Neoadjuvant camrelizumab plus apatinib for locally advanced microsatellite instability-high or mismatch repair-deficient colorectal cancer (NEOCAP): a single-arm, open-label, phase 2 study.

BACKGROUND: PD-1 blockade is highly efficacious for mismatch repair-deficient colorectal cancer in both metastatic and neoadjuvant settings. We aimed to explore the activity and safety of neoadjuvant therapy with PD-1 blockade plus an angiogenesis inhibitor and the feasibility of organ preservation in patients with locally advanced mismatch repair-deficient colorectal cancer. METHODS: We initiated a single-arm, open-label, phase 2 trial (NEOCAP) at Sun Yat-sen University Cancer Center and the Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China. Patients aged 18-75 years with untreated mismatch repair-deficient or microsatellite instability-high or POLE/POLD1-mutated locally advanced colorectal cancer (cT3 or N+ for rectal cancer, and T3 with invasion ≥5mm or T4, with or without N+ for colon cancer) and an Eastern Cooperative Oncology Group performance score of 0-1 were enrolled and given 200 mg camrelizumab intravenously on day 1 and 250 mg apatinib orally from day 1-14, every 3 weeks for 3 months followed by surgery or 6 months if patients did not have surgery. Patients who had a clinical complete response did not undergo surgery and proceeded with a watch-and-wait approach. The primary endpoint was the proportion of patients with a pathological or clinical complete response. Eligible enrolled patients who received at least one cycle of neoadjuvant treatment and had at least one tumour response assessment following the baseline assessment were included in the activity analysis, and patients who received at least one dose of study drug were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT04715633) and is ongoing. FINDINGS: Between Sept 29, 2020, and Dec 15, 2022, 53 patients were enrolled; one patient was excluded from the activity analysis because they were found to be mismatch repair-proficient and microsatellite-stable. 23 (44%) patients were female and 29 (56%) were male. The median follow-up was 16·4 (IQR 10·5-23·5) months. 28 (54%; 95% CI 35-68) patients had a clinical complete response and 24 of these patients were managed with a watch-and-wait approach, including 20 patients with colon cancer and multiple primary colorectal cancer. 23 (44%) of 52 patients underwent surgery for the primary tumour, and 14 (61%; 95% CI 39-80) had a pathological complete response. 38 (73%; 95% CI 59-84) of 52 patients had a complete response. Grade 3-5 adverse events occurred in 20 (38%) of 53 patients; the most common were increased aminotransferase (six [11%]), bowel obstruction (four [8%]), and hypertension (four [8%]). Drug-related serious adverse events occurred in six (11%) of 53 patients. One patient died from treatment-related immune-related hepatitis. INTERPRETATION: Neoadjuvant camrelizumab plus apatinib show promising antitumour activity in patients with locally advanced mismatch repair-deficient or microsatellite instability-high colorectal cancer. Immune-related adverse events should be monitored with the utmost vigilance. Organ preservation seems promising not only in patients with rectal cancer, but also in those with colon cancer who have a clinical complete response. Longer follow-up is needed to assess the oncological outcomes of the watch-and-wait approach. FUNDING: The National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, and the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.

The effects of oxaliplatin-based adjuvant chemotherapy in high-risk stage II colon cancer with mismatch repair-deficient: a retrospective study.

BACKGROUND: For high-risk stageIImismatch repair deficient (dMMR) colon cancers, the benefit of adjuvant chemotherapy remains debatable. The principal aim of this study was to evaluate the prognostic value of high-risk factors and the effect of oxaliplatin-based adjuvant chemotherapy among dMMR stageIIcolon cancers. METHODS: Patients with stage II dMMR colon cancers diagnosed between June 2011 and May 2018 were enrolled in the study. Clinicopathological characteristics, treatment, and follow-up data were retrospectively collected. The high-risk group was defined as having one of the following factors: pT4 disease, fewer than twelve lymph nodes harvested (< 12 LNs), poorly differentiated histology, perineural invasion (PNI), lymphatic vascular invasion (LVI), or elevated preoperative carcinoembryonic antigen (CEA). The low-risk group did not have any risk factors above. Factors associated with disease-free survival (DFS) were included in univariate and multivariate Cox analyses. RESULTS: We collected a total of 262 consecutive patients with stage II dMMR colon cancer. 179 patients (68.3%) have at least one high-risk factor. With a median follow-up of 50.1 months, the low-risk group was associated with a tended to have a better 3-year DFS than the high-risk group (96.4% vs 89.4%; P = 0.056). Both elevated preoperative CEA (HR 2.93; 95% CI 1.26-6.82; P = 0.013) and pT4 disease (HR 2.58; 95% CI 1.06-6.25; P = 0.037) were independent risk factors of recurrence. Then, the 3-year DFS was 92.6% for the surgery alone group and 88.1% for the adjuvant chemotherapy group (HR 1.64; 95% CI 0.67-4.02; P = 0.280). Furthermore, no survival benefit from oxaliplatin-based adjuvant chemotherapy was observed in the high-risk group and in the subgroups with pT4 disease or < 12 LNs. CONCLUSIONS: These data suggests that not all high-risk factors have a similar impact on stage II dMMR colon cancers. Elevated preoperative CEA and pT4 tumor stage are associated with increased recurrence risk. However, oxaliplatin-based adjuvant chemotherapy shows no survival benefits in stage II dMMR colon cancers, either with or without high-risk factors.

