A Population-Level Validation of the New 9th Edition of the American Joint Commission on Cancer Staging System for Anal Squamous Cell Carcinoma.

BACKGROUND AND OBJECTIVES: The staging system for anal squamous cell carcinoma (ASCC) was recently revised, downstaging selected node-positive patients and upstaging some with larger tumors. We aimed to validate this staging system using a population-based cohort. METHODS: The Surveillance, Epidemiology, and End Results database was analyzed to identify adult ASCC patients. Patients were staged according to the American Joint Committee on Cancer (AJCC) 8th and 9th edition systems. Survival probabilities were estimated using Kaplan-Meier curves. Cox regression models were utilized to estimate the effect of stage on overall (OS) and cancer-specific survival (CSS). RESULTS: A total of 2117 patients were identified and staged based on the two AJCC classifications. At 24 months when comparing stage IIB versus stage IIIA, the 8th edition revealed an improved OS (79% vs. 88%) and CSS (84% vs. 91%) for stage IIIA disease, while the 9th edition restored the hierarchical OS (IIB 88% vs. IIIA 78%) and CSS (91% vs. 82%) order. CONCLUSIONS: The hierarchical increase of the OS HRs, and nearly all CSS HRs, across disease stages validated the updated edition of the AJCC classification. Although this change may not have significant implication on the management of ASCC, it does provide better prognostication.

Splenic flexure adenocarcinoma: A national cohort analysis of extent of surgical resection and outcomes.

AIM: The optimal extent of resection for splenic flexure adenocarcinoma remains debated. These tumours straddle the left- and right-sided vasculature with lymphatic drainage in a watershed area; current guidelines recommend either segmental or extended colectomy. We analysed surgical management of splenic flexure tumours and compared outcomes between approaches. METHOD: The Surveillance, Epidemiology and End Results database was searched for adults with Stage I-III splenic flexure adenocarcinoma, 2004-2019. RESULTS: Of 5238 patients, 55% underwent extended colectomy. Compared to segmental colectomy, these patients were more likely to have advanced stage. On multivariable analysis, age ≤ 65 years remained independently associated with extended colectomy. Although fewer nodes were examined in segmental colectomy (median 14 vs. 16, p < 0.001), the number of positive nodes (both, median 0 [interquartile ratio 0-2], p = 0.20) and the lymph node ratio were similar between cohorts. Surgical approach was not significantly associated with increased positive nodal yield in adjusted analyses. Five-year overall and disease-specific survival were 73% and 84% for segmental and 72% and 83% for extended colectomy (p > 0.4); these remained comparable after adjustment. CONCLUSIONS: Nationally, we observed similar rates of segmental and extended colectomy for splenic flexure adenocarcinoma. Extended colectomy was not more common in Stage III disease, indicating lack of stage migration, and was not associated with better oncological outcomes. These observations support current practice involving either approach, which should be tailored to patient-related factors and preferences, while considering technical aspects and quality of life.

Treatment of Stages I-III Squamous Cell Anal Cancer: A Comparative Effectiveness Systematic Review.

PURPOSE: To assess the effectiveness and harms of initial treatment strategies for stages I-III anal squamous cell cancer (SCC). METHODS: We searched Medline®, Embase®, and CENTRAL®, between January 1, 2000- March 2024, for randomized controlled trials and nonrandomized studies of interventions comparing initial treatment strategies. Individual study risk of bias (RoB) and overall strength of evidence (SOE) were evaluated for a prespecified outcome list using standardized methods. RESULTS: We identified 33 eligible studies and extracted data. Six were deemed low/moderate RoB. Compared with radiotherapy (RT) alone, chemoradiotherapy (CRT) with 5-fluorouracil (FU) and mitomycin C (MMC) probably shows a benefit in locoregional failure (LRF), disease-specific (DSS), and colostomy-free survival (CFS) (moderate SOE) yet may result in greater overall and acute hematologic toxicity, with no difference in late harms (low SOE). CRT with 5FU+MMC may show a benefit in LRF, DSS, and CFS rates compared with 5FU alone (low SOE). CRT with 5FU+cisplatin vs 5FU+MMC probably results in no differences in several effectiveness outcomes or overall acute or late harms, and probably increases hematologic toxicity with MMC (moderate SOE). Compared with CRT using capecitabine+MMC, CRT with capecitabine+MMC+paclitaxel may improve OS, DSS, and CFS, yet cause more acute harms (low SOE). Evidence was insufficient for remaining comparisons. CONCLUSIONS: CRT with 5FU+MMC or 5FU+cisplatin is likely more effective yet incurs greater acute hematologic toxicity than RT alone or single-agent CRT. Adding paclitaxel to capecitabine+MMC may increase treatment efficacy and toxicity. Evidence is insufficient comparing post-treatment surveillance strategies and patient-reported outcomes, highlighting research opportunities.

