What is the role of modified Ryan scoring versus complete metabolic and radiological response in assessing treatment efficacy in patients with rectal adenocarcinoma post neoadjuvant therapy?

Modified Ryan Scoring vs Complete Metabolic and Radiological Response Post-Neoadjuvant Therapy for Rectal Adenocarcinoma

Primary Recommendation

For assessing treatment efficacy post-neoadjuvant therapy in rectal adenocarcinoma, pathological response grading (including modified Ryan scoring) remains the gold standard for prognostic stratification and treatment planning, while clinical complete response (cCR) assessment using combined MRI, endoscopy, and digital rectal examination is the appropriate method for selecting patients for organ preservation strategies. 1

Understanding the Two Assessment Paradigms

Pathological Response Assessment (Modified Ryan Scoring)

Modified Ryan scoring provides definitive prognostic information but requires surgical resection, making it incompatible with organ preservation approaches. 2

• Ryan Grade 0 (pathological complete response/pCR) occurs in approximately 18-26% of patients after neoadjuvant chemoradiotherapy and represents the best prognostic category with 10-year distant metastasis rates of only 10.5% and disease-free survival of 89.5%. 1

• Ryan Grade 0-1 patients may require only standard adjuvant chemotherapy with total treatment duration not exceeding 6 months, while high-risk patients with poor Ryan grades require intensified FOLFOX regimens for up to 12 cycles. 2

• Pathological assessment correlates strongly with long-term outcomes: 5-year recurrence-free survival rates are 90.5% for complete response, 78.7% for intermediate response, and 58.5% for poor response (P<.001). 1

Clinical Complete Response Assessment (Metabolic and Radiological)

cCR assessment is specifically designed for selecting patients for nonoperative management (NOM) and cannot be used interchangeably with pathological grading. 1

The 2024 ASCO guideline provides a strict definition of cCR for NOM eligibility 1:

• Digital rectal examination and rectoscopy: No palpable tumor, no residual tumor material, and critically—no erythematous ulcer or scar present
• MRI criteria: Substantial downsizing with no observable residual tumor or residual fibrosis only (with limited signal on diffusion-weighted imaging), no suspicious lymph nodes
• Endoscopic biopsy: Not mandatory and actually not recommended if DRE, rectoscopy, and MRI criteria are fulfilled

Critical Discordance Between cCR and pCR

The fundamental limitation is that cCR and pCR are not concordant, creating significant challenges in patient selection. 1

• cCR rates are generally much lower than pCR rates in randomized trials, indicating difficulties with detecting preoperative response. 1

• In the OPRA trial, combined cCR and near-complete response rates were 71-76%, but these included patients who would not have met strict cCR criteria. 1

• MRI has only 64% overall accuracy for response assessment, with 65% sensitivity for detecting complete response and 63% specificity for detecting residual tumor, according to a 2023 multireader study. 3

• MRI tends to overstage residual disease: Complete T2 hypointensity demonstrated only 70% accuracy for pCR with negative predictive value of only 66.7%. 1

Algorithmic Approach to Post-Neoadjuvant Assessment

Step 1: Define Treatment Intent Before Neoadjuvant Therapy

If organ preservation is a potential goal (particularly for low rectal tumors requiring abdominoperineal resection):

• Plan for long-course chemoradiotherapy rather than short-course radiotherapy, as the RAPIDO trial showed 10% locoregional failure with short-course RT versus 6% with long-course CRT at 5 years. 1, 4
• Consider total neoadjuvant therapy with consolidation chemotherapy after radiation. 4

If surgical resection is planned regardless of response:

• Either radiation approach is acceptable
• Focus will be on pathological Ryan grading to guide adjuvant therapy

Step 2: Timing of Response Assessment

First assessment for cCR eligibility should occur at 8 ± 4 weeks following completion of any total neoadjuvant therapy regimen. 1

• In the OPRA trial, median time from restaging to TME was 7 weeks for patients recommended immediate surgery versus 30 weeks for those with subsequent regrowth. 1

Step 3: Response Assessment Protocol

For patients being considered for NOM, perform multimodal assessment 1:

1. Digital rectal examination: Must show no palpable tumor
2. Flexible sigmoidoscopy: Must show no residual tumor material and no ulcer
3. Pelvic MRI with diffusion-weighted imaging: Must show substantial downsizing with no residual tumor or only fibrosis with limited DWI signal
4. Do NOT perform biopsy if the above three criteria are met, as negative biopsies do not reliably predict pCR 1, 5

For patients proceeding to surgery, pathological Ryan grading will be performed on the resection specimen to guide adjuvant therapy. 2

Step 4: Management Based on Assessment

If strict cCR criteria are met and patient desires organ preservation 1:

• Discuss NOM as alternative to total mesorectal excision
• Implement intensive surveillance: DRE and flexible sigmoidoscopy every 4 months for 2 years, then every 6 months for 3 years
• Rectal MRI every 6 months for 2 years, then yearly for 3 years
• Critical caveat: In a 2019 Memorial Sloan Kettering study, 22 of 113 patients (19%) in the watch-and-wait group developed local regrowth, and those with regrowth had 36% distant metastasis rate versus 1% in those without regrowth. 6

If cCR criteria are not met or patient prefers surgery:

• Proceed with total mesorectal excision
• Use pathological Ryan grading to determine adjuvant therapy intensity
• Initiate adjuvant treatment within 8 weeks post-surgery (delays beyond 12 weeks significantly compromise survival). 2

Role of FDG-PET/CT

FDG-PET/CT has limited utility for confirming complete response but can help exclude patients from organ preservation. 1

• Post-CRT SUVmax >4.3 is highly correlated with lack of complete response (negative predictive value up to 94%). 1
• PET/CT is more useful for ruling out pCR than confirming it, making it appropriate for identifying patients who should proceed to surgery rather than selecting patients for NOM. 1

Common Pitfalls to Avoid

Do not use cCR assessment to guide adjuvant chemotherapy decisions—this requires pathological Ryan grading from surgical specimens. 2

Do not rely on MRI alone for cCR determination—the 2023 multireader study showed substantial interobserver variability and only 64% overall accuracy. 3

Do not perform endoscopic biopsies to "confirm" cCR—negative biopsies are unreliable, and the 2024 ASCO guideline explicitly states biopsies are not recommended when clinical, endoscopic, and MRI criteria are met. 1

Do not offer NOM to patients with residual ulceration or erythema on endoscopy, even if other criteria suggest response—the strict ASCO definition requires no ulcer present. 1

Do not delay adjuvant therapy beyond 8 weeks post-surgery when pathological assessment shows high-risk features—optimal timing is critical for outcomes. 2

Recognize that patients achieving cCR who develop local regrowth have dramatically higher distant metastasis rates (36% vs 1%), emphasizing the importance of strict surveillance protocols. 6