Long-Term Outcomes of dMMR/MSI-H Rectal Cancer Treated With Anti-PD-1-Based Immunotherapy as Curative-Intent Treatment.

BACKGROUND: Neoadjuvant anti-PD-1 therapy has shown encouraging efficacy in patients with deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) locally advanced rectal cancer (LARC), which suggests its potential as a curative-intent therapy and a promising treatment option for organ preservation. We aimed to investigate the long-term outcomes of patients with dMMR/MSI-H LARC who experienced clinical complete response (cCR) after anti-PD-1 therapy. METHODS: We retrospectively analyzed patients with dMMR/MSI-H LARC who achieved cCR and received nonoperative management following neoadjuvant anti-PD-1-based treatment from 4 Chinese medical centers. Patients were followed up for at least 1 year after they achieved cCR, their clinical data were collected, and survival outcomes were analyzed using the Kaplan-Meier method. RESULTS: A total of 24 patients who achieved cCR and received nonoperative management from March 2018 to May 2022 were included, with a median age of 51.0 years (range, 19.0-77.0 years). The median treatment course to reach cCR was 6.0 (range, 1.0-12.0). Fifteen patients (62.5%) continued their treatments after experiencing cCR, and the median treatment course was 17.0 (range, 3.0-36.0). No local regrowth or distant metastasis was observed in a median follow-up time of 29.1 months (range, 12.6-48.5 months) after cCR. The 3-year disease-free and overall survivals were both 100%. CONCLUSIONS: Patients with dMMR/MSI-H locally advanced or low-lying rectal cancer who achieved cCR following anti-PD-1-based therapy had promising long-term outcomes. A prospective clinical trial with a larger sample size is required to further validate these findings.

Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Initial Results of a Phase III Trial.

OBJECTIVE: To compare neoadjuvant chemotherapy (nCT) with CAPOX alone versus neoadjuvant chemoradiotherapy (nCRT) with capecitabine in locally advanced rectal cancer (LARC) with uninvolved mesorectal fascia (MRF). BACKGROUND DATA: nCRT is associated with higher surgical complications, worse long-term functional outcomes, and questionable survival benefits. Comparatively, nCT alone seems a promising alternative treatment in lower-risk LARC patients with uninvolved MRF. METHODS: Patients between June 2014 and October 2020 with LARC within 12 cm from the anal verge and uninvolved MRF were randomly assigned to nCT group with 4 cycles of CAPOX (Oxaliplatin 130 mg/m2 IV day 1 and Capecitabine 1000 mg/m2 twice daily for 14 d. Repeat every 3 wk) or nCRT group with Capecitabine 825 mg/m² twice daily administered orally and concurrently with radiation therapy (50 Gy/25 fractions) for 5 days per week. The primary end point is local-regional recurrence-free survival. Here we reported the results of secondary end points: histopathologic response, surgical events, and toxicity. RESULTS: Of the 663 initially enrolled patients, 589 received the allocated treatment (nCT, n=300; nCRT, n=289). Pathologic complete response rate was 11.0% (95% CI, 7.8-15.3%) in the nCT arm and 13.8% (95% CI, 10.1-18.5%) in the nCRT arm ( P =0.33). The downstaging (ypStage 0 to 1) rate was 40.8% (95% CI, 35.1-46.7%) in the nCT arm and 45.6% (95% CI, 39.7-51.7%) in the nCRT arm ( P =0.27). nCT was associated with lower perioperative distant metastases rate (0.7% vs. 3.1%, P =0.03) and preventive ileostomy rate (52.2% vs. 63.6%, P =0.008) compared with nCRT. Four patients in the nCT arm received salvage nCRT because of local disease progression after nCT. Two patients in the nCT arm and 5 in the nCRT arm achieved complete clinical response and were treated with a nonsurgical approach. Similar results were observed in subgroup analysis. CONCLUSIONS: nCT achieved similar pCR and downstaging rates with lower incidence of perioperative distant metastasis and preventive ileostomy compared with nCRT. CAPOX could be an effective alternative to neoadjuvant therapy in LARC with uninvolved MRF. Long-term follow-up is needed to confirm these results.

