Systematic review of treatment intensification using novel agents for chemoradiotherapy in rectal cancer

Abstract

BackgroundWith the well established shift to neoadjuvant treatment for locally advanced rectal cancer, there is increasing focus on the use of radiosensitizers to improve the efficacy and tolerability of radiotherapy. There currently exist few randomized data exploring novel radiosensitizers to improve response and it is unclear what the clinical endpoints of such trials should be.MethodsA qualitative systematic review was performed according to the PRISMA guidelines using preset search criteria across the PubMed, Cochrane and Scopus databases from 1990 to 2017. Additional results were generated from the reference lists of included papers.ResultsA total of 123 papers were identified, of which 37 were included; a further 60 articles were obtained from additional referencing to give a total of 97 articles. Neoadjuvant radiosensitization for locally advanced rectal cancer using fluoropyrimidine‐based chemotherapy remains the standard of treatment. The oral derivative capecitabine has practical advantages over 5‐fluorouracil, with equal efficacy, but the addition of a second chemotherapeutic agent has yet to show a consistent significant efficacy benefit in randomized clinical assessment. Preclinical and early‐phase trials are progressing with promising novel agents, such as small molecular inhibitors and nanoparticles.ConclusionDespite extensive research and promising preclinical studies, a definite further agent in addition to fluoropyrimidines that consistently improves response rate has yet to be found.

Combination of 5-Fluorouracil with Epigenetic Modifiers Induces Radiosensitization, Somatostatin Receptor 2 Expression, and Radioligand Binding in Neuroendocrine Tumor Cells In Vitro

“…5-fluorouracil, DNMT inhibitors, and HDAC inhibitors radiosensitize cancer cells by suppressing DNA repair activity (22)(23)(24). Fluoropyrimidine-mediated radiosensitization is extensively used in chemoradiotherapy in solid cancers (25,26).…”

“…DNMT inhibitors and HDAC inhibitors are extensively examined as epigenetic modifiers, radiosensitizers, chemosensitizers, and sensitizers to immunotherapy in oncology (10,26,30). There are numerous preclinical studies on the combination of epigenetic modifiers with fluoropyrimidine-based chemotherapy in various cancers (26,30). However, so far, there are only limited clinical phase I/II data available on the tolerability and toxicity of a fluoropyrimidine-based chemotherapy in combination with DNMT inhibitors or HDAC inhibitors (30).…”

CD73 blockade enhances the local and abscopal effects of radiotherapy in a murine rectal cancer model

“…Splenocytes (5×10 6 ) from treated mice (as described above) were cultured with 1 × 10 6 irradiated (11 min) -95% (15 min) -95% (20 min) -0% (20.1 min). Nitrogen gas was used as the nebulizer gas with drying gases at flow rates of 3.0 and 10 L/min, respectively.…”

Delivery of Personalized Care for Locally Advanced Rectal Cancer: Incorporating Pathological, Molecular Genetic, and Immunological Biomarkers Into the Multimodal Paradigm

“…However, there are many patients whose outcomes do not match those typical for their tumor stage and accurate prognostic information for individual patients can be difficult to estimate owing to the heterogeneous nature of the disease. Many new combinations of chemotherapy with radiotherapy, including total neoadjuvant therapy (TNT) with targeted therapies that aim to diminish toxicity and increase survival, are being evaluated in clinical trials (10,11). Despite these advances, local recurrence and distant metastasis remain an issue, with one-third of LARC patients dying within 5 years of initial treatment (10).…”