The Role of Tumor Location on Endoscopic and Surgical Management of Malignant Colon Polyps.

BACKGROUND: Endoscopic polypectomy could be an appropriate, definitive treatment for pathologic T1 (pT1) colon polyps without high-risk features. Prior studies suggested worse prognosis for proximal versus distal advanced-stage colon cancers following curative treatment. However, there is limited evidence on the prognostic impact of tumor location for pT1s. PATIENTS AND METHODS: This was a retrospective cohort study using the Surveillance, Epidemiology, and End Results database to identify adults with T1NxMx or T1N0-3M0/x colon adenocarcinoma from 2000 to 2019. RESULTS: A total of 3398 patients underwent endoscopic polypectomy (17% proximal) and 28,334 had a partial colectomy (49% proximal) for pT1 adenocarcinoma. Following endoscopic polypectomy, 5-year overall and cancer-specific survival rates were 64% and 91% for proximal versus 83% and 96% for distal polyps, compared with 82% and 95% for proximal versus 88% and 97% for distal tumors after colectomy. In multivariable models, there was a greater difference in overall survival between proximal and distal polyps for those who underwent endoscopic versus surgical resection [hazard ratio (HR) 1.73, 95% confidence interval (CI) 1.49-2.02 vs. HR 1.13, 95% CI 1.08-1.18]. Patients with proximal versus distal polyps who underwent polypectomy also exhibited increased cancer-specific mortality (HR 1.94, 95% CI 1.37-2.75). However, cancer-specific survival variations based on tumor location were no longer observed in patients undergoing partial colectomy (HR 1.09, 95% CI 0.98-1.21). CONCLUSIONS: Proximal tumor location was independently associated with worse overall and cancer-specific survival following endoscopic polypectomy. However, after colectomy, the cancer-specific disparity based on tumor laterality was mitigated. These findings suggest that proximal location may be considered a high-risk feature in endoscopic polypectomy.

Pathologic Complete Response, Total Neoadjuvant Therapy and the Survival Paradox in Locally Advanced Rectal Cancer.

BACKGROUND: Pathologic complete response (pCR) after preoperative chemoradiation (nCRT) correlates with improved overall survival for patients with locally advanced rectal cancers (LARCs). Escalation protocols including total neoadjuvant therapy (TNT), which delivers multi-agent chemotherapy and chemoradiation before surgery, are associated with increased complete response rates. However, TNT is not associated with improved overall survival. The authors hypothesized that the route to pCR may be an important predictor of oncologic outcome. METHODS: Adults with LARC between 2006 and 2017 were identified in the National Cancer Database. The cohort was limited to those who received neoadjuvant radiation (45-70 Gy) and underwent proctectomy. RESULTS: Of 25,880 patients, 16 % received TNT and 84 % had nCRT followed by either multi-agent (27 %), single-agent (14 %), or no adjuvant chemotherapy (44 %). Overall, 18 % achieved pCR, with higher rates in the TNT cohort than in the nCRT (18 %) or multi-agent (14 %) chemotherapy cohorts. With control for covariates, the OS in the pCR cohort was similar for the patients that received single-agent therapy and those that received multi-agent adjuvant therapy, and superior to the TNT and no adjuvant therapy cohorts. Conversely, among the patients who did not achieve pCR, those who received single-agent chemotherapy had OS comparable with those who had multi-agent adjuvant therapy and TNT, which was better than no adjuvant therapy. CONCLUSION: Patients achieving pCR after TNT had worse OS than those who had CRT alone, suggesting that the neoadjuvant route by which pCR is achieved is prognostically relevant. Therefore, in the era of neoadjuvant therapy escalation, pCR does not necessarily portend a uniformly favorable prognosis.

