Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. To assess long-term risk of local tumor regrowth, we report updated organ preservation rate and oncologic outcomes of the OPRA trial (ClinicalTrials.gov identifier: NCT02008656 ). Patients with stage II/III rectal cancer were randomly assigned to receive induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Patients who achieved a complete or near-complete response after finishing treatment were offered watch-and-wait (WW). Total mesorectal excision (TME) was recommended for those who achieved an incomplete response. The primary end point was disease-free survival (DFS). The secondary end point was TME-free survival. In total, 324 patients were randomly assigned (INCT-CRT, n = 158; CRT-CNCT, n = 166). Median follow-up was 5.1 years. The 5-year DFS rates were 71% (95% CI, 64 to 79) and 69% (95% CI, 62 to 77) for INCT-CRT and CRT-CNCT, respectively ( P = .68). TME-free survival was 39% (95% CI, 32 to 48) in the INCT-CRT group and 54% (95% CI, 46 to 62) in the CRT-CNCT group ( P = .012). Of 81 patients with regrowth, 94% occurred within 2 years and 99% occurred within 3 years. DFS was similar for patients who underwent TME after restaging (64% [95% CI, 53 to 78]) and patients in WW who underwent TME after regrowth (64% [95% CI, 53 to 78]; P = .94). Updated analysis continues to show long-term organ preservation in half of the patients with rectal cancer treated with total neoadjuvant therapy. In patients who enter WW, most cases of tumor regrowth occur in the first 2 years.

As cancers progress, they become increasingly aggressive—metastatic tumours are less responsive to first-line therapies than primary tumours, they acquire resistance to successive therapies and eventually cause death^1,2. Mutations are largely conserved between primary and metastatic tumours from the same patients, suggesting that non-genetic phenotypic plasticity has a major role in cancer progression and therapy resistance^3–5. However, we lack an understanding of metastatic cell states and the mechanisms by which they transition. Here, in a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that, although primary tumours largely adopt LGR5⁺ intestinal stem-like states, metastases display progressive plasticity. Cancer cells lose intestinal cell identities and reprogram into a highly conserved fetal progenitor state before undergoing non-canonical differentiation into divergent squamous and neuroendocrine-like states, a process that is exacerbated in metastasis and by chemotherapy and is associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues compared with their intestinal lineage-restricted primary tumour counterparts. We identify PROX1 as a repressor of non-intestinal lineage in the fetal progenitor state, and show that downregulation of PROX1 licenses non-canonical reprogramming.

Despite improvements in surgical techniques, functional outcomes and quality of life after therapy for rectal cancer remain suboptimal. We sought to prospectively evaluate the effect of bowel, bladder, and sexual functional outcomes on health-related quality of life (QOL) in patients with restorative versus non-restorative resections after rectal cancer surgery. A cohort of 211 patients with clinical stage I-III rectal cancer who underwent open surgery between 2006 and 2009 at Memorial Sloan Kettering were included. Subjects were asked to complete surveys preoperatively and at 6, 12, and 24 months after surgery. Validated instruments were used to measure QOL, bowel, bladder, and sexual function. Univariable and multivariable regression analyses evaluated predictors of 24- month QOL. In addition, longitudinal trends over the study period were evaluated using repeated measures models. In total, 180 patients (85%) completed at least 1 survey, and response rates at each time point were high (>70%). QOL was most impaired at 6 and 12 months and returned to baseline levels at 24 months. Among patients who underwent sphincter-preserving surgery (SPS; n=153 [85%]), overall bowel function at 24 months was significantly impaired and never returned to baseline. There were no differences in QOL at 24 months between patients who underwent SPS and those who did not (p=.29). Bowel function was correlated with QOL at 24 months (Pearson correlation,.41; p<.001). QOL among patients who have undergone SPS for rectal cancer is good despite poor function. Patients with ostomies are able to adjust to the functional changes and, overall, have good global QOL. Patients with low anastomoses had lower global QOL at 24 months than patients with permanent stomas. Our findings can help patients set expectations about function and quality of life after surgery for rectal cancer with and without a permanent stoma.

Background: Neoadjuvant therapy leads to a clinical complete response in a considerable proportion of patients with locally advanced rectal cancer, allowing for possible nonoperative management. The presence of mucin on magnetic resonance imaging (MRI) after neoadjuvant therapy leads to uncertainty about residual disease and appropriateness of a watch-and-wait strategy in patients with no evidence of disease on proctoscopy (endoscopic clinical complete response). Methods: MRI reports for locally advanced rectal cancer patients seen between July 2016 and January 2020 at Memorial Sloan Kettering Cancer Center were queried for presence of mucin in the tumor bed on MRI following neoadjuvant therapy. Clinicodemographic, pathologic, and outcome data were compiled and analyzed. Results: Of 71 patients with mucin on posttreatment MRI, 20 had a clinical complete response, and 51 had abnormalities on endoscopy and/or physical exam. One patient with a clinical complete response opted out of watch-and-wait; thus, 19 (27%) patients entered watch-and-wait, and 52 (73%) patients were planned for surgery (non–watch-and-wait). Of the 19 watch-and-wait patients, 15 (79%) have had no local regrowth with median follow-up of 50 months (range = 29-76 months), while 4 (21%) experienced regrowth between 9 and 29 months after neoadjuvant therapy. Of the 52 patients who were planned to have surgery (non–watch-and-wait), 49 underwent resection while 3 developed metastatic disease that precluded curative-intent surgery. Of the 49 patients who underwent surgery, 5 (10%) had a pathologic complete response (including the patient with an endoscopic clinical complete response). Conclusions: The presence of mucin after neoadjuvant therapy for locally advanced rectal cancer does not preclude watch-and-wait management in otherwise appropriate candidates who achieve an endoscopic clinical complete response.

