National Cancer Institute (NCI) state of the science: Targeted radiosensitizers in colorectal cancer

Abstract

Colorectal cancer (CRC) represents a major public health problem as the second leading cause of cancer‐related mortality in the United States. Of an estimated 140,000 newly diagnosed CRC cases in 2018, roughly one‐third of these patients will have a primary tumor located in the distal large bowel or rectum. The current standard‐of‐care approach includes curative‐intent surgery, often after preoperative (neoadjuvant) radiotherapy (RT), to increase rates of tumor down‐staging, clinical and pathologic response, as well as improving surgical resection quality. However, despite advancements in surgical techniques, as well as sharpened precision of dosimetry offered by contemporary RT delivery platforms, the oncology community continues to face challenges related to disease relapse. Ongoing investigations are aimed at testing novel radiosensitizing agents and treatments that might exploit the systemic antitumor effects of RT using immunotherapies. If successful, these treatments may usher in a new curative paradigm for rectal cancers, such that surgical interventions may be avoided. Importantly, this disease offers an opportunity to correlate matched paired biopsies, radiographic response, and molecular mechanisms of treatment sensitivity and resistance with clinical outcomes. Herein, the authors highlight the available evidence from preclinical models and early‐phase studies, with an emphasis on promising developmental therapeutics undergoing prospective validation in larger scale clinical trials. This review by the National Cancer Institute's Radiation Research Program Colorectal Cancer Working Group provides an updated, comprehensive examination of the continuously evolving state of the science regarding radiosensitizer drug development in the curative treatment of CRC.

Phase I Trial of Trametinib with Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer

“…47 Recent strategies to improve neoadjuvant therapy response have included the concept of total neoadjuvant therapy (TNT), in which systemic chemotherapy is delivered in the neoadjuvant setting rather than the adjuvant setting. 48 The rationale for TNT is that approximately 30-40% patients do not receive their adjuvant therapy due to post-operative healing problems or complications. Thus, the benefits from the TNT approach are to ensure that patients do receive their intended systemic on May 5, 2021.…”

CHIP-mediated ubiquitination of Galectin-1 predicts colorectal cancer prognosis

“…At present, the treatment of CRC is still based on surgery, chemotherapy, radiotherapy, and molecular targeted drugs [5]. Although various clinical treatment methods have made significant progress, the mortality rate of CRC is still gradually increasing, mainly due to local recurrence or distant metastasis [6,7].…”

Phase I and Pharmacology Study of Ropidoxuridine (IPdR) as Prodrug for Iododeoxyuridine-Mediated Tumor Radiosensitization in Advanced GI Cancer Undergoing Radiation

“…The choice to target patients with GI malignancies in this trial was based in part on the expressed interest by the NCI Colorectal Cancer Working Group to investigate the addition of IPdR to standard-of-care therapy for patients with rectal cancer. (11) The intermediate RT dose, schedule and use of IMRT in this study provided results that can be applied to the development of follow-up clinical trials in patients with GI malignancies. Based on the results of this trial, a phase I/II trial of IPdR combining once daily IPdR with standard-ofcare RT (45 -50.4Gy over 5-6 weeks) and twice daily capecitabine as neoadjuvant treatment of locally advanced (T 3 , T 4 , N 1 ) rectal cancer using pathologic complete response rate as the primary endpoint is under consideration.…”

“…Indeed, the development of radiosensitizers has been targeted as a priority in a collaborative project involving the National Cancer Institute (NCI), the Radiation Therapy Oncology Group (RTOG; now part of NRG Oncology Group) and investigators from the United Kingdom. (2,3) A number of systemic agents are used in clinical practice to enhance the effect of RT (2), including platinum compounds (4-6), signal transduction inhibitors (7), fluoropyrimidines (8)(9)(10)(11), gemcitabine (12) and temozolomide (13). The use of cytotoxic agents with RT has been found to benefit patients with select tumor types, e.g.…”