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.

Locally Advanced Rectal Cancer Clinical Trial

— TransValid-A  

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.

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03034473
• Other study ID #: TransValid-KFO179/GRCSG-A
• Secondary ID: DRKS00003659UTN
• Status: Active, not recruiting
• Phase: N/A
• Start date: August 2011
• Est. completion date: August 2024

Study information

• Verified date: December 2023
• Source: University Medical Center Goettingen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 200
• Est. completion date: August 2024
• Est. primary completion date: August 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• Locally Advanced Rectal Cancer
• Rectal Neoplasms

Intervention

Other:
• Translational Research and multimodal treatment
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].

Locations

Country	Name	City	State
Germany	University Medical Center Goettingen	Gottingen	Lower Saxony

Sponsors (2)

Lead Sponsor	Collaborator
University Medical Center Goettingen	German Research Foundation

Country where clinical trial is conducted

Germany, 

References & Publications (62)

Bleckmann A, Conradi LC, Menck K, Schmick NA, Schubert A, Rietkotter E, Arackal J, Middel P, Schambony A, Liersch T, Homayounfar K, Beissbarth T, Klemm F, Binder C, Pukrop T. beta-catenin-independent WNT signaling and Ki67 in contrast to the estrogen receptor status are prognostic and associated with poor prognosis in breast cancer liver metastases. Clin Exp Metastasis. 2016 Apr;33(4):309-23. doi: 10.1007/s10585-016-9780-3. Epub 2016 Feb 9. — View Citation

Conradi LC, Styczen H, Sprenger T, Wolff HA, Rodel C, Nietert M, Homayounfar K, Gaedcke J, Kitz J, Talaulicar R, Becker H, Ghadimi M, Middel P, Beissbarth T, Ruschoff J, Liersch T. Frequency of HER-2 positivity in rectal cancer and prognosis. Am J Surg Pathol. 2013 Apr;37(4):522-31. doi: 10.1097/PAS.0b013e318272ff4d. — View Citation

Danner BC, Gerdes JS, Jung K, Sander B, Enders C, Liersch T, Seipelt R, Gutenberg A, Gunawan B, Schondube FA, Fuzesi L. Comparison of chromosomal aberrations in primary colorectal carcinomas to their pulmonary metastases. Cancer Genet. 2011 Mar;204(3):122-8. doi: 10.1016/j.cancergen.2010.12.003. — View Citation

Fietkau R, Rodel C, Hohenberger W, Raab R, Hess C, Liersch T, Becker H, Wittekind C, Hutter M, Hager E, Karstens J, Ewald H, Christen N, Jagoditsch M, Martus P, Sauer R; German Rectal Cancer Study Group. Rectal cancer delivery of radiotherapy in adequate time and with adequate dose is influenced by treatment center, treatment schedule, and gender and is prognostic parameter for local control: results of study CAO/ARO/AIO-94. Int J Radiat Oncol Biol Phys. 2007 Mar 15;67(4):1008-19. doi: 10.1016/j.ijrobp.2006.10.020. Epub 2006 Dec 29. — View Citation

Fokas E, Conradi L, Weiss C, Sprenger T, Middel P, Rau T, Dellas K, Kitz J, Rodel F, Sauer R, Ruschoff J, Beissbarth T, Arnold D, Ghadimi BM, Rodel C, Liersch T. Preoperative chemoradiation therapy with capecitabine/oxaliplatin and cetuximab in rectal cancer: long-term results of a prospective phase 1/2 study. Int J Radiat Oncol Biol Phys. 2013 Dec 1;87(5):992-9. doi: 10.1016/j.ijrobp.2013.09.011. Epub 2013 Oct 24. — View Citation

Fokas E, Liersch T, Fietkau R, Hohenberger W, Beissbarth T, Hess C, Becker H, Ghadimi M, Mrak K, Merkel S, Raab HR, Sauer R, Wittekind C, Rodel C. Tumor regression grading after preoperative chemoradiotherapy for locally advanced rectal carcinoma revisited: updated results of the CAO/ARO/AIO-94 trial. J Clin Oncol. 2014 May 20;32(15):1554-62. doi: 10.1200/JCO.2013.54.3769. Epub 2014 Apr 21. — View Citation