Neoadjuvant Immunotherapy Leads to Major Response and Low Recurrence in Localized Mismatch Repair-Deficient Colorectal Cancer.

BACKGROUND: Our study aimed to evaluate the efficacy and feasibility of neoadjuvant anti-PD-1 treatment for localized mismatch repair-deficient (dMMR) colorectal cancer (CRC). PATIENTS AND METHODS: The study cohort included patients with localized dMMR CRC who received PD-1 inhibitors as neoadjuvant therapy from 3 medical centers in Southern China. Main eligibility criteria included age between 18 and 75 years, ECOG performance status of 0 or 1, and receipt of ≥2 doses of PD-1 inhibitors. RESULTS: A total of 73 patients were included. Most of the tumors were locally advanced, including 19 (26.0%) T4a and 29 (39.7%) T4b. Most patients (79.5%) received PD-1 inhibitor monotherapy. Objective response per radiologic assessment was achieved in 62 (84.9%) patients, including 17 (23.3%) with complete response (CR) and 45 (61.6%) with partial response, with a median time to response of 9.6 weeks. Patients with T4a/4b disease had a similar response rate as those with T2-3 disease (84.0% vs 85.4%; P=.999). As of writing, a total of 50 patients have undergone surgery. Pathologic CR was achieved in most (57.1%) patients and remained high (59.5%) even among the 38 patients with T4a/4b disease. The 17 patients with CR did not undergo surgery and adopted a watch-and-wait strategy. After a median follow-up of 17.2 months (range, 3.4-45.1 months), the overall median recurrence-free and overall survivals were not reached. Among patients undergoing surgery or achieving CR, the 2-year tumor-specific disease-free and overall survival rates were both 100%. During neoadjuvant treatment, grade 3-4 adverse events occurred in 8 patients; 4 required acute intervention. Severe postoperative complications were recorded in 4 patients, 3 of whom required a second surgery. CONCLUSIONS: Neoadjuvant therapy with PD-1 blockade is highly effective for localized dMMR CRC, with an acceptable safety profile and low recurrence rate. This treatment holds promise for becoming the new standard of care for localized dMMR CRCs.

A Longitudinal MRI-Based Artificial Intelligence System to Predict Pathological Complete Response After Neoadjuvant Therapy in Rectal Cancer: A Multicenter Validation Study.

