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Optimizing Triage to Preoperative Chemoradiation in T2 Rectal Cancer Based on Mesorectal Lymph Node Size: A Decision Analysis Informed by Patient Outcomes Chang, Connie Y., M.D., Pandharipande, Pari, M.D., M.P.H., Harisinghani, Mukesh, M.D., Gazelle, G. Scott, M.D., M.P.H., Ph.D. HARVARD MEDICAL SCHOOL Background: Rectal Cancer MRI has had increasing role in preoperative planning for rectal cancer (T-stage) Large degree of overlap of size of normal/reactive and cancercontaining peri-rectal lymph nodes. Lymph Node Staging in Rectal Cancer Stage T2 rectal cancer Perirectal lymph nodes Purpose To optimize key patient outcomes in T2 rectal cancer by identifying mesorectal lymph node size criteria for triage to preoperative chemoradiation. Methods Decision-Analytic Model Model inputs derived from literature T2 rectal cancer Methods Treat All Patients with Pre-operative Chemoradiation Treat If any Mesorectal Lymph Nodes are > 3 mm Stage T2 Rectal Cancer Treat If any Mesorectal Lymph Nodes are > 5 mm Treat If any Mesorectal Lymph Nodes are > 7 mm No Preoperative Chemoradiation for Any Patients Methods: Four Disease Scenarios True Positive (TP) False Negative (FN) False Positive (FP) True Negative (TN) Methods: Four Disease Scenarios Preoperative chemoradiation No preoperative chemoradiation True Positive (TP) False Negative (FN) False Positive (FP) True Negative (TN) Methods: Four Disease Scenarios Lymph node metastases at pathology Preoperative chemoradiation No preoperative chemoradiation No lymph node metastases at pathology True Positive (TP) False Negative (FN) False Positive (FP) True Negative (TN) Methods: Four Disease Scenarios Lymph node metastases at pathology No lymph node metastases at pathology TP Appropriate FP Preoperative treatment – chemoradiation expected morbidity of preoperative chemoradiation TN Appropriate No preoperative FN treatment chemoradiation Methods: Four Disease Scenarios Lymph node metastases at pathology No lymph node metastases at pathology TP Appropriate FP Unnecessary Preoperative treatment – chemoradiation chemoradiation expected morbidity of preoperative chemoradiation TN Appropriate No preoperative FN treatment chemoradiation Methods: Four Disease Scenarios Lymph node metastases at pathology No lymph node metastases at pathology TP Appropriate FP Unnecessary Preoperative treatment – chemoradiation chemoradiation expected morbidity of preoperative chemoradiation TN Appropriate No preoperative FN Increased morbidity of treatment chemoradiation post-operative chemoradiation, increased likelihood of local recurrence Base Case Analysis All nodes considered malignant Nodes considered malignant if any node > 3 mm Nodes considered malignant if any node > 5 mm Nodes considered malignant if any node > 7 mm No nodes considered malignant * From Kim, et al (2004) Sensitivity 1 Specificity 0 0.91 0.43 0.73 0.75 0.55 0.91 0 1 Base Case Analysis Pre-operative Post-operative Chemoradiation Chemoradiation Acute Chemoradiation Toxic Effects Long-term Chemoradiation Toxic Effects 5-year Probability of Local Recurrence * Sauer, et al (2004) 27% 40% 14% 24% 6% 13% Secondary Analysis Individual node radiology-pathology correlation Schnall et al (1994), Brown et al (2003) Expanded data (318 nodes from 78 patients) Subject to “clustering bias” USPIO lymph node contrast agent Lahaye et al (2008) Sensitivity Analysis Performed to assess the impact of uncertainty in key model parameter estimates upon clinical outcomes Calculated 95% confidence intervals for sensitivity and specificity of each strategy Repeated analysis with upper and lower limits of the confidence intervals. Results – Base Case Analysis 30.00% 25.00% 20.00% 15.00% 10.00% 5.00% 0.00% Treat All Treat > 3mm Treat > 5mm Treat > 7 mm Treat None % Patients with Acute Chemoradiation Toxicity % Patients with Long-Term Chemoradiation Toxicity 5-Year Local Recurrence Results – Base Case Analysis 30.00% ● 25.00% Lowest Value ● 20.00% 15.00% ● 10.00% 5.00% 0.00% Treat All Treat > 3mm Treat > 5mm Treat > 7 mm Treat None % Patients with Acute Chemoradiation Toxicity % Patients with Long-Term Chemoradiation Toxicity 5-Year Local Recurrence Results – Base Case Analysis 30.00% ● 25.00% Lowest Value 20.00% 15.00% 10.00% 5.00% * ** * ●* * * 0.00% Treat All Treat > 3mm Treat > 5mm Treat > 7 mm Treat None % Patients with Acute Chemoradiation Toxicity % Patients with Long-Term Chemoradiation Toxicity 5-Year Local Recurrence Results – Base Case Analysis 30.00% ● 25.00% Lowest Value 20.00% 15.00% 10.00% 5.00% ● 0.00% Treat All Treat > 3mm Treat > 5mm Treat > 7 mm Treat None % Patients with Acute Chemoradiation Toxicity % Patients with Long-Term Chemoradiation Toxicity 5-Year Local Recurrence Results – Secondary and Sensitivity Analysis Individual node analysis – similar pattern of results to base case analysis Upper limits of all confidence intervals – differed for long-term chemoradiation toxicity Minimized if treat no patients preoperatively Lower limits of all confidence intervals – differed only for acute chemoradiation toxicity Minimized if treat patients with LNs > 7 mm Results – Sensitivity Analysis USPIO-Enhancement 30.00% 25.00% 20.00% 15.00% 10.00% * 5.00% ** 0.00% Treat All Treat > Treat > Treat > 7 Treat USPIO 3mm 5mm mm None Positivity % Patients with Acute Chemoradiation Toxicity % Patients with Long-Term Chemoradiation Toxicity 5-Year Local Recurrence Limitations Reduction of a complex disease into a simple decision model. Correct identification of stage T2 rectal cancer Conclusions Lymph node size criteria used is based on outcome prioritized at the individual patient level Acute toxicity – treat no patients Long-term toxicity – treat > 7 mm Local recurrence – treat all patients A higher threshold may better balance all three outcomes. Conclusions USPIO-positivity should be better than all size criteria for triaging patients to pre-operative chemoradiation. Thank you! References Brown G, Richards, CJ, Bourne, MW, et al. Morphologic predictors of lymph node status in rectal cancer with use of highspatial-resolution MR imaging with histopathologic comparison. Radiology 2003; 227:371-377. Kim JH, Beets GL, Kim, MJ, et al. High resolution MR imaging for nodal staging in rectal cancer: are there any criteria in addition to the size? EJR 2004; 52:78-83. References Lahaye MJ, Engelen SME, Kessels AGH, et al. USPIO-enhanced MR Imaging for Nodal Staging in Patients with Primary Rectal Cancer: Predictive Criteria. Radiology 2008; 246(3), 804-811. Schnall MD, Furth EE, Rosato EF, Kressel HY. Rectal tumor stage: Correlation of endorectal MR imaging and pathologic findings. Radiology 1994; 190:709-714. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. NEJM 2004; 351;17:1731-40. Secondary Analysis Sensitivity Specificity 1 0 0.30 0.94 0.86 0.51 0.57 0.82 0 1 All nodes considered malignant Nodes considered malignant if > 3 mm Nodes considered malignant if > 3 mm Nodes considered malignant if > 3 mm No nodes considered malignant * Schnall et al (1994) and Brown et al (2003)