Fokas E, Liersch T, Fietkau R, Hohenberger W, Hess C, Becker H, Sauer R, Wittekind C, Rodel C. Downstage migration after neoadjuvant chemoradiotherapy for rectal cancer: the reverse of the Will Rogers phenomenon? Cancer. 2015 Jun 1;121(11):1724-7. doi: 10.1002/cncr.29260. Epub 2015 Jan 21. — View Citation

Folprecht G, Gruenberger T, Bechstein W, Raab HR, Weitz J, Lordick F, Hartmann JT, Stoehlmacher-Williams J, Lang H, Trarbach T, Liersch T, Ockert D, Jaeger D, Steger U, Suedhoff T, Rentsch A, Kohne CH. Survival of patients with initially unresectable colorectal liver metastases treated with FOLFOX/cetuximab or FOLFIRI/cetuximab in a multidisciplinary concept (CELIM study). Ann Oncol. 2014 May;25(5):1018-25. doi: 10.1093/annonc/mdu088. Epub 2014 Feb 27. — View Citation

Folprecht G, Gruenberger T, Bechstein WO, Raab HR, Lordick F, Hartmann JT, Lang H, Frilling A, Stoehlmacher J, Weitz J, Konopke R, Stroszczynski C, Liersch T, Ockert D, Herrmann T, Goekkurt E, Parisi F, Kohne CH. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol. 2010 Jan;11(1):38-47. doi: 10.1016/S1470-2045(09)70330-4. Epub 2009 Nov 26. — View Citation

Gaedcke J, Liersch T, Hess C, Becker H, Rodel C, Ghadimi BM. [Rectal cancer: current status of multimodal therapy--when and how?]. Zentralbl Chir. 2011 Aug;136(4):334-42. doi: 10.1055/s-0031-1271581. Epub 2011 Aug 23. German. — View Citation

Gehoff A, Basten O, Sprenger T, Conradi LC, Bismarck C, Bandorski D, Merkelbach-Bruse S, Schneider-Stock R, Stoehr R, Wirtz RM, Kitz J, Muller A, Hartmann A, Becker H, Ghadimi BM, Liersch T, Ruschoff J. Optimal lymph node harvest in rectal cancer (UICC stages II and III) after preoperative 5-FU-based radiochemotherapy. Acetone compression is a new and highly efficient method. Am J Surg Pathol. 2012 Feb;36(2):202-13. doi: 10.1097/PAS.0b013e31823fa35b. — View Citation

Ghadimi 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. — View Citation

Ghadimi BM, Grade M, Monkemeyer C, Kulle B, Gaedcke J, Gunawan B, Langer C, Liersch T, Becker H. Distinct chromosomal profiles in metastasizing and non-metastasizing colorectal carcinomas. Cell Oncol. 2006;28(5-6):273-81. doi: 10.1155/2006/529190. — View Citation

Grade M, Becker H, Liersch T, Ried T, Ghadimi BM. Molecular cytogenetics: genomic imbalances in colorectal cancer and their clinical impact. Cell Oncol. 2006;28(3):71-84. doi: 10.1155/2006/173815. — View Citation

Grade M, Gaedcke J, Wangsa D, Varma S, Beckmann J, Liersch T, Hess C, Becker H, Difilippantonio MJ, Ried T, Ghadimi BM. Chromosomal copy number changes of locally advanced rectal cancers treated with preoperative chemoradiotherapy. Cancer Genet Cytogenet. 2009 Aug;193(1):19-28. doi: 10.1016/j.cancergencyto.2009.03.016. — View Citation

Grade M, Ghadimi BM, Varma S, Simon R, Wangsa D, Barenboim-Stapleton L, Liersch T, Becker H, Ried T, Difilippantonio MJ. Aneuploidy-dependent massive deregulation of the cellular transcriptome and apparent divergence of the Wnt/beta-catenin signaling pathway in human rectal carcinomas. Cancer Res. 2006 Jan 1;66(1):267-82. doi: 10.1158/0008-5472.CAN-05-2533. — View Citation

Grade M, Hormann P, Becker S, Hummon AB, Wangsa D, Varma S, Simon R, Liersch T, Becker H, Difilippantonio MJ, Ghadimi BM, Ried T. Gene expression profiling reveals a massive, aneuploidy-dependent transcriptional deregulation and distinct differences between lymph node-negative and lymph node-positive colon carcinomas. Cancer Res. 2007 Jan 1;67(1):41-56. doi: 10.1158/0008-5472.CAN-06-1514. — View Citation