BACKGROUND: The watch-and-wait strategy provides an opportunity to pursue nonoperative management in rectal cancer patients with clinical complete response after neoadjuvant therapy. The management of those with near-complete response remains controversial. OBJECTIVE: We assessed the oncologic outcomes of patients managed by watch-and-wait versus total mesorectal excision according to clinical response to neoadjuvant therapy. DESIGN: Retrospective cohort study. SETTINGS: Comprehensive cancer center in New York. PATIENTS: Patients with rectal adenocarcinoma diagnosed between January 2006 and December 2020. INTERVENTIONS: A watch-and-wait strategy of active surveillance was offered to patients if they achieved clinical complete response. Salvage surgery was used for watch-and-wait patients with local regrowth. Patients with an incomplete response underwent total mesorectal excision. MAIN OUTCOME MEASURES: Local regrowth rate, organ preservation rate, disease-free survival, and overall survival. RESULTS: Patients with rectal adenocarcinoma (n = 1230) were divided into 3 response cohorts—incomplete (n = 646), near-complete (n = 189), and complete (n = 395). Eighty-one patients (43%) in the near-complete group and 351 patients (89%) in the complete group entered watch-and-wait. Three-year local regrowth rates were 40% and 24% in the near-complete and complete response cohorts, respectively. The 5-year organ preservation rate was 53% in near-complete responders and 73% in complete responders. Five-year disease-free survival increased with greater clinical response to neoadjuvant therapy, with intermediate outcomes noted for patients with a near-complete (73%) compared to complete (82%) or incomplete (68%) response. Overall survival at 5 years was similar between the 3 cohorts (complete 90%, near-complete 86%, and incomplete 85%). LIMITATIONS: Retrospective nature. CONCLUSIONS: Greater clinical response to neoadjuvant therapy is associated with improved oncologic outcomes. Near-complete responders may avoid surgery and still achieve high organ preservation rates yet experience greater local regrowth rates than clinical complete response patients. Ongoing prospective trials integrating watch-and-wait after complete response as determined by uniform criteria will bolster the work to help treating physicians better select patients who qualify for active surveillance. See Video Abstract. CORRELACIÓN ENTRE EL GRADO DE RESPUESTA CLÍNICA A LA TERAPIA NEOADYUVANTE CONTRA EL CÁNCER DEL RECTO Y LOS RESULTADOS ONCOLÓGICOS EN LA ERA DE OBSERVAR Y ESPERAR: ANTECEDENTES: La estrategia de observar y esperar brinda la oportunidad de buscar un tratamiento no quirúrgico en pacientes con cáncer del recto con respuesta clínica completa después de la terapia neoadyuvante. El tratamiento de aquellos con respuesta casi completa sigue siendo controversial. OBJETIVO: Evaluamos los resultados oncológicos de los pacientes tratados con observar y esperar versus escisión mesorrectal total según la respuesta clínica a la terapia neoadyuvante. DISEÑO: Estudio de cohorte retrospectivo. CONFIGURACIÓN: Centro oncológico integral en Nueva York. PACIENTES: Pacientes con adenocarcinoma rectal diagnosticado entre enero de 2006 y diciembre de 2020. INTERVENCIONES: Se ofreció una estrategia de observar y esperar de vigilancia activa a los pacientes si lograban una respuesta clínica completa. Se utilizó cirugía de rescate para pacientes en observar y esperar con recrecimiento local. Los pacientes con una respuesta incompleta se sometieron a escisión mesorrectal total. PRINCIPALES MEDIDAS DE RESULTADO: Tasa de recrecimiento local, tasa de preservación de órganos, supervivencia libre de enfermedad y supervivencia general. RESULTADOS: Los pacientes con adenocarcinoma rectal (n = 1230) se dividieron en 3 cohortes de respuesta: incompleta (n = 646), casi completa (n = 189) y completa (n = 395). Ochenta y un (43%) pacientes en el grupo casi completo y 351 (89%) pacientes en el grupo completo ingresaron en observar y esperar. Las tasas de recrecimiento local a tres años fueron del 40% y 24% en las cohortes de respuesta casi completa y completa, respectivamente. La tasa de preservación de órganos a 5 años fue del 53% en los respondedores casi completos y del 73% en los respondedores completos. La supervivencia libre de enfermedad a cinco años aumentó con una mayor respuesta clínica a la terapia neoadyuvante con resultados intermedios observados para pacientes con una respuesta casi completa (73%) en comparación con la completa (82%) o incompleta (68%). La supervivencia global a los 5 años fue similar entre las tres cohortes (completa 90%, casi completa 86% e incompleta 85%). LIMITACIONES: Naturaleza retrospectiva. CONCLUSIÓN: Una mayor respuesta clínica a la terapia neoadyuvante se asocia con mejores resultados oncológicos. Los pacientes con respuesta casi completa pueden evitar la cirugía y aun así lograr altas tasas de preservación de órganos, pero experimentar mayores tasas de recrecimiento local que los pacientes con respuesta clínica completa. Los ensayos prospectivos en curso que integran observar y esperar después de la respuesta completa según lo determinado por criterios uniformes reforzarán el trabajo para ayudar a los médicos tratantes a seleccionar mejor a los pacientes que califican para la vigilancia activa. (Traducción—Dr. Aurian Garcia Gonzalez)