Prediction of Poor Response to Neoadjuvant Chemoradiation in Patients With Rectal Cancer Using a DNA Repair Deregulation Score: Picking the Losers Instead of the Winners.

BACKGROUND: Patients with rectal cancer may undergo neoadjuvant chemoradiation even in early stages in an attempt to achieve complete clinical response and undergo organ preservation. However, prediction of tumor response is unavailable. In this setting, accurate identification of poor responders could spare patients with early stage disease from potentially unnecessary chemoradiation. OBJECTIVE: This study focused on development/test of a score based on DNA repair gene expression to predict response to neoadjuvant chemoradiation in patients with rectal cancer. DESIGN: Pretreatment biopsy samples from patients with rectal cancer undergoing neoadjuvant chemoradiation were collected and underwent gene expression analysis using RNA-Seq (test cohort). A score was constructed using 8 differentially expressed DNA repair genes between good (complete clinical) and poor responders (incomplete clinical) to treatment. The score was validated in 2 independent cohorts of patients undergoing similar treatment strategies and using quantitative polymerase chain reaction and microarray gene expression data. SETTINGS: This was a retrospective analysis of gene expression data from 3 independent institutions. PATIENTS: Patients with rectal cancer undergoing neoadjuvant chemoradiation (50.4-54.0 Gy and 5-fluorouracil-based chemotherapy) were eligible. Patients with complete clinical response, complete pathological response, or ≤10% residual cancer cells were considered good responders. Patients with >10% residual cancer cells were considered poor responders. The test cohort included 25 patients (16 poor responders). Validation cohort 1 included 28 patients (18 poor responders), and validation cohort 2 included 46 patients (22 poor responders). MAIN OUTCOMES MEASURES: Response was correlated with the DNA repair score calculated using the expression levels of 8 DNA repair genes. DNA repair score sensitivity, specificity, and positive and negative predictive values were determined in test and validation cohorts. RESULTS: Poor responders had significantly lower DNA repair scores when compared with good responders across all 3 cohorts, regardless of the gene expression platform used. A low score correctly predicted poor response in 93%, 90%, and 71% in test, validation 1, and validation 2 cohorts. LIMITATIONS: This study was limited by its small sample size, different gene expression platforms, and treatment regimens across different cohorts used. CONCLUSIONS: A DNA repair gene score may predict patients likely to have poor response to chemoradiation. This score may be a relevant tool to be investigated in future studies focused on chemoradiation used in the context of organ preservation. See Video Abstract at http://links.lww.com/DCR/B104. PREDICCIÓN DE RESPUESTA DEFICIENTE A LA RADIO-QUIMIOTERAPIA NEOADYUVANTE EN PACIENTES CON CÁNCER RECTAL UTILIZANDO UNA PUNTUACIÓN DE DESREGULACIÓN DE REPARACIÓN DE ADN: ESCOGER LOS PERDEDORES EN LUGAR DE LOS GANADORES: Los pacientes con cáncer rectal pueden someterse a radio-quimioterapia neoadyuvante incluso en estadios tempranos en el intento por lograr una respuesta clínica completa y permitir una preservación de órgano. Sin embargo, aun no existen herramientas disponible para la prediccion de la respuesta tumoral al tratamiento. En este contexto, la identificación precisa de los tumores con mala respuesta al tratamiento podría evitar que los pacientes con enfermedad en estadio temprano sean sometidos a radio-quimioterapia potencialmente innecesaria.Desarrollo / testeo de una puntuación basada en la expresión genes reparadores del ADN para predecir la respuesta a la nCRT en pacientes con cáncer rectal.Se recogieron muestras de biopsia de pre-tratamiento de pacientes con cáncer rectal sometidos a radio-quimioterapia neoadyuvante y se les realizó un análisis de expresión génica utilizando RNAseq (cohorte de prueba). Se construyó una puntuación utilizando 8 genes de reparación de ADN expresados diferencialmente entre buenos (respuesta clinica completa) y pobres respondedores (respuesta clinica incompleta) al tratamiento. La puntuación se validó en 2 cohortes independientes de pacientes sometidos a estrategias de tratamiento similares y utilizando qPCR y datos de expresión de genes en chips ADN (biotecnología -microarrays).Análisis retrospectivo de los datos de expresión génica de 3 instituciones independientes.Fueron incluidos aquellos pacientes con cáncer rectal sometidos a radio-quimioterapia neoadyuvante (50,4-54 Gy y quimioterapia basada en 5FU). Los pacientes con respuesta clínica completa, respuesta patológica completa o ≤10% de células cancerosas residuales se consideraron buenos respondedores. Los pacientes con> 10% de células cancerosas residuales se consideraron de respuesta deficiente. La cohorte de prueba incluyó a 25 pacientes (16 respondedores pobres). La cohorte de validación n. ° 1 incluyó a 28 pacientes (18 respondedores pobres) y la cohorte de validación n. ° 2 incluyó a 46 pacientes (22 respondedores pobres).La respuesta se correlacionó con la puntuación de reparación de ADN calculada utilizando los niveles de expresión de 8 genes de reparación de ADN. La sensibilidad del puntaje de reparación del ADN, la especificidad, los valores predictivos positivos y negativos se determinaron en las cohortes de prueba y validación.Los malos respondedores tuvieron puntuaciones de reparación de ADN significativamente más bajas en comparación con los buenos respondedores en las 3 cohortes, independientemente de la plataforma de expresión génica utilizada. Una puntuación baja predijo correctamente una respuesta pobre en el 93%, 90% y 71% en las cohortes de prueba, validación n. ° 1 y validación n. ° 2, respectivamente.Pequeño tamaño de la muestra, diferentes plataformas de expresión génica y regímenes de tratamiento en diferentes cohortes utilizadas.La puntuacion basada en genes de reparación del ADN puede predecir los pacientes con respuesta pobre a la radio-quimioterapia. Esta puntuación puede ser una herramienta relevante para investigar en futuros estudios centrados en la radio-quimioterapia utilizada en el contexto de la preservación de órganos. Consulte Video Resumen en http://links.lww.com/DCR/B104. (Traducción-Dr. Xavier Delgadillo and Dr. Laura Melina Fernandez).