Gutenberg A, Gerdes JS, Jung K, Sander B, Gunawan B, Bock HC, Liersch T, Bruck W, Rohde V, Fuzesi L. High chromosomal instability in brain metastases of colorectal carcinoma. Cancer Genet Cytogenet. 2010 Apr 1;198(1):47-51. doi: 10.1016/j.cancergencyto.2009.12.006. — View Citation

Homayounfar K, Bleckmann A, Helms HJ, Lordick F, Ruschoff J, Conradi LC, Sprenger T, Ghadimi M, Liersch T. Discrepancies between medical oncologists and surgeons in assessment of resectability and indication for chemotherapy in patients with colorectal liver metastases. Br J Surg. 2014 Apr;101(5):550-7. doi: 10.1002/bjs.9436. Epub 2014 Feb 20. — View Citation

Ilgen P, Stoldt S, Conradi LC, Wurm CA, Ruschoff J, Ghadimi BM, Liersch T, Jakobs S. STED super-resolution microscopy of clinical paraffin-embedded human rectal cancer tissue. PLoS One. 2014 Jul 15;9(7):e101563. doi: 10.1371/journal.pone.0101563. eCollection 2014. — View Citation

Jakob 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. — View Citation

Jakob 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. — View Citation

Jakob C, Liersch T, Meyer W, Baretton GB, Schwabe W, Hausler P, Kulle B, Becker H, Aust DE. Prognostic value of histologic tumor regression, thymidylate synthase, thymidine phosphorylase, and dihydropyrimidine dehydrogenase in rectal cancer UICC Stage II/III after neoadjuvant chemoradiotherapy. Am J Surg Pathol. 2006 Sep;30(9):1169-74. doi: 10.1097/01.pas.0000213302.13435.6e. Erratum In: Am J Surg Pathol. 2006 Nov;30(11):1489. — View Citation

Jakob C, Liersch T, Meyer W, Becker H, Baretton GB, Aust DE. Predictive value of Ki67 and p53 in locally advanced rectal cancer: correlation with thymidylate synthase and histopathological tumor regression after neoadjuvant 5-FU-based chemoradiotherapy. World J Gastroenterol. 2008 Feb 21;14(7):1060-6. doi: 10.3748/wjg.14.1060. — View Citation

Jo P, Nietert M, Gusky L, Kitz J, Conradi LC, Muller-Dornieden A, Schuler P, Wolff HA, Ruschoff J, Strobel P, Grade M, Liersch T, Beissbarth T, Ghadimi MB, Sax U, Gaedcke J. Neoadjuvant Therapy in Rectal Cancer - Biobanking of Preoperative Tumor Biopsies. Sci Rep. 2016 Oct 18;6:35589. doi: 10.1038/srep35589. — View Citation

Kalata P, Martus P, Zettl H, Rodel C, Hohenberger W, Raab R, Becker H, Liersch T, Wittekind C, Sauer R, Fietkau R; German Rectal Cancer Study Group. Differences between clinical trial participants and patients in a population-based registry: the German Rectal Cancer Study vs. the Rostock Cancer Registry. Dis Colon Rectum. 2009 Mar;52(3):425-37. doi: 10.1007/DCR.0b013e318197d13c. — View Citation

Liersch T, Grade M, Gaedcke J, Varma S, Difilippantonio MJ, Langer C, Hess CF, Becker H, Ried T, Ghadimi BM. Preoperative chemoradiotherapy in locally advanced rectal cancer: correlation of a gene expression-based response signature with recurrence. Cancer Genet Cytogenet. 2009 Apr 15;190(2):57-65. doi: 10.1016/j.cancergencyto.2008.11.011. — View Citation

Liersch T, Langer C, Ghadimi BM, Kulle B, Aust DE, Baretton GB, Schwabe W, Hausler P, Becker H, Jakob C. Lymph node status and TS gene expression are prognostic markers in stage II/III rectal cancer after neoadjuvant fluorouracil-based chemoradiotherapy. J Clin Oncol. 2006 Sep 1;24(25):4062-8. doi: 10.1200/JCO.2005.04.2739. — View Citation

Liersch T, Meller J, Bittrich M, Kulle B, Becker H, Goldenberg DM. Update of carcinoembryonic antigen radioimmunotherapy with (131)I-labetuzumab after salvage resection of colorectal liver metastases: comparison of outcome to a contemporaneous control group. Ann Surg Oncol. 2007 Sep;14(9):2577-90. doi: 10.1245/s10434-006-9328-x. Epub 2007 Jun 15. — View Citation