BACKGROUND: Accurate prediction of response to neoadjuvant chemoradiotherapy is critical for subsequent treatment decisions for patients with locally advanced rectal cancer. OBJECTIVE: To develop and validate a deep learning model based on the comparison of paired MRI before and after neoadjuvant chemoradiotherapy to predict pathological complete response. DESIGN: By capturing the changes from MRI before and after neoadjuvant chemoradiotherapy in 638 patients, we trained a multitask deep learning model for response prediction (DeepRP-RC) that also allowed simultaneous segmentation. Its performance was independently tested in an internal and 3 external validation sets, and its prognostic value was also evaluated. SETTINGS: Multicenter study. PATIENTS: We retrospectively enrolled 1201 patients diagnosed with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy before total mesorectal excision. Patients had been treated at 1 of 4 hospitals in China between January 2013 and December 2020. MAIN OUTCOME MEASURES: The main outcome was the accuracy of predicting pathological complete response, measured as the area under receiver operating curve for the training and validation data sets. RESULTS: DeepRP-RC achieved high performance in predicting pathological complete response after neoadjuvant chemoradiotherapy, with area under the curve values of 0.969 (0.942-0.996), 0.946 (0.915-0.977), 0.943 (0.888-0.998), and 0.919 (0.840-0.997) for the internal and 3 external validation sets, respectively. DeepRP-RC performed similarly well in the subgroups defined by receipt of radiotherapy, tumor location, T/N stages before and after neoadjuvant chemoradiotherapy, and age. Compared with experienced radiologists, the model showed substantially higher performance in pathological complete response prediction. The model was also highly accurate in identifying the patients with poor response. Furthermore, the model was significantly associated with disease-free survival independent of clinicopathological variables. LIMITATIONS: This study was limited by its retrospective design and absence of multiethnic data. CONCLUSIONS: DeepRP-RC could be an accurate preoperative tool for pathological complete response prediction in rectal cancer after neoadjuvant chemoradiotherapy. UN SISTEMA DE IA BASADO EN RESONANCIA MAGNTICA LONGITUDINAL PARA PREDECIR LA RESPUESTA PATOLGICA COMPLETA DESPUS DE LA TERAPIA NEOADYUVANTE EN EL CNCER DE RECTO UN ESTUDIO DE VALIDACIN MULTICNTRICO: ANTECEDENTES:La predicción precisa de la respuesta a la quimiorradioterapia neoadyuvante es fundamental para las decisiones de tratamiento posteriores para los pacientes con cáncer de recto localmente avanzado.OBJETIVO:Desarrollar y validar un modelo de aprendizaje profundo basado en la comparación de resonancias magnéticas pareadas antes y después de la quimiorradioterapia neoadyuvante para predecir la respuesta patológica completa.DISEÑO:Al capturar los cambios de las imágenes de resonancia magnética antes y después de la quimiorradioterapia neoadyuvante en 638 pacientes, entrenamos un modelo de aprendizaje profundo multitarea para la predicción de respuesta (DeepRP-RC) que también permitió la segmentación simultánea. Su rendimiento se probó de forma independiente en un conjunto de validación interna y tres externas, y también se evaluó su valor pronóstico.ESCENARIO:Estudio multicéntrico.PACIENTES:Volvimos a incluir retrospectivamente a 1201 pacientes diagnosticados con cáncer de recto localmente avanzado y sometidos a quimiorradioterapia neoadyuvante antes de la escisión total del mesorrecto. Eran de cuatro hospitales en China en el período entre enero de 2013 y diciembre de 2020.PRINCIPALES MEDIDAS DE RESULTADO:Los principales resultados fueron la precisión de la predicción de la respuesta patológica completa, medida como el área bajo la curva operativa del receptor para los conjuntos de datos de entrenamiento y validación.RESULTADOS:DeepRP-RC logró un alto rendimiento en la predicción de la respuesta patológica completa después de la quimiorradioterapia neoadyuvante, con valores de área bajo la curva de 0,969 (0,942-0,996), 0,946 (0,915-0,977), 0,943 (0,888-0,998), y 0,919 (0,840-0,997) para los conjuntos de validación interna y las tres externas, respectivamente. DeepRP-RC se desempeñó de manera similar en los subgrupos definidos por la recepción de radioterapia, la ubicación del tumor, los estadios T/N antes y después de la quimiorradioterapia neoadyuvante y la edad. En comparación con los radiólogos experimentados, el modelo mostró un rendimiento sustancialmente mayor en la predicción de la respuesta patológica completa. El modelo también fue muy preciso en la identificación de los pacientes con mala respuesta. Además, el modelo se asoció significativamente con la supervivencia libre de enfermedad independientemente de las variables clinicopatológicas.LIMITACIONES:Este estudio estuvo limitado por el diseño retrospectivo y la ausencia de datos multiétnicos.CONCLUSIONES:DeepRP-RC podría servir como una herramienta preoperatoria precisa para la predicción de la respuesta patológica completa en el cáncer de recto después de la quimiorradioterapia neoadyuvante. (Traducción-Dr. Felipe Bellolio ).

Neoadjuvant Immune Checkpoint Inhibition Improves Organ Preservation in T4bM0 Colorectal Cancer With Mismatch Repair Deficiency: A Retrospective Observational Study.