Evaluation of association between center colorectal neuroendocrine neoplasm volume and survival among patients with colorectal neuroendocrine carcinoma.

BACKGROUND: Although correlation between center volume and survival has been reported for several complex cancers, it remains unknown if this is true for colorectal neuroendocrine carcinomas (CRNECs). We hypothesized that higher center annual volume of colorectal neuroendocrine neoplasm resections would be associated with overall survival (OS) for patients with CRNECs. METHODS: Patients in the National Cancer Database diagnosed with stages I-III CRNEC between 2006 and 2018 and who underwent surgical resection were identified. The mean annual colorectal neuroendocrine neoplasm resection volume threshold associated with significantly worse mortality hazard was determined using restricted cubic splines. Kaplan-Meier (KM) method was used to compare OS, while Cox proportional hazards model was used for multivariable analysis. RESULTS: There were 694 patients with CRNEC who met inclusion criteria across 1229 centers. Based on the cubic spline, centers treating fewer than one colorectal neuroendocrine neoplasm patient every 3 years on average had worse outcomes. Centers below this threshold were classified as low-volume (LV) centers corresponding with 42% of centers and about 15% of the patient cohort. In unadjusted survival analysis, LV patients had a median OS of 14 months (95% confidence interval [CI]: 10-19) while those treated at HV centers had a median OS of 33 months (95% CI: 25-49). In multivariable analysis, resection at a LV center was associated with increased risk of mortality (1.42 [95% CI: 1.01-2.00], p = 0.04). CONCLUSION: CRNEC patients have a dire prognosis; however, treatment at an HV center may be associated with decreased risk of mortality.

Management and staging of anal adenocarcinoma in the United States: a population-based analysis.

BACKGROUND: Anal adenocarcinoma is rare with no standardized treatment regimen or staging system. Therefore, different combinations of chemotherapy, radiation, and surgery are used in management. Within the staging system, tumor stage can be based on the depth of invasion, as for rectal adenocarcinoma, or size, as in anal squamous cell carcinoma. This study aimed to analyze patterns of care and clinically available staging systems for anal adenocarcinoma using a national database. METHODS: Adults diagnosed with anal adenocarcinoma were identified in the Surveillance, Epidemiology, and End Results database (2004-2019). In addition, 6 different treatment regimens were identified. Stages were categorized according to the American Joint Committee on Cancer classifications of rectal adenocarcinoma and anal squamous cell carcinoma. RESULTS: Of 1040 patients, 48% were female, the median age was 67 years, and 18% had distant metastases. Chemoradiotherapy + abdominoperineal resection was the most common treatment regimen (22%). Moreover, 5-year overall survival (OS) and disease-specific survival (DSS) were the highest for local excision only (67% and 85%) and the lowest in the alternative group (34% and 48%). After adjustment, the treatment groups that did not include surgery were associated with worse 5-year OS. In multivariable analysis, the T stage based on depth of invasion showed incrementally lower OS for T2 and T3 anal adenocarcinomas. CONCLUSION: Omission of surgical resection in combination with chemoradiotherapy was associated with worse OS and DSS, suggesting the relevance of surgery in anal adenocarcinoma management. Prognostically, rectal staging based on depth of invasion better discriminated between T stages, indicating that providers should consider using this system in practice.

NSQIP 5-factor modified frailty index and complications after ileal anal pouch anastomosis for ulcerative colitis.

Background: Frailty has been associated with worse postoperative outcomes. The 5-factor modified frailty index (mFI-5) is an objective measure although its validity in measuring frailty in patients undergoing ileal pouch-anal anastomosis (IPAA) for chronic ulcerative colitis (CUC) has not been reported. Methods: This study used the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) targeted proctectomy database. The mFI-5 was calculated by five preoperative diagnoses: insulin-dependent or noninsulin-dependent diabetes, congestive heart failure, hypertension, chronic obstructive pulmonary disease, and dependent or partially dependent functional status. The impact of mFI-5 on minor and major postoperative morbidity in CUC patients undergoing IPAA was analyzed. Results: The cohort included 1454 patients (median age 38 years, median body mass index [BMI] 26 kg/m2) of which 87 % had a mFI-5 = 0, 11 % had a mFI-5 = 1, and 2.5 % a mFI-5 ≥ 2. In multivariable logistic regression, mFI-5 ≥ 2 was significantly associated with minor complications (OR = 2.29, 95 % CI [1.00-5.22], p = 0.049), but not with major complications (p = 0.860). Conclusion: IPAA for CUC is associated with high postoperative morbidity, however, the mFI-5 alone has limited utility in determining which patients are at a higher risk of complications due to frailty. These observations suggest there is a need for more relevant instruments to measure frailty in this patient cohort.