Liersch 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. — View Citation

Liersch T, Rothe H, Ghadimi BM, Becker H. [Individualizing treatment for locally advanced rectal cancer]. Chirurg. 2009 Apr;80(4):281-93. doi: 10.1007/s00104-008-1617-4. German. — View Citation

Meller B, Rave-Franck M, Breunig C, Schirmer M, Baehre M, Nadrowitz R, Liersch T, Meller J. Novel Carcinoembryonic-Antigen-(CEA)-Specific Pretargeting System to Assess Tumor Cell Viability after Irradiation of Colorectal Cancer Cells. Strahlenther Onkol. 2011 Feb;187(2):120-6. doi: 10.1007/s00066-010-2191-5. Epub 2011 Jan 24. — View Citation

Meller J, Liersch T, Oezerden MM, Sahlmann CO, Meller B. Targeting NCA-95 and other granulocyte antigens and receptors with radiolabeled monoclonal antibodies (Mabs). Q J Nucl Med Mol Imaging. 2010 Dec;54(6):582-98. — View Citation

Poschau M, Dickreuter E, Singh-Muller J, Zscheppang K, Eke I, Liersch T, Cordes N. EGFR and beta1-integrin targeting differentially affect colorectal carcinoma cell radiosensitivity and invasion. Radiother Oncol. 2015 Sep;116(3):510-6. doi: 10.1016/j.radonc.2015.06.005. Epub 2015 Jun 18. — View Citation

Quack H, Erpenbeck L, Wolff HA, Sprenger T, Seitz CS, Schon MP, Neumann S, Stanek K, Ghadimi BM, Michels B, Middel P, Schaefer IM, Liersch T, Conradi LC. Oxaliplatin-Induced Leukocytoclastic Vasculitis under Adjuvant Chemotherapy for Colorectal Cancer: Two Cases of a Rare Adverse Event. Case Rep Oncol. 2013 Dec 11;6(3):609-15. doi: 10.1159/000357166. eCollection 2013 Sep. — View Citation

Rodel C, Arnold D, Becker H, Fietkau R, Ghadimi M, Graeven U, Hess C, Hofheinz R, Hohenberger W, Post S, Raab R, Sauer R, Wenz F, Liersch T. Induction chemotherapy before chemoradiotherapy and surgery for locally advanced rectal cancer : is it time for a randomized phase III trial? Strahlenther Onkol. 2010 Dec;186(12):658-64. doi: 10.1007/s00066-010-2194-2. Epub 2010 Nov 30. — View Citation

Rodel C, Arnold D, Hipp M, Liersch T, Dellas K, Iesalnieks I, Hermann RM, Lordick F, Hinke A, Hohenberger W, Sauer R. Phase I-II trial of cetuximab, capecitabine, oxaliplatin, and radiotherapy as preoperative treatment in rectal cancer. Int J Radiat Oncol Biol Phys. 2008 Mar 15;70(4):1081-6. doi: 10.1016/j.ijrobp.2007.07.2356. Epub 2007 Sep 19. — View Citation

Rodel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, Hofheinz RD, Ghadimi M, Wolff HA, Lang-Welzenbach M, Raab HR, Wittekind C, Strobel P, Staib L, Wilhelm M, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R, Liersch T; German Rectal Cancer Study Group. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Aug;16(8):979-89. doi: 10.1016/S1470-2045(15)00159-X. Epub 2015 Jul 15. — View Citation

Rodel C, Hofheinz R, Liersch T. Rectal cancer: state of the art in 2012. Curr Opin Oncol. 2012 Jul;24(4):441-7. doi: 10.1097/CCO.0b013e328352ea02. — View 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. — View Citation

Rodel C, Liersch T, Hermann RM, Arnold D, Reese T, Hipp M, Furst A, Schwella N, Bieker M, Hellmich G, Ewald H, Haier J, Lordick F, Flentje M, Sulberg H, Hohenberger W, Sauer R. Multicenter phase II trial of chemoradiation with oxaliplatin for rectal cancer. J Clin Oncol. 2007 Jan 1;25(1):110-7. doi: 10.1200/JCO.2006.08.3675. Erratum In: J Clin Oncol. 2007 May 20;25(15):2149. — View Citation