BACKGROUND: Colorectal cancer with mismatch repair deficiency is usually less aggressive and associated with a lower risk of distant metastasis. Immune checkpoint inhibition, rather than traditional chemoradiotherapy, has shown great advantages in treating such patients. OBJECTIVE: This study aimed to verify the hypothesis that locally very advanced (T4b) colorectal cancer without distant metastases might present with higher probability of mismatch repair deficiency and be more sensitive to neoadjuvant immune checkpoint inhibition. DESIGN: This study was designed as a single-center retrospective observational study. SETTINGS: The study was conducted in a tertiary referral center in China. PATIENTS: The study included patients who were clinically diagnosed with T4bM0 colorectal cancer from 2008 to 2019. MAIN OUTCOME MEASURES: Clinicopathological characteristics, mismatch repair status, and survival outcomes of patients with mismatch repair deficiency were analyzed. RESULTS: A total of 268 patients were included. The incidence of patients with mismatch repair deficiency in the T4bM0 population was 27.6% (75/268), with 84.0% (63/75) in the colon and 16.0% (12/75) in the rectum. For tumors located in the proximal colon, 45.0% (50/111) exhibited mismatch repair deficiency, whereas the incidence of mismatch repair deficiency in sigmoid colon cancer and rectal cancer was only 15.9% (25/157). Neoadjuvant immune checkpoint inhibition significantly reduced the open surgery rate ( p = 0.000) and multivisceral resection rate ( p = 0.025). The pathological complete remission rate in the neoadjuvant immune checkpoint inhibition group was significantly higher than that in neoadjuvant chemoradiotherapy/chemotherapy group (70.0% vs 0%; p = 0.004). No tumor downstaging was observed after neoadjuvant chemotherapy. Neoadjuvant immune checkpoint inhibition provided significantly better disease-free survival ( p = 0.0078) and relatively longer overall survival ( p = 0.15) than other groups. LIMITATIONS: This study is limited by the possible selection bias and small sample size. CONCLUSIONS: Our data depicted the high incidence of mismatch repair deficiency in T4bM0 mismatch repair deficiency and the effectiveness of the neoadjuvant immune checkpoint inhibition group in organ preservation. Precision oncology requires identification of the protein status of mismatch repair at initial diagnosis to make a rational treatment decision for these patients. See Video Abstract at http://links.lww.com/DCR/B952 . LA INHIBICIN DEL PUNTO DE CONTROL INMUNITARIO NEOADYUVANTE MEJORA LA PRESERVACIN DE RGANOS EN EL CNCER COLORRECTAL TBM CON DEFICIENCIA DE REPARACIN DE ERRORES DE COINCIDENCIA UN ESTUDIO OBSERVACIONAL RETROSPECTIVO: ANTECEDENTES:Los pacientes con cáncer colorrectal con deficiencia en la reparación de desajustes suelen (dMMR) ser menos agresivos y se asocian con un menor riesgo de metástasis a distancia. La inhibición del punto de control inmunitario, en lugar de la quimiorradioterapia tradicional, ha mostrado grandes ventajas en el tratamiento de estos pacientes.OBJETIVO:Este estudio tuvo como objetivo verificar nuestra hipótesis de que el CCR localmente muy avanzado (T4b) sin metástasis a distancia podría presentarse con una mayor probabilidad de dMMR y ser más sensible a la inhibición del punto de control inmunitario neoadyuvante.DISEÑO:Este estudio fue diseñado como un estudio observacional retrospectivo de un solo centro.CONFIGURACIÓN:El estudio se realizó en un centro de referencia terciario en China.PACIENTES:Se incluyeron pacientes con diagnóstico clínico de CCR T4bM0 desde 2008 hasta 2019.PRINCIPALES MEDIDAS DE RESULTADO:Se analizaron las características clinicopatológicas, el estado de MMR y los resultados de supervivencia de los pacientes con dMMR.RESULTADOS:Se incluyeron un total de 268 pacientes. La incidencia de dMMR en la población T4bM0 fue del 27,6% (75/268), con un 84,0% (63/75) en colon y un 16,0% (12/75) en recto. Para los tumores ubicados en el colon proximal, el 45,0% (50/111) exhibió dMMR, mientras que la incidencia de dMMR en el cáncer de colon sigmoideo y el cáncer de recto fue solo del 15,9% (25/157). La inhibición del punto de control inmunitario neoadyuvante redujo significativamente la cirugía abierta y la tasa de resección multivisceral ( p = 0,000 y p = 0,025, respectivamente). La tasa de PCR en el grupo de inhibición del punto de control inmunitario neoadyuvante fue significativamente mayor que en el grupo de quimiorradioterapia/quimioterapia neoadyuvante (70,0% frente a 0%, p = 0,004). No se observó reducción del estadio del tumor después de la quimioterapia neoadyuvante. La inhibición del punto de control inmunitario neoadyuvante proporcionó una supervivencia sin enfermedad significativamente mejor ( p = 0,0078) y una supervivencia general relativamente más larga ( p = 0,15) que otros grupos.LIMITACIONES:Este estudio está limitado por el posible sesgo de selección y el pequeño tamaño de la muestra.CONCLUSIONES:Nuestros datos representan la alta incidencia de dMMR en T4bM0 CRC y la eficacia del grupo de inhibición del punto de control inmunitario neoadyuvante en la preservación de órganos. La oncología de precisión requiere la identificación del estado de la proteína MMR en el diagnóstico inicial para tomar una decisión de tratamiento racional para estos pacientes especiales. Consulte el Video Resumen en http://links.lww.com/DCR/B952 . (Traducción-Dr. Yesenia Rojas-Khalil ).

Universal germline testing among patients with colorectal cancer: clinical actionability and optimised panel.