A population-based analysis on the incidence of metachronous colon cancer after endoscopic resection of advanced adenomas with high-grade dysplasia: does location matter?

BACKGROUND: Advanced adenomas (AAs) with high-grade dysplasia (HGD) represent a risk factor for metachronous neoplasia, with guidelines recommending short-interval surveillance. Although the worse prognosis of proximal (vs distal) colon cancers (CCs) is established, there is paucity of evidence on the impact of laterality on the risk of subsequent neoplasia for these AAs. METHODS: Adults with HGD adenomas undergoing polypectomy were identified in the Surveillance, Epidemiology, and End Results database (2000-2019). Cumulative incidence of malignancy was estimated using the Kaplan-Meier method. Fine-Gray models assessed the effect of patient and disease characteristics on CC incidence. RESULTS: Of 3199 patients, 26% had proximal AAs. A total of 65 cases of metachronous adenocarcinoma were identified after polypectomy of 35 proximal and 30 distal adenomas with HGD. The 10-year cumulative incidence of CC was 2.3%; when stratified by location, it was 4.8% for proximal vs 1.4% for distal adenomas. Proximal location was significantly associated with increased incidence of metachronous cancer (adjusted hazard ratio, 3.32; 95% CI, 2.05-5.38). CONCLUSION: Proximal location of AAs with HGD was associated with >3-fold increased incidence of metachronous CC and shorter time to diagnosis. These data suggest laterality should be considered in the treatment and follow-up of these patients.

Epidemiology and survival outcomes of colorectal mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinoma.

BACKGROUND: Mixed neuroendocrine-non-neuroendocrine neoplasms are a rare subtype of neuroendocrine neoplasm consisting of ≥30% each of neuroendocrine and non-neuroendocrine differentiation. Neuroendocrine carcinomas are poorly differentiated neuroendocrine tumors. The epidemiology and prognosis of colorectal mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas are not clearly defined in the literature. We sought to examine the presentation, patterns of care, and outcomes of patients with mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas. METHODS: We identified patients diagnosed with stage I-III colorectal (excluding appendix) mixed neuroendocrine-non-neuroendocrine neoplasms or neuroendocrine carcinomas with only one-lifetime cancer diagnosis who underwent surgical resection between 2010 and 2018 from the National Cancer Database. We performed bidirectional selection to identify variables to include in a multivariable Cox proportional hazards model. RESULTS: We identified 189 patients with a diagnosis of stage I to III colorectal mixed neuroendocrine-non-neuroendocrine neoplasms, 66% of whom had poorly differentiated tumors and 482 with neuroendocrine carcinomas. Among patients with stage III disease, 68% of patients with mixed neuroendocrine-non-neuroendocrine neoplasms and 54% of patients with neuroendocrine carcinomas received adjuvant chemotherapy. The median survival for the overall patients with mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas cohorts were 38 and 42 months, respectively (P = .22), and the median survival for patients with mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas with stage III disease were 30 and 25 months, respectively (P = .27). In multivariable analysis, fewer number of positive nodes and receipt of adjuvant chemotherapy were independently associated with decreased risk of mortality for patients with mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas. CONCLUSION: Adjuvant chemotherapy is associated with improved survival in stage III mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas. Future studies are warranted to identify subsets of patients benefiting most from adjuvant therapy.

Prediction of Pathologic Complete Response for Rectal Cancer Based on Pretreatment Factors Using Machine Learning.

