Management of Locally Advanced Rectal Cancer

Qualifying statements for Recommendation 2.1:

• Clinical lymph node staging has limited accuracy. Therefore, the Expert Panel recommends against making treatment decisions based solely on radiographic nodal assessment.
• While this patient population is defined by validated prognostic factors, randomized controlled trial (RCT) data is not available for specific prognostic subpopulations, therefore, clinicians and patients should discuss the potential benefits and risks of harm associated with various treatment options relative to patients’ individual clinical and MRI prognostic features, as well as their values and preferences.

• Recommendations for patients with a tumor depth of extramural invasion of ≤5 mm and no other risk factors will be addressed in an ASCO guideline on earlier stage rectal cancer.

• Other options for patients with lower risk of recurrence include neoadjuvant long-course CRT or short-course radiation (RT). A discussion of the benefits and harms of neoadjuvant chemotherapy alone compared to neoadjuvant long-course CRT is included within the full text of the guideline.
• TNT may also be an option for some patients in this group, depending on the goals of treatment, e.g., complete response, and potentially nonoperative management (NOM). Choice of treatment should be made with consideration to toxicity profile, likelihood of identifying a complete response following neoadjuvant therapy, duration of treatment, and feasibility.

• In the OPRA phase II RCT, patients treated with chemotherapy after CRT had a higher rate of TME-free survival at 3 years, but no difference in disease-free survival compared to patients treated with chemotherapy before CRT.
• TNT with triplet chemotherapy before CRT may be discussed for patients at greater risk of distant metastases. Consideration of the higher rates of adverse events that may occur with triplet vs. doublet chemotherapy should be made for patients with comorbidities or older age, e.g., in the PRODIGE 23 trial, eligibility to the trial was limited to patients under 76 years of age to improve the safety of FOLFIRINOX chemotherapy.
• Delivery of chemotherapy prior to CRT is an additional recommended option for TNT candidates, particularly in settings where the initiation of radiation therapy may be slower than the initiation of chemotherapy.

Note for Recommendation 4.1:

• This recommendation is based on longer-term results of the RAPIDO phase III RCT showing a significantly higher rate of 5-year locoregional failure with TNT with short-course RT (10%), compared to standard CRT (6%), while the reduction in the rate of disease-related treatment failure and distant metastases with TNT compared to CRT was maintained at 5 years post-treatment.

Qualifying statements for Recommendation 4.1:

• Short-course RT may also be a viable treatment option. The choice of long-course CRT or short-course RT is patient-circumstance driven, and long-course CRT may be more appropriate for patients with higher risk features similar to those required for inclusion in the RAPIDO trial or for patients considering a goal of NOM.
• Research on duration of RT is currently ongoing, including the CAO/ARO/AIO-18.1 phase III trial, in which intermediate-and high-risk patients with locally advanced rectal cancer are randomly assigned to short-course RT as in the RAPIDO trial, or long-course CRT, both followed by chemotherapy and surgery or NOM for patients with a clinical complete response (cCR).

Note for Recommendation 5.1:

• Studies of NOM in this review included patients who underwent neoadjuvant therapy that included radiation; no studies of NOM after neoadjuvant chemotherapy alone were included in this review.

Qualifying statements for Recommendation 5.1:

• Decision making should include a discussion of the potential for improved functional outcomes, surgical risk, surveillance requirements, and reduced risk of a permanent ostomy if NOM is offered.
• A preference for this approach may be greater among those patients who require an abdominoperineal resection (APR) or a coloanal anastomosis. The benefits of organ preservation among those with distal tumors include avoiding a TME with ultra-low anastomosis, and a location that is more amenable to close surveillance for regrowth, compared to more proximal tumors.
• In the OPRA trial, the surveillance protocol included digital rectal examination (DRE) and flexible sigmoidoscopy every 4 months for the first 2 years from the time of assessment of response, continuing every 6 months for the following 3 years. Rectal MRI was to be performed every 6 months for the first 2 years and yearly for the following 3 years. Guidance on the imaging component of response assessment and in follow-up of NOM is beyond the scope of this guideline.
• First assessment of complete response for the purpose of determining eligibility for NOM should be made at 8 +/–4 weeks following the completion of any TNT regimen.
• A definition of cCR is provided (Fokas, et al 2021, p. 808, doi: 10.1038/s41571-021-00538-5). Note that this definition has been slightly modified from the original to indicate that when using cCR to inform eligibility for NOM, there should be no ulcer present:
  • DRE and rectoscopy: no palpable tumor material present, no residual tumor material, and no erythematous ulcer or scar; and
  • MRI: substantial downsizing with no observable residual tumor material, or residual fibrosis only (with limited signal on diffusion weighted imaging), sometimes associated with residual wall thickening owing to edema, no suspicious lymph nodes.
  • Endoscopic biopsy: not mandatory or required to define cCR, biopsy should not be performed and is not recommended, especially if the DRE, rectoscopy and MRI criteria for cCR are all fulfilled.

Qualifying statement for Recommendation 6.1:

• The treatment options outlined in Recommendations 2.1 to 4.1 are recommended for patients with tumors that are MSI-H or dMMR and have contraindications to immunotherapy. dMMR tumors have been shown to be sensitive to CRT. Historically, fluorouracil-based chemotherapy has been less effective in patients with dMMR.