Association of Lateral Pelvic Lymph Nodes with Disease Recurrence and Organ Preservation in Patients with Distal Rectal Adenocarcinoma Treated with Total Neoadjuvant Therapy.

OBJECTIVE: Assess the significance of enlarged lateral lymph nodes (LLN) for disease recurrence, metastasis, and organ preservation in patients with rectal cancer. BACKGROUND: Optimal treatment of rectal adenocarcinoma involving LLN is subject to debate. METHODS: A post hoc analysis of the OPRA trial, a multicenter study of patients with rectal cancer treated with total neoadjuvant therapy (TNT) followed by total mesorectal excision or watch-and-wait management. We analyzed the association of visible LLN (LLN+), LLN≥7 mm (short axis) on baseline MRI, and LLN≥4 mm on restaging MRI with recurrence, metastasis, and rectum preservation. RESULTS: At baseline, 57 out of 324 (18%) patients had LLN+. In 30 (53%) of 57 patients with LLN+ on baseline MRI, the LLN disappeared after TNT. Disease recurrence in LLN was rare (3.5% of patients with LLN+ and 0.4% of patients with LLN-). All patients with recurrence in LLN also had distant metastasis. The rate of organ preservation was significantly lower in patients with LLN≥4 mm on restaging MRI (P=0.013). We found no significant differences in rates of local recurrence or metastasis between patients with LLN+ vs. LLN- and in patients with LLN≥7 vs.<7 mm on baseline MRI. LLN dissection was performed in 3 patients; 2 of them died of distant metastasis. CONCLUSIONS: LLN involvement is not associated with disease recurrence or metastasis, but persistence of LLN≥4 mm after TNT is negatively associated with rectum preservation in patients with locally advanced rectal cancer treated with TNT. Dissection of lateral nodes likely benefits few patients.

Long-Term Results of Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy: The Randomized Phase II OPRA Trial.

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.

Endoscopic Predictors of Residual Tumor After Total Neoadjuvant Therapy: A Post Hoc Analysis From the Organ Preservation in Rectal Adenocarcinoma Trial.