BACKGROUND: Pathologic complete response after neoadjuvant therapy is an important prognostic indicator for locally advanced rectal cancer and may give insights into which patients might be treated nonoperatively in the future. Existing models for predicting pathologic complete response in the pretreatment setting are limited by small data sets and low accuracy. OBJECTIVE: We sought to use machine learning to develop a more generalizable predictive model for pathologic complete response for locally advanced rectal cancer. DESIGN: Patients with locally advanced rectal cancer who underwent neoadjuvant therapy followed by surgical resection were identified in the National Cancer Database from years 2010 to 2019 and were split into training, validation, and test sets. Machine learning techniques included random forest, gradient boosting, and artificial neural network. A logistic regression model was also created. Model performance was assessed using an area under the receiver operating characteristic curve. SETTINGS: This study used a national, multicenter data set. PATIENTS: Patients with locally advanced rectal cancer who underwent neoadjuvant therapy and proctectomy. MAIN OUTCOME MEASURES: Pathologic complete response defined as T0/xN0/x. RESULTS: The data set included 53,684 patients. Pathologic complete response was experienced by 22.9% of patients. Gradient boosting showed the best performance with an area under the receiver operating characteristic curve of 0.777 (95% CI, 0.773-0.781), compared with 0.684 (95% CI, 0.68-0.688) for logistic regression. The strongest predictors of pathologic complete response were no lymphovascular invasion, no perineural invasion, lower CEA, smaller size of tumor, and microsatellite stability. A concise model including the top 5 variables showed preserved performance. LIMITATIONS: The models were not externally validated. CONCLUSIONS: Machine learning techniques can be used to accurately predict pathologic complete response for locally advanced rectal cancer in the pretreatment setting. After fine-tuning a data set including patients treated nonoperatively, these models could help clinicians identify the appropriate candidates for a watch-and-wait strategy. See Video Abstract . EL CNCER DE RECTO BASADA EN FACTORES PREVIOS AL TRATAMIENTO MEDIANTE EL APRENDIZAJE AUTOMTICO: ANTECEDENTES:La respuesta patológica completa después de la terapia neoadyuvante es un indicador pronóstico importante para el cáncer de recto localmente avanzado y puede dar información sobre qué pacientes podrían ser tratados de forma no quirúrgica en el futuro. Los modelos existentes para predecir la respuesta patológica completa en el entorno previo al tratamiento están limitados por conjuntos de datos pequeños y baja precisión.OBJETIVO:Intentamos utilizar el aprendizaje automático para desarrollar un modelo predictivo más generalizable para la respuesta patológica completa para el cáncer de recto localmente avanzado.DISEÑO:Los pacientes con cáncer de recto localmente avanzado que se sometieron a terapia neoadyuvante seguida de resección quirúrgica se identificaron en la Base de Datos Nacional del Cáncer de los años 2010 a 2019 y se dividieron en conjuntos de capacitación, validación y prueba. Las técnicas de aprendizaje automático incluyeron bosque aleatorio, aumento de gradiente y red neuronal artificial. También se creó un modelo de regresión logística. El rendimiento del modelo se evaluó utilizando el área bajo la curva característica operativa del receptor.ÁMBITO:Este estudio utilizó un conjunto de datos nacional multicéntrico.PACIENTES:Pacientes con cáncer de recto localmente avanzado sometidos a terapia neoadyuvante y proctectomía.PRINCIPALES MEDIDAS DE VALORACIÓN:Respuesta patológica completa definida como T0/xN0/x.RESULTADOS:El conjunto de datos incluyó 53.684 pacientes. El 22,9% de los pacientes experimentaron una respuesta patológica completa. El refuerzo de gradiente mostró el mejor rendimiento con un área bajo la curva característica operativa del receptor de 0,777 (IC del 95%: 0,773 - 0,781), en comparación con 0,684 (IC del 95%: 0,68 - 0,688) para la regresión logística. Los predictores más fuertes de respuesta patológica completa fueron la ausencia de invasión linfovascular, la ausencia de invasión perineural, un CEA más bajo, un tamaño más pequeño del tumor y la estabilidad de los microsatélites. Un modelo conciso que incluye las cinco variables principales mostró un rendimiento preservado.LIMITACIONES:Los modelos no fueron validados externamente.CONCLUSIONES:Las técnicas de aprendizaje automático se pueden utilizar para predecir con precisión la respuesta patológica completa para el cáncer de recto localmente avanzado en el entorno previo al tratamiento. Después de realizar ajustes en un conjunto de datos que incluye pacientes tratados de forma no quirúrgica, estos modelos podrían ayudar a los médicos a identificar a los candidatos adecuados para una estrategia de observar y esperar. (Traducción-Dr. Ingrid Melo ).