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Gastrointestinal Oncology Editorial “New” Drugs in Localized Rectal Cancer Cathy Eng, MD, FACP Professor, Sophie Caroline Steves Endowed Professorship in Cancer Research; Associate Medical Director, Colorectal Center; Director of Network Clinical Research, GI Medical Oncology, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, US Abstract This editorial reports on the abstract “‘New’ Drugs in Localized Rectal Cancer” presented at the American Society of Clinical Oncology Annual Congress, Chicago, IL, US, June 2015. Keywords Rectal cancer, oxaliplatin, cetuximab, veliparib, ganetespib, PROSPECT trial, total neoadjuvant therapy (TNT) umbrella trial Disclosure: Cathy Eng, MD, FACP, has nothing to disclose in relation to this article. No funding was received in the publication of this article. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: October 3, 2015 Published Online: November 10, 2015 Citation: Oncology & Hematology Review, 2015;11(2):139–40 Correspondence: Cathy Eng, MD, FACP, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 426, Houston, TX 77030, US. E: ceng@mdanderson.org Colorectal cancer will be diagnosed in 132,700 individuals in the US this year alone with rectal cancer being that of 39,610 patients. 1 In contrast to the treatment developments in metastatic colorectal cancer, the treatment of locally advanced rectal cancer has remained at a standstill for the past decade with little development of novel therapies. 5-Fluorouracil (5-FU) has remained the standard of care for radiation sensitization, resulting in a pathologic complete response rate (pCR) of 5–20 %. Until recently, there appeared to be little interest from pharmaceutical companies in the role of radiation sensitization as an important component of drug development. Historically, no new treatment paradigm has evolved since the pivotal phase III German trial CAO/ARO/AIO-94 of neoadjuvant 5-FU-based chemoradiation therapy, resulting in a change in treatment sequence for a reduction in local recurrence (p=0.048). 2 Multiple trials (STAR-01, ACCORD12/0405 PRODIGE 2, NSABP R-04, and PETACC-6) evaluated the potential benefit of oxaliplatin as a radiation sensitizer, but failed to demonstrate an improvement in pCR often at the risk for increased grade 3/4 toxicities. 3–6 The recent phase III trial of CAO/ ARO/AIO-04 evaluated the role of oxaliplatin as a radiation sensitizer but also its role in the adjuvant FOLFOX (folinic acid, 5-FU, oxaliplatin) setting. The investigators noted improved 3-year disease-free survival for oxaliplatin versus standard 5-FU (p=0.03). Grade 3/4 toxicities developed in 23 % of patients with no improvement in pCR. 7 Currently, oxaliplatin is not considered a standard of care in the treatment of rectal cancer. Highlighted at the annual American Society of Clinical Oncology (ASCO) meeting this year was the potential of novel agents. The phase II trial of SWOG S0713 evaluated the role of the chimeric antiepidermal growth factor antibody cetuximab in combination with CapeOx in stage II/III rectal cancer Tou ch MEd ica l MEdia as a radiation sensitizer. pCR was the primary objective that was achieved in 25 % of patients, yet grade 3/4 diarrhea was noted in 35 % of patients. 8 Other contemporary agents explored include the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib and the heat shock protein agent ganetespib. 9,10 Poly (ADP-ribose) polymerase (PARP) binds to single- strand DNA breaks and facilitates repair. PARP inhibitors should prevent the repair of DNA breaks in the setting of radiation therapy resulting in increased apoptosis. Veliparib (ABT-888) is an oral PARP 1/2 inhibitor. A phase I study of veliparib in combination with capecitabine was pursued in treatment-naive stage II/III rectal cancer patients. Patients received standard dose capecitabine (825 mg/m 2 po BID, Monday to Friday [M- F]) and 50.4 Gy. Veliparib was initiated on day 2 of therapy (Monday to Sunday) and completed 2 days after the conclusion of radiation therapy (20–400  mg po BID). A total of 32 patients were enrolled. The most common toxicities included nausea (53 %), fatigue (50 %), and diarrhea (50 %). A maximal tolerated dose was not reached. Two minor grade 2 dose limiting toxicities (DLTs) were noted, including radiation dermatitis and nausea. Patients proceeded onto total mesorectal excision (TME) within 5–10 weeks of completion of their radiation therapy. The pCR rate was 28 %. The recommended phase II dose for the further development of veliparib is 400  mg po BID. Ganetespib is a selective heat shock 90 protein inhibitor (HSP90) with promising preclinical activity in colorectal cancer cell lines. A phase I study of ganetespib (60–150 mg/m 2 IV) in combination with capecitabine was pursued in treatment-naive stage II/III rectal cancer patients. Patients received standard dose capecitabine (825 mg/m 2 po BID, M-F) and 50.4 Gy. Ganetespib was started on day 14 and continued until the completion of radiation therapy, but was held during week 4 of chemoradiation treatment. Sixteen patients were enrolled; 139