BACKGROUND: Restaging endoscopy plays a critical role in selecting patients with locally advanced rectal cancer who respond to neoadjuvant therapy for nonoperative management. OBJECTIVE: This study evaluated the restaging endoscopic features that best predict the presence of residual tumor in the bowel wall. DESIGN: This was a post hoc analysis of a prospective randomized trial. SETTINGS: The Organ Preservation in Rectal Adenocarcinoma Trial randomly assigned patients across 18 institutions with stage II/III rectal adenocarcinoma to receive either induction or consolidation total neoadjuvant therapy. Surgeons completed a restaging tumor assessment form, which stratified patients across 3 tiers of clinical response. PATIENTS: Patients enrolled in the Organ Preservation in Rectal Adenocarcinoma Trial with a completed tumor assessment form were included. MAIN OUTCOME MEASURES: The main outcome was residual tumor, which was defined as either an incomplete clinical response or local tumor regrowth within 2 years of restaging. Independent predictors of residual tumor were identified using backward-selected multivariable logistic regression analysis. Subgroup analyses for complete and near complete clinical responders were performed. RESULTS: Surgeons completed restaging forms for 263 patients at a median of 7.7 weeks after neoadjuvant therapy; 128 patients (48.7%) had a residual tumor. On multivariable regression analysis, several characteristics of a near complete response, including ulcer (OR 6.66; 95% CI, 2.54-19.9), irregular mucosa (OR 3.66; 95% CI, 1.61-8.68), and nodularity (OR 2.96; 95% CI, 1.36-6.58), remained independent predictors of residual tumor. A flat scar was associated with lower odds of harboring residual disease (OR 0.32; 95% CI, 0.11-0.93) for patients categorized as clinical complete responders. LIMITATIONS: Limitations include analysis of endoscopic features at a single time point and ambiguities in tumor assessment form response criteria. CONCLUSIONS: Patients with ulcer, nodularity, or irregular mucosa, on restaging endoscopy have higher odds of residual tumor. Recognizing negative prognostic implications of these features will help surgeons better select candidates for nonoperative management and suggests that patients with high-risk characteristics would benefit from close interval surveillance. See Video Abstract . PREDICTORES ENDOSCPICOS DE TUMOR RESIDUAL DESPUS DE TERAPIA NEOADYUVANTE TOTAL UN ANLISIS POST HOC DEL ENSAYO DE PRESERVACIN DE RGANOS EN ADENOCARCINOMA RECTAL: ANTECEDENTES:La reestadificación por endoscopia juega un papel crítico en la selección de pacientes con cáncer de recto localmente avanzado que responden a la terapia neoadyuvante para el manejo no quirúrgico.OBJETIVO:Este estudio evaluó las características endoscópicas de reestadificación que mejor predicen la presencia de tumor residual en la pared intestinal.DISEÑO:Este fue un análisis post hoc de un ensayo prospectivo aleatorizado.ESCENARIO:El ensayo Organ Preservation in Rectal Adenocarcinoma aleatorizó a pacientes de 18 instituciones con adenocarcinoma de recto en estadio II/III para recibir terapia neoadyuvante total de inducción o consolidación. Los cirujanos completaron un formulario de reestadificación de evaluación del tumor, que estratificó a los pacientes en tres niveles de respuesta clínica.PACIENTES:Se incluyeron pacientes inscritos en el ensayo de preservación de órganos en adenocarcinoma rectal con un formulario de evaluación del tumor completado.PRINCIPALES MEDIDAS DE RESULTADO:El resultado principal fue presencia de tumor residual, que se definió como una respuesta clínica incompleta o un nuevo crecimiento local del tumor dentro de los dos años posteriores a la reestadificación. Los predictores independientes de tumor residual se identificaron mediante un análisis de regresión logística multivariable seleccionado hacia atrás. Se realizaron análisis de subgrupos para pacientes con respuesta clínica completa y casi completa.RESULTADOS:Los cirujanos completaron formularios de reestadificación para 263 pacientes en una mediana de 7.7 semanas después de la terapia neoadyuvante; 128 (48.7%) tenían tumor residual. En el análisis de regresión multivariable, varias características de una respuesta casi completa, incluyendo úlcera (OR 6.66; IC 95% 2.54-19.9), mucosa irregular (OR 3.66; IC 95% 1.61-8.68) y nodularidad (OR 2.96; IC 95% 1.36 -6.58) siguieron siendo predictores independientes de tumor residual. Una cicatriz plana se asoció con menores probabilidades de albergar enfermedad residual (OR 0.32; IC del 95 %: 0.11-0.93) para los pacientes clasificados como respondedores clínicos completos.LIMITACIONES:Las limitaciones de este estudio incluyen el análisis de las características endoscópicas en un solo momento y las ambigüedades en los criterios de respuesta.en la forma de evaluación del tumorCONCLUSIONES:Los pacientes con úlcera, nodularidad o mucosa irregular en la endoscopia de reestadificación tienen mayores probabilidades de tumor residual. El reconocer las implicaciones pronósticas negativas de estas características ayudará a los cirujanos a seleccionar mejor a los candidatos para el tratamiento no quirúrgico y sugiere que los pacientes con características de alto riesgo se beneficiarían de una vigilancia a intervalos estrechos. (Traducción-Dr. Jorge Silva Velazco ).

Nonoperative management of the primary tumor in patients with unresectable stage IV colon cancer treated with systemic chemotherapy: Higher complication rates for left-sided colon tumors.

INTRODUCTION: Treatment of the primary tumor in asymptomatic patients with unresectable colorectal metastases remains controversial. METHODS: Data from patients with synchronous stage IV colon cancer and an untreated primary tumor who started treatment aimed at metastatic disease at a specialized cancer center between 2014 and 2018 were analyzed retrospectively. Main outcome was primary tumor-related complications comparing left-sided and right-sided colon cancer. A competing-risk regression model was used to identify predictors of complications. RESULTS: Of 523 patients with metastatic colon cancer at presentation, 221 started treatment aimed at metastatic disease; these patients constituted the study cohort. The primary tumor was left-sided in 109 patients (49%) and right-sided in 112 patients (51%). In total, 46 patients (21%) developed a complication that required invasive intervention. Complications occurred more frequently in patients with left-sided tumors than in patients with right-sided tumors (29% vs 13%, P = 0.003). Eighteen patients (8%) underwent non-surgical intervention. Six patients (33%) failed non-surgical management and underwent surgery. Of 34 patients (15%) who underwent surgical intervention, 20 underwent an emergency colectomy and 14 underwent diversion with a permanent stoma. Overall, 10% of patients ended up with a permanent stoma. In competing-risk analysis, only left-sided primary tumor (hazard ratio 2.62; 95% CI 1.40-4.89; P = 0.003) was significantly associated with primary tumor-related complications requiring invasive intervention. CONCLUSIONS: Patients with asymptomatic metastatic left-sided tumors have a higher risk for primary tumor-related complications than patients with right-sided tumors. Close monitoring and early surgical rescue should be considered for patients with left-sided colon cancer who are managed nonoperatively.

