Biologics in rectal cancer.

INTRODUCTION: Despite the use of multimodality therapy, locally advanced rectal cancer (LARC) still presents high rates of disease recurrence. Fluoropyrimidine-based chemotherapy concurrently with radiation therapy (RT) remains the cornerstone of neoadjuvant therapy of LARC, and novel therapies are urgently needed in order to improve the clinical outcomes. AREAS COVERED: We aim to summarize data from completed and ongoing clinical trials addressing the role of biological therapies, including monoclonal antibodies, immune checkpoint inhibitors (ICIs), antibody-drug conjugates, bispecific antibodies, and gene therapies in the systemic therapy of rectal cancer. EXPERT OPINION: Deeper understanding of the molecular biology of colorectal cancer (CRC) has allowed meaningful advances in the systemic therapy of metastatic disease in the past few years. The larger applicability of biological therapy in CRC, including genome-guided targeted therapy, antiangiogenics, and immunotherapy, gives us optimism for the personalized management of rectal cancer. Microsatellite instability (MSI) tumors have demonstrated high sensitivity to ICIs, and preliminary findings in the neoadjuvant setting of rectal cancer are promising. To date, antiangiogenic and anti-EGFR therapies in LARC have not demonstrated the same benefit seen in metastatic disease. The outstanding results accomplished by biomarker-guided therapy in metastatic CRC will guide future developments of biological therapy in LARC.

Induction Chemotherapy and Chemoradiotherapy Combined to ASA vs. Placebo for High-Risk Rectal Cancer: Results of a Randomized Trial.

INDUCTION: chemotherapy (IC) followed by chemoradiation (CRT) is an attractive approach in high-risk locally advanced rectal cancer. Additionally, ASA has shown potential to improve outcomes alongside CRT in rectal cancer. The ICAR trial aimed to evaluate the safety and efficacy of IC followed by CRT with or without ASA on MRI tumor response. METHODS: Single-center, double-blind, randomized phase II trial to evaluate induction treatment with CAPOX, followed by capecitabine-based chemoradiotherapy with ASA (arm 1) or placebo (arm 2) in high-risk stage II-III rectal adenocarcinoma staged by MRI. The primary endpoint was MRI tumor regression grade (mrTRG). Secondary endpoints were pathological response, surgical outcomes, postoperative complications, treatment tolerance, DFS, and OS. RESULTS: Between January 2018 and August 2019, 27 patients were eligible, 25 (92.5%) completed IC, and 23 patients were randomly assigned (12 to ASA group; 11 to placebo group). In the ASA arm, 3 pts (25%) presented distant disease progression at restaging. Seven patients (30.4%) had cCR after neoadjuvant treatment. All 13 patients submitted to surgery after neoadjuvant treatment underwent R0 resections except for 1 patient with positive CRM, and 12 patients (92.3%) had sphincter preservation. After a median follow-up of 34.9 months, the 2-year DFS was 83.1% and 3-year OS was 81.5%. CONCLUSION: There was good compliance in both treatment arms and encouraging cCR rate. ASA during CRT was safe but failed to improve on MRI tumor response. The study was closed due to the absence of benefits.

The Evolving Field of Neoadjuvant Therapy in Locally-advanced Rectal Cancer: Evidence and Prospects.

The standard treatment of locally advanced rectal cancer comprises neoadjuvant chemoradiation followed by total mesorectal excision. This strategy provides low local recurrence rate, however distant recurrence is still an issue and may impact on survival rates. Novel approaches in the neoadjuvant setting have been tested to improve early and late outcomes, as well as to reduce treatment-related toxicity and morbidity. In this review, we discuss the current literature of neoadjuvant treatment in locally advanced rectal cancer, including total neoadjuvant methods, protocols for radiation delivery, chemotherapy regimen and efforts to add novel targeted therapies, selective withdrawal of surgery or radiotherapy, and future perspectives. Moreover, we highlight relevant issues that have emerged with these new treatment possibilities.