Neoadjuvant Therapy for Low Rectal Cancer with High-Grade Histology

Introduction to Neoadjuvant Therapy

The American College of Radiology recommends neoadjuvant chemoradiotherapy for low rectal cancer with high-grade histology, due to the high-risk features of the tumor, despite the absence of lymph node involvement on imaging 1, 2

Tumors located below 9-12 cm from the anal verge have higher local recurrence risk and benefit significantly from neoadjuvant chemoradiotherapy, as stated by the American College of Radiology 3, 1
High-grade adenocarcinoma represents an aggressive tumor biology with poorer prognosis, making neoadjuvant therapy essential even in node-negative disease, according to the Journal of the American College of Radiology 4

The National Comprehensive Cancer Network recommends a complete staging assessment, including high-resolution pelvic MRI with dedicated rectal sequence, CT chest/abdomen/pelvis, and assessment of microsatellite instability (MSI) or mismatch repair (MMR) status, before finalizing treatment 1, 2, 3
Long-course chemoradiotherapy is preferred over short-course radiotherapy, with a radiation dose of 45-50 Gy in 1.8-2.0 Gy fractions over 5-6 weeks, and concurrent chemotherapy with continuous infusion 5-fluorouracil or oral capecitabine, as recommended by the American College of Radiology 3, 6
Total neoadjuvant therapy, involving both chemoradiotherapy and systemic chemotherapy before surgery, should be strongly considered for high-risk features, with a preferred sequence of long-course chemoradiotherapy followed by consolidation chemotherapy (FOLFOX or CAPOX for 3-4 cycles), according to the American College of Radiology 2

Response evaluation 8-12 weeks after completing neoadjuvant therapy is mandatory, including digital rectal examination, proctoscopy, and restaging MRI to assess tumor regression and surgical planning, as stated by the American College of Radiology 1, 5

Following neoadjuvant therapy, the surgical options depend on response, with low anterior resection with total mesorectal excision if 1-2 cm distal margin achievable with sphincter preservation, or abdominoperineal resection with permanent colostomy if inadequate response or sphincter involvement, according to the American College of Surgeons 1

If the tumor demonstrates microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR), neoadjuvant immunotherapy (pembrolizumab or dostarlimab) is the preferred treatment, rather than chemoradiotherapy, as recommended by the American Society of Clinical Oncology 2