Conditional Survival in Patients With Rectal Cancer and Complete Clinical Response Managed by Watch and Wait After Chemoradiation: Recurrence Risk Over Time.

OBJECTIVE: Analyze conditional recurrence-free survival (cRFS) for rectal cancer patients with complete clinical response (cCR) after neoadjuvant chemoradiation (nCRT) managed nonoperatively after each year without recurrence. SUMMARY BACKGROUND DATA: Select patients with cCR after nCRT have been managed nonoperatively. Risk factors for local recurrence, the need for prolonged follow-up, and the risk of recurrence over time are not well defined. METHODS: Retrospective review of patients with rectal cancer cT2-4N0-2M0 treated with nCRT. Mean follow-up was 64 months. Patients who achieved cCR were managed nonoperatively. cRFS was used to investigate the evolution of recurrence-odds, as patients remain recurrence-free after completion of nCRT. Three-year cRFS was estimated at "x" years after completion of nCRT based on the formula cRFS3 = RFS(x+3)/RFS(x). RESULTS: One hundred ninety-seven patients with cCR after nCRT were included. Overall survival and recurrence-free survival (RFS) at 5 years were 81.9% (95% CI 74.0%-87.6%) and 60.4% (95% CI 52.5%-67.4%) respectively. Using cRFS estimates, the probability of remaining disease-free for an additional 3 years if the patient survived without disease at 1, 3, and 5 years, was 77.4% (95% CI 68.8%-83.8%), 91.0% (95% CI 81.9%-95.7%), and 94.3% (95% CI 82.9%-98.2%), respectively. In contrast, actuarial RFS rates for similar intervals were 79.1% (95% CI 72.5%-84.2%), 64.2% (95% CI 56.5%-70.8%), and 60.4% (95% CI 52.5%-67.4%). After 2 years disease-free, 3 year cRFS became similar for T2 and T3 cancers. In contrast, patients undergoing extended nCRT became less likely to develop recurrences only after initial 2 years of successful organ-preservation. CONCLUSIONS: Conditional survival suggests that patients have significantly lower risks (≤10%) of developing recurrences after 2 years of achieving cCR following nCRT.