Compliance and Toxicity of Total Neoadjuvant Therapy for Rectal Cancer: A Secondary Analysis of the OPRA Trial.

PURPOSE: Patients with locally advanced rectal cancer treated with total neoadjuvant therapy (TNT) may achieve organ preservation without a compromise to oncologic outcomes. However, reports on patient compliance with TNT and with treatment-related toxicities are limited. METHODS AND MATERIALS: The OPRA trial assessed organ preservation rates and oncologic outcomes in patients with clinical stage II/III rectal adenocarcinoma randomized to induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Systemic chemotherapy consisted of 8 cycles (16 weeks) of fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or 5 cycles (15 weeks) of capecitabine and oxaliplatin (CAPEOX). Patients received >4500 cGy of radiation with sensitizing capecitabine or fluorouracil. In this report, we compare compliance and treatment-related toxicity in patients receiving INCT-CRT versus CRT-CNCT. Additionally, we evaluate the association of compliance to chemotherapy, compliance to chemoradiation, and toxicity with organ preservation and disease-free survival (DFS). RESULTS: Of the 324 patients randomized, fewer patients started chemoradiation in the INCT-CRT group compared with the CRT-CNCT group (93% vs 98%, P = .03), and fewer patients started systemic chemotherapy in the CRT-CNCT group compared with the INCT-CRT group (94% vs 99%, P = .04). Order of TNT did not affect the ability to complete all intended cycles of FOLFOX (86% INCT-CRT vs 83% CRT-CNCT, P = .60) or CAPEOX (74% INCT-CRT vs 77% CRT-CNCT, P = .80). A total of 97% of INCT and 98% of CRT-CNCT patients received >4500 cGy radiation (P = .93). Sixty-four patients (41%) treated with INCT-CRT and 57 CRT-CNCT patients (34%) experienced a grade 3+ adverse event (P = .30). Compliance and toxicity were not associated with organ preservation or DFS. CONCLUSIONS: We identified only minor differences in treatment compliance between patients treated with INCT-CRT and CRT-CNCT. No difference in adverse events was observed between groups. Treatment compliance and toxicity did not correlate with organ preservation rates or DFS.

Central Nervous System Disease in Patients With RET Fusion-Positive NSCLC Treated With Selpercatinib.

INTRODUCTION: Central nervous system (CNS) metastases develop in nearly half of patients with RET fusion-positive NSCLCs and cause morbidity and mortality. The selective RET inhibitor selpercatinib treats existing intracranial disease, but no studies have investigated whether early initiation of selpercatinib is associated with decreased development of CNS metastases. METHODS: A total of 61 patients with RET fusion-positive advanced NSCLC with and without CNS metastases treated with selpercatinib on the LIBRETTO-001 trial (NCT03157128) or the LIBRETTO-201 expanded access program (NCT03906331) were identified. Cumulative incidence rates (CIRs) for CNS metastases were assessed as an event of interest; systemic progression of disease and death were considered competing risks. RESULTS: The median age was 65 years, and the most common 5' fusion partners were KIF5B (67%) and CCDC6 (18%). There were 24 patients (39%) who received prior platinum chemotherapy and 20 patients (33%) who received prior multikinase inhibition. The median time on selpercatinib was 21.8 months. Furthermore, 30 patients (49%) had CNS disease at baseline and 31 patients (51%) had no baseline CNS disease. CIRs of CNS progression among patients with baseline CNS disease were 3% (95% confidence interval [CI]: 0%-10%), 10% (95% CI: 0%-22%), 17% (3%-30%), 17% (3%-30%), and 20% (5%-35%) at 6, 12, 18, 24, and 36 months, respectively. CIR for CNS progression among patients without baseline CNS disease was 0% at 6, 12, 18, 24, and 36 months (95% CI: 0%-0%). CONCLUSIONS: CNS progression was not observed with selpercatinib therapy in patients without baseline CNS disease. CNS progression on selpercatinib was rare in patients with baseline CNS disease. Early initiation of selpercatinib is associated with decreased rates of CNS metastasis formation and progression and may play a preventive role.