PURPOSE: Universal germline testing in patients with colorectal cancer (CRC) with a multigene panel can detect various hereditary cancer syndromes. This study was performed to understand how to choose a testing panel and whether the result would affect clinical management. METHODS: We prospectively enrolled 486 eligible patients with CRC, including all patients with CRC diagnosed under age 70 years and patients with CRC diagnosed over 70 years with hereditary risk features between November 2017 and January 2018. All participants received germline testing for various hereditary cancer syndromes. RESULTS: The prevalence of germline pathogenic variants (PVs) in cancer susceptibility genes was 7.8% (38/486), including 25 PVs in genes with high-risk CRC susceptibility (the minimal testing set) and 13 PVs in genes with moderate-risk CRC susceptibility or increased cancer risk other than CRC (the additional testing set). All the clinically relevant PVs were found in patients diagnosed under age 70 years. Among them, 11 patients would not have been diagnosed if testing reserved to present guidelines. Most (36/38) of the patients with PVs benefited from enhanced surveillance and tailored treatment. PVs in genes from the minimal testing set were found in all age groups, while patients carried PVs in genes from the additional testing set were older than 40 years. CONCLUSION: Universal germline testing for cancer susceptibility genes should be recommended among all patients with CRC diagnosed under age 70 years. A broad panel including genes from the additional testing set might be considered for patients with CRC older than 40 years to clarify inheritance risks. TRIAL REGISTRATION NUMBER: NCT03365986.

Translation and validation of chinese version of MDASI immunotherapy for early-phase trials module: a cross-sectional study.

BACKGROUND: During immunotherapy treatment and survival, identifying symptoms requires a standardized and validated assessment tool. The aim of this study was to translate, validate and use the Chinese version of the Immunotherapy of the M.D. Anderson Symptom Inventory for Early-Phase Trials module (MDASI-Immunotherapy EPT) to assess the symptom burden of cancer patients receiving immunotherapy in China. METHODS: The MDASI-Immunotherapy EPT was translated into Chinese using Brislin's translation model and the back-translation method. In total, 312 Chinese-speaking colorectal cancer patients receiving immunotherapy were enrolled in the trial from August 2021 to July 2022 after receiving definitive diagnoses in our cancer center. The reliability and validity of the translated version was evaluated. RESULTS: Cronbach's α values were 0.964 and 0.935 for the symptom severity and interference scales, respectively. Significant correlations were found between the MDASI-Immunotherapy EPT-C and FACT-G scores (-0.617-0.732, P < 0.001). Known-group validity was supported by significant differences in the scores of the four scales grouped by ECOG PS (all P < 0.01). The overall mean subscale scores for the core and interference subscales were 1.92 ± 1.75 and 1.46 ± 1.87, respectively. Fatigue, numbness/tingling, and disturbed sleep had the highest scores for the most serious symptoms. CONCLUSION: The MDASI-Immunotherapy EPT-C showed adequate reliability and validity for measuring symptoms among Chinese-speaking colorectal cancer patients receiving immunotherapy. The tool could be used in clinical practice and clinical trials to gather patients' health and quality of life data and manage their symptoms in a timely manner in the future.

Update on Familial Adenomatous Polyposis-Associated Desmoid Tumors.

Desmoid tumors (DT) represent the second high risk of tumor in familial adenomatous polyposis (FAP) patients. Although FAP-associated DTs (FAP-DT) are caused by germline mutations in the adenomatous polyposis coli (APC) gene, extracolonic manifestations, sex, family history, genotype, and the ileal pouch anal anastomosis procedure are all linked to the development of DTs in FAP patients. Multidisciplinary management has replaced aggressive surgery as the preferred treatment of DTs. There is growing evidence to support the use of active surveillance strategy as first-line treatment for FAP-DT patients. Radiotherapy for intra-abdominal desmoids is now rarely used because of severe late toxicity. Pharmacotherapy, however, represents a promising future with the improvement of traditional cytotoxic drugs and the investigation of targeted drugs. Although nonsurgery treatment has been used widely nowadays, surgery remains the mainstay when symptomatic or life-threatening DTs are present. Further research will be needed for more optimal clinical practice.

Nonoperative Management of dMMR/MSI-H Colorectal Cancer following Neoadjuvant Immunotherapy: A Narrative Review.

Immunotherapy with PD-1 blockade has achieved a great success in colorectal cancers (CRCs) with high microsatellite instability (MSI-H) and deficient mismatch repair (dMMR), and has become the first-line therapy in metastatic setting. Studies of neoadjuvant immunotherapy also report exciting results, showing high rates of clinical complete response (cCR) and pathological complete response. The high efficacy and long duration of response of immunotherapy has prompt attempts to adopt watch-and-wait strategy for patients achieving cCR following the treatment. Thankfully, the watch-and-wait approach has been proposed for nearly 20 years for patients undergoing chemoradiotherapy and has gained ground among patients as well as clinicians. In this narrative review, we combed through the available information on immunotherapy for CRC and on the watch-and-wait strategy in chemoradiotherapy, and looked forward to a future where neoadjuvant immunotherapy as a curative therapy would play a big part in the treatment of MSI-H/dMMR CRC.