Rodel 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. — View Citation

Rodel F, Reichert S, Sprenger T, Gaipl US, Mirsch J, Liersch T, Fulda S, Rodel C. The role of survivin for radiation oncology: moving beyond apoptosis inhibition. Curr Med Chem. 2011;18(2):191-9. doi: 10.2174/092986711794088362. — View Citation

Rodel F, Sprenger T, Kaina B, Liersch T, Rodel C, Fulda S, Hehlgans S. Survivin as a prognostic/predictive marker and molecular target in cancer therapy. Curr Med Chem. 2012;19(22):3679-88. doi: 10.2174/092986712801661040. — View Citation

Sahlmann CO, Homayounfar K, Niessner M, Dyczkowski J, Conradi LC, Braulke F, Meller B, Beissbarth T, Ghadimi BM, Meller J, Goldenberg DM, Liersch T. Repeated adjuvant anti-CEA radioimmunotherapy after resection of colorectal liver metastases: Safety, feasibility, and long-term efficacy results of a prospective phase 2 study. Cancer. 2017 Feb 15;123(4):638-649. doi: 10.1002/cncr.30390. Epub 2016 Oct 20. — 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

Scheel AH, Reineke RA, Sprenger T, Lokka S, Kitz J, Ghadimi BM, Ruschoff J, Liersch T, Middel P. Comprehensive lymph node morphometry in rectal cancer using acetone compression. J Clin Pathol. 2015 Jun;68(6):458-64. doi: 10.1136/jclinpath-2014-202555. Epub 2015 Mar 16. — View Citation

Sprenger T, Conradi LC, Beissbarth T, Ermert H, Homayounfar K, Middel P, Ruschoff J, Wolff HA, Schuler P, Ghadimi BM, Rodel C, Becker H, Rodel F, Liersch T. Enrichment of CD133-expressing cells in rectal cancers treated with preoperative radiochemotherapy is an independent marker for metastasis and survival. Cancer. 2013 Jan 1;119(1):26-35. doi: 10.1002/cncr.27703. Epub 2012 Jun 26. — View Citation

Sprenger T, Rodel F, Beissbarth T, Conradi LC, Rothe H, Homayounfar K, Wolff HA, Ghadimi BM, Yildirim M, Becker H, Rodel C, Liersch T. Failure of downregulation of survivin following neoadjuvant radiochemotherapy in rectal cancer is associated with distant metastases and shortened survival. Clin Cancer Res. 2011 Mar 15;17(6):1623-31. doi: 10.1158/1078-0432.CCR-10-2592. Epub 2010 Nov 30. — View Citation

Sprenger T, Rothe H, Becker H, Beissbarth T, Homayounfar K, Gauss K, Kitz J, Wolff H, Scheel AH, Ghadimi M, Rodel C, Conradi LC, Liersch T. Lymph node metastases in rectal cancer after preoperative radiochemotherapy: impact of intramesorectal distribution and residual micrometastatic involvement. Am J Surg Pathol. 2013 Aug;37(8):1283-9. doi: 10.1097/PAS.0b013e3182886ced. — View Citation

Sprenger T, Rothe H, Conradi LC, Beissbarth T, Kauffels A, Kitz J, Homayounfar K, Wolff H, Strobel P, Ghadimi M, Wittekind C, Sauer R, Rodel C, Liersch T. Stage-Dependent Frequency of Lymph Node Metastases in Patients With Rectal Carcinoma After Preoperative Chemoradiation: Results from the CAO/ARO/AIO-94 Trial and From a Comparative Prospective Evaluation With Extensive Pathological Workup. Dis Colon Rectum. 2016 May;59(5):377-85. doi: 10.1097/DCR.0000000000000570. — View Citation

Sprenger T, Rothe H, Homayounfar K, Beissbarth T, Ghadimi BM, Becker H, Liersch T. Preoperative chemoradiotherapy does not necessarily reduce lymph node retrieval in rectal cancer specimens--results from a prospective evaluation with extensive pathological work-up. J Gastrointest Surg. 2010 Jan;14(1):96-103. doi: 10.1007/s11605-009-1057-6. Epub 2009 Oct 15. — View Citation

Sprenger T, Rothe H, Jung K, Christiansen H, Conradi LC, Ghadimi BM, Becker H, Liersch T. Stage II/III rectal cancer with intermediate response to preoperative radiochemotherapy: do we have indications for individual risk stratification? World J Surg Oncol. 2010 Apr 13;8:27. doi: 10.1186/1477-7819-8-27. — View Citation

