langer C, Ghadimi BM, Wegener WA, Kovacs J, Horak ID, Becker H, Goldenberg DM. Phase II trial of carcinoembryonic antigen radioimmunotherapy with 131I-labetuzumab after salvage resection of colorectal metastases in the liver: five-year safety and efficacy results. J Clin Oncol. 2005 Sep 20;23(27):6763-70. doi: 10.1200/JCO.2005.18.622. PMID 16170184
• BACKGROUNDRodel C, Martus P, Papadoupolos T, Fuzesi L, Klimpfinger M, Fietkau R, Liersch T, Hohenberger W, Raab R, Sauer R, Wittekind C. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol. 2005 Dec 1;23(34):8688-96. doi: 10.1200/JCO.2005.02.1329. Epub 2005 Oct 24.