Advances and challenges in treatment of locally advanced rectal cancer

Abstract

Dramatic improvements in the outcomes of patients with rectal cancer have occurred over the past 30 years. Advances in surgical pathology, refinements in surgical techniques and instrumentation, new imaging modalities, and the widespread use of neoadjuvant therapy have all contributed to these improvements. Several questions emerge as we learn of the benefits or lack thereof for components of the current multimodality treatment in subgroups of patients with nonmetastatic locally advanced rectal cancer (LARC). What is the optimal surgical technique for distal rectal cancers? Do all patients need postoperative chemotherapy? Do all patients need radiation? Do all patients need surgery, or is a nonoperative, organ-preserving approach warranted in selected patients? Answering these questions will lead to more precise treatment regimens, based on patient and tumor characteristics, that will improve outcomes while preserving quality of life. However, the idea of shifting the treatment paradigm (chemoradiotherapy, total mesorectal excision, and adjuvant therapy) currently applied to all patients with LARC to a more individually tailored approach is controversial. The paradigm shift toward organ preservation in highly selected patients whose tumors demonstrate clinical complete response to neoadjuvant treatment is also controversial. Herein, we highlight many of the advances and resultant controversies that are likely to dominate the research agenda for LARC in the modern era.

Fig 1.

The anatomic considerations for extralevator abdominoperineal excision (ELAPE) are shown. (A-B) Blue arrows demonstrate a “waist” in the ELAPE specimen versus (C-D) a specimen with no “waist” (orange arrows). (D) A locally advanced rectal cancer specimen (patient underwent chemoradiotherapy) with an intact mesorectum (white arrow) and an acceptable ELAPE with no waist (orange arrow). (B) Adapted with permission.

Fig 2.

Representative T2-weighted (T2W) magnetic resonance images of a locally advanced rectal cancer tumor located at 1 cm above the dentate line. The yellow arrow indicates the tumor and the white arrow indicates its relationship to the levators. These images show high resolution and clear anatomic depictions of critical relationships involving the levator musculature, the tumor, and the mesorectum. (A) Coronal and (B) axial T2W magnetic resonance image.

Fig 3.

(A) The National Comprehensive Cancer Network guidelines, version 1.2015 for locally advanced rectal cancer. Adapted with permission. (B) The European/Scandinavian model of stratification for patients with locally advanced rectal cancer based on magnetic resonance imaging and then subsequent treatment decisions. Adapted with permission. Cape, capecitabine; CapeOx, capecitabine plus oxaliplatin; CRT, chemoradiotherapy; CT, chemotherapy; FLOX, fluorouracil, leucovorin, and oxaliplatin; FOLFOX, infusional fluorouracil, leucovorin, and oxaliplatin; FU, fluorouracil; inf., infusional; LR, local recurrence; LV, leucovorin; MRF, mesorectal fascia; RT, radiotherapy; TME, total mesorectal excision.

Fig 4.

(A) The PROSPECT trial (Chemotherapy Alone or Chemotherapy Plus Radiation Therapy in Treating Patients With Locally Advanced Rectal Cancer Undergoing Surgery) study schema is shown.^, This is a phase II/III randomized trial to evaluate the impact of selective use of radiotherapy compared with nonselective use of chemoradiotherapy (CRT) for all patients with locally advanced rectal cancer. Cycle length, 14 days; fluorouracil or capecitabine plus radiotherapy (FUCMT) duration, 5.5 weeks. Regression is estimated by tumor imaging and clinical tumor response on endoscopy. If there is evidence of progressive disease at restaging of the primary tumor after six cycles of infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX), group 1 patients would proceed to FUCMT instead of event monitoring. (B) Memorial Sloan Kettering Cancer Center phase II trial schema that is underway to test the feasibility of incorporating a nonoperative management (NOM) approach to the multimodality treatment of rectal cancer in a multi-institutional setting. This study will evaluate 3-year disease-free survival in patients with locally advanced rectal cancer treated with chemotherapy (CT) plus induction (INCT) or chemotherapy plus consolidation (CNCT) and total mesorectal excision (TME) or NOM. CapeOx, capecitabine plus oxaliplatin; DRE, digital rectal examination; LAR, low anterior resection; MRI, magnetic resonance imaging. (*) Patients with tumor progression at the interval evaluation will be treated according to standard of care.