Sprenger T, Rothe H, Langer C, Becker H, Liersch T. Comment on "lymph nodes after preoperative chemoradiotherapy for rectal carcinoma: number, status, and impact on survival". Am J Surg Pathol. 2009 Jul;33(7):1107; author reply 1108. doi: 10.1097/PAS.0b013e31819ca2a4. No abstract available. — View Citation

Stoehlmacher J, Goekkurt E, Mogck U, Aust DE, Kramer M, Baretton GB, Liersch T, Ehninger G, Jakob C. Thymidylate synthase genotypes and tumour regression in stage II/III rectal cancer patients after neoadjuvant fluorouracil-based chemoradiation. Cancer Lett. 2008 Dec 18;272(2):221-5. doi: 10.1016/j.canlet.2008.07.008. Epub 2008 Aug 21. — View Citation

Styczen H, Nagelmeier I, Beissbarth T, Nietert M, Homayounfar K, Sprenger T, Boczek U, Stanek K, Kitz J, Wolff HA, Ghadimi BM, Middel P, Liersch T, Ruschoff J, Conradi LC. HER-2 and HER-3 expression in liver metastases of patients with colorectal cancer. Oncotarget. 2015 Jun 20;6(17):15065-76. doi: 10.18632/oncotarget.3527. — View Citation

Vorwerk H, Hermann RM, Christiansen H, Liersch T, Hess CF, Weiss E. A special device (double-hole belly board) and optimal radiation technique to reduce testicular radiation exposure in radiotherapy of rectal cancer. Radiother Oncol. 2007 Sep;84(3):320-7. doi: 10.1016/j.radonc.2007.06.017. Epub 2007 Aug 13. — View Citation

Weiss C, Arnold D, Dellas K, Liersch T, Hipp M, Fietkau R, Sauer R, Hinke A, Rodel C. Preoperative radiotherapy of advanced rectal cancer with capecitabine and oxaliplatin with or without cetuximab: A pooled analysis of three prospective phase I-II trials. Int J Radiat Oncol Biol Phys. 2010 Oct 1;78(2):472-8. doi: 10.1016/j.ijrobp.2009.07.1718. Epub 2010 Feb 3. — View Citation

Wolff HA, Conradi LC, Beissbarth T, Leha A, Hohenberger W, Merkel S, Fietkau R, Raab HR, Tschmelitsch J, Hess CF, Becker H, Wittekind C, Sauer R, Rodel C, Liersch T; German Rectal Cancer Study Group. Gender affects acute organ toxicity during radiochemotherapy for rectal cancer: long-term results of the German CAO/ARO/AIO-94 phase III trial. Radiother Oncol. 2013 Jul;108(1):48-54. doi: 10.1016/j.radonc.2013.05.009. Epub 2013 Jun 11. — View Citation

Wolff HA, Conradi LC, Schirmer M, Beissbarth T, Sprenger T, Rave-Frank M, Hennies S, Hess CF, Becker H, Christiansen H, Liersch T. Gender-specific acute organ toxicity during intensified preoperative radiochemotherapy for rectal cancer. Oncologist. 2011;16(5):621-31. doi: 10.1634/theoncologist.2010-0414. Epub 2011 May 9. — View Citation

Wolff HA, Gaedcke J, Jung K, Hermann RM, Rothe H, Schirmer M, Liersch T, Herrmann MKA, Hennies S, Rave-Frank M, Hess CF, Christiansen H. High-grade acute organ toxicity during preoperative radiochemotherapy as positive predictor for complete histopathologic tumor regression in multimodal treatment of locally advanced rectal cancer. Strahlenther Onkol. 2010 Jan;186(1):30-35. doi: 10.1007/s00066-009-2037-1. Epub 2009 Dec 28. — View Citation

* Note: There are 62 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	post-operative 30-day mortality		30 days after surgery
Secondary	post-operative morbidity (esp. rate of anastomotic insufficiencies)		30 days after surgery
Secondary	post-operative late complications (defecation problems, anastomotic, stenoses, loss of sphincter function)		up to 5 years after surgery
Secondary	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
Secondary	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
Secondary	Disease free survival (DSF) after 2 and 3 years (local and/or distant recurrences)		up to 3 years after surgery
Secondary	Cumulative incidence of local relapses and distant metastases		up to 5 years after surgery
Secondary	Overall cancer specific survival (CSS) after 3 and 5 years		up to 5 years after surgery
Secondary	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
Secondary	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