Screening and Management of Lynch Syndrome: The Chinese Experience.

Lynch syndrome (LS), caused by germline mutations in the mismatch repair genes, is the most common hereditary colorectal cancer. While LS is also associated with various cancers, early detection of the proband is meaningful for tumor prevention, treatment, and familial management. It has been a dramatic shift on the screening approaches for LS. As the rapid development of the molecular biological methods, a comprehensive understanding of the LS screening strategies will help to improve the clinical care for this systematic disease. The current screening strategies have been well validated but mainly by evidence derived from western population, lacking consideration of the ethnic heterogeneity, which hampers the universality and clinical application in China. Hence, this review will focus on the Chinese experience in LS screening, aiming to help better understand the ethnic diversity and further optimize the screening strategies.

Beneficiaries of radical surgery among clinical complete responders to neoadjuvant chemoradiotherapy in rectal cancer.

This study aimed to identify patients who benefit from radical surgery among those with rectal cancer who achieved clinical complete response (cCR). Patients with locally advanced rectal cancer (LARC; stage II/III) who achieved cCR after neoadjuvant chemoradiotherapy (nCRT) were included (n = 212). Univariate/multivariate Cox analysis was performed to validate predictors for distant metastasis-free survival (DMFS). A decision tree was generated using recursive partitioning analysis (RPA) to categorize patients into different risk stratifications. Total mesorectal excision (TME) was compared with the watch-and-wait (W&W) strategy in each risk group. Two molecular predicators of CEA and CA19-9 were selected to establish the RPA-based risk stratification, categorizing LARC patients into low-risk (n = 139; CA19-9 < 35 U/mL and CEA < 5 ng/mL) and high-risk (n = 73; CA19-9 ≥ 35 U/mL or CEA ≥5 ng/mL) groups. Superior 5-y DMFS was observed in the low-risk group vs. the high-risk group (92.9% vs. 76.2%, P = .002). Low-risk LARC patients who underwent TME had significantly improved 5-y DMFS compared with their counterparts receiving the W&W strategy (95.9% vs. 84.3%; P = .028). No significant survival difference was observed in high-risk patients receiving the 2 treatment modalities (77.9% vs. 94.1%; P = .143). LARC patients with cCR who had both baseline CA19-9 < 35 U/mL and CEA < 5 ng/mL may benefit from radical surgery.

A fecal-based test for the detection of advanced adenoma and colorectal cancer: a case-control and screening cohort study.

BACKGROUND: Colorectal cancer (CRC) is the leading cause of cancer death worldwide. Screening is a confirmed way to reduce the incidence and mortality rates of CRC. This study aimed to identify a fecal-based, noninvasive, and accurate method for detection of colorectal cancer (CRC) and advanced adenoma (AA). METHODS: Through detection in tissue (n = 96) and fecal samples (n = 88) and tested in an independent group of fecal samples (n = 294), the methylated DNA marker ITGA4 and bacterial markers Fusobacterium nucleatum (Fn) and Pepetostreptococcusanaerobius (Pa) were identified from the candidate biomarkers for CRC and AA detection. A prediction score (pd-score) was constructed using the selected markers and fecal immunochemical test (FIT) for distinguishing AA and CRC from healthy subjects by logistic regression method. The diagnostic performance of the pd-score was compared with FIT and validated in the external validation cohort (n = 117) and in a large CRC screening cohort. RESULTS: The pd-score accurately identified AA and CRC from healthy subjects with an area under the curve (AUC) of 0.958, at a specificity of 91.37%; the pd-score showed sensitivities of 95.38% for CRC and 70.83% for AA, respectively. In the external validation cohort, the sensitivities of the pd-score for CRC and AA detection were 94.03% and 80.00%, respectively. When applied in screening, the pd-score identified 100% (11/11) of CRC and 70.83% (17/24) of AA in participants with both colonoscopy results and qualified fecal samples, showing an improvement by 41.19% compared to FIT. CONCLUSIONS: The current study developed a noninvasive and well-validated approach for AA and CRC detection, which could be applied widely as a diagnostic and screening test.

Clinical characteristics and prognostic factors of colorectal cancer patients with ovarian metastasis: a multicenter retrospective study.