Risk factors for prolonged length of stay after colorectal surgery / Fatores de risco para prolongamento do tempo de permanencia apos cirurgia colorretal

OBJECTIVE: Colorectal surgeons often struggle to explain to administrators/payers reasons for prolonged length of stay (LOS). This study aim was to identify factors associated with increased LOS after colorectal surgery. DESIGN: The study population included patients from the 2007 American-College-of-Surgeons-National-Surgical-Quality-Improvement-Program (ACS-NSQIP) database undergoing ileocolic resection, segmental colectomy, or anterior resection. The study population was divided into normal (below 75th percentile) and prolonged LOS (above the 75th percentile). A multivariate analysis was performed using prolonged LOS as dependent variable and ACS-NSQIP variables as predictive variables. P-value < 0.01 was considered significant. RESULTS: 12,269 patients with a median LOS of 6 (inter-quartile range 4-9) days were included. There were 2,617 (21.3%) patients with prolonged LOS (median 15 days, inter-quartile range 13-22). 1,308 (50%) were female, and the median age was 69 (inter-quartile range 57-79) years. Risk factors for prolonged LOS were male gender, congestive heart failure, weight loss, Crohn's disease, preoperative albumin < 3.5 g/dL and hematocrit < 47%, baseline sepsis, ASA class ≥ 3, open surgery, surgical time ≥ 190 min min, postoperative pneumonia, failure to wean from mechanical ventilation, deep venous thrombosis, urinary-tract infection, systemic sepsis, surgical site infection and reoperation within 30-days from the primary surgery. CONCLUSION: Multiple factors are associated with increased LOS after colorectal surgery. Our results are useful for surgeons to explain prolonged LOS to administrators/payers who are critical of this metric. (AU)

OBJETIVO: Os cirurgiões proctologistas muitas vezes enfrentam dificuldades para explicar aos administradores/contribuintes as razões para o prolongamento do tempo de internação hospitalar (TIH). O objetivo deste estudo foi identificar os fatores associados ao aumento do TIH após cirurgia colorretal. MÉTODO: A população do estudo incluiu pacientes que constam do banco de dados do American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) no ano de 2007 e que foram submetidos à ressecção ileocólica, colectomia segmentar ou ressecção anterior. A população do estudo foi dividida em normal (abaixo do percentil 75) e TIH prolongado (acima do percentil 75). A análise multivariada foi realizada usando o TIH prolongado como variável dependente e as variáveis do ACS-NSQIP como preditivas. Um valor de p < 0,01 foi considerado significativo. RESULTADOS: No total, 12.269 pacientes com um TIH mediano de 6 dias (intervalo interquartil, 4-9) foram incluídos. Havia 2.617 pacientes (21,3%) com TIH prolongado (mediana, 15 dias; intervalo interquartil, 13-22). A idade média dos pacientes era de 69 anos (intervalo interquartil, 57-79) e 1.308 (50%) eram do sexo feminino. Os fatores de risco para TIH prolongado foram sexo masculino, insuficiência cardíaca congestiva, perda de peso, doença de Crohn, albumina < 3,5 g/dL e hematócrito < 47% no pré-operatório, sepse basal, classe ASA ≥ 3, cirurgia aberta, tempo cirúrgico ≥ 190 minutos, pneumonia no pós-operatório, falha no desmame da ventilação mecânica, trombose venosa profunda, infecção do trato urinário, sepse sistêmica, infecção do sítio cirúrgico e reoperação dentro de 30 dias da cirurgia primária. CONCLUSÃO: Vários fatores estão associados ao aumento do TIH após a cirurgia colorretal. Nossos resultados são úteis para que os cirurgiões possam explicar os TIH prolongados aos administradores/contribuintes que são críticos dessa métrica. (AU)