PURPOSE: As a kind of secondary tumor of the ovary, ovarian metastasis from colorectal cancer (OMCRC) happens rarely. Prognostic factors of OMCRC are still undetermined. This study was conducted to analyze clinical characteristics and prognostic factors of OMCRC patients. METHODS: Data of patients with OMCRC were collected retrospectively from four large-capacity hospitals in China. Kaplan-Meier method was applied to estimate disease-specific overall survival (OS), and multivariate Cox regression analysis was used to identify prognostic factors. A novel nomogram was developed to estimate individual survival probability, whose performance was internally validated using concordance index (C-index) and calibration curve. RESULTS: Totally, 162 cases were eligible, with a median age at diagnosis of 49 years old. The median size of ovarian metastases was 9.0 cm (95% CI: 8.5-10.4 cm). 93.8% of patients received surgery of ovarian metastases. Median time from CRC diagnosis to metachronous ovarian metastasis was 13.0 months (95% CI: 13.5-17.7 months). Median OS after ovarian metastasis diagnosis was 26.0 months (95% CI: 22.3-29.7 months). Integrating univariate and multivariate analyses, eight factors (including age, menopausal status, primary tumor location, N stage of primary tumor, surgery of primary tumor, differentiation grade, bilateral metastasis, and systemic chemotherapy) were used to develop a novel nomogram, with a C-index of 0.65 (95% CI: 0.595-0.705). Calibration curves indicated relatively good agreement between predicted and actual survival. CONCLUSIONS: This nomogram could be a promising tool to help clinicians to estimate individual survival outcome of patients with OMCRC. Further study is warranted to validate the practicality of this model.

[Construction and practice of cancer genetic clinic].

OBJECTIVE: To explore the effect and precautions of setting up a genetic clinic for hereditary colorectal cancers. METHODS: To collect the information of the patients who received genetic screening and genetic counseling at our hospital from January 2016 to June 2018, and analyze the role of family history collection and follow-up management. RESULTS: The detection rate of family history of tumors has increased by 13.6%. Follow up management was carried out in 156 families with hereditary colorectal cancer confirmed by detection of germline mutations. Five cases of early colorectal cancers and 12 cases of adenomatous polyps were detected and treated. CONCLUSION: To set up genetic clinic is helpful to standardize the management of high-risk population, and attention should be paid to the role of family history collection and follow-up management.

Histopathological growth patterns correlate with the immunoscore in colorectal cancer liver metastasis patients after hepatectomy.

Various scoring systems have been proposed to predict the postoperative prognosis of colorectal liver metastasis (CRLM), including the clinical risk score (CRS), the immunoscore and so on. Recently, histopathological growth patterns (HGPs) have been recognized. However, the correlation between HGPs and the immunoscore, and their prognostic values in patients with CRLM after liver resection remain undetermined. In this study, HGPs were retrospectively evaluated in H&E-stained slides from 166 CRLM patients. The immunoscore was calculated according to the densities of immunostained CD3 + and CD8 + cells. A risk score combining HGPs, the immunoscore and the CRS was defined and divided patients into the low-, medium- and high-risk group. Our results showed that the densities of CD3 + and CD8 + cells were higher in the desmoplastic HGP (dHGP) group than in the non-dHGP group, and the proportion of high immunoscores was also higher in the dHGP group (51.9% vs. 33.0%, respectively, P = 0.020). Patients with the dHGP had significantly longer relapse-free survival (RFS) and overall survival (OS) than those with the non-HGP. The low-risk group showed significantly higher 2-year RFS and 5-year OS rates than the other two groups (RFS: 76.2%, 43.7% and 33.1%, respectively; P < 0.001; OS: 89.7%, 54.4% and 33.3%, respectively; P < 0.001). In conclusion, the dHGP correlates with relatively high immunoscores, predicting a favorable prognosis independent of the immunoscore and CRS. A novel risk score combining HGPs, the immunoscore and the CRS may be used for the stratification of CRLM patients' survival.

Anatomical characteristics and classifications of gastrocolic trunk of Henle in laparoscopic right colectomy: preliminary results of multicenter observational study.

BACKGROUND: As a key landmark during laparoscopic right colectomy, the classification and variation of the gastrocolic trunk of Henle (GTH) remains to be clarified. The aim of this nationwide multicenter study was to describe the characteristics of the GTH intra-operatively during laparoscopic right colectomies. METHODS: Three hundred seventy-one patients who underwent laparoscopic right colectomies from January 2018 to March 2019 in 25 hospitals across China were enrolled in the study. The length of the GTH, the classification with a precise description of confluent tributaries, and other variations were analyzed. RESULTS: Of the 371 patients, 363 had a GTH. The proportion of type-0, type-I, type-II, and type-III was 15.2% (n = 55), 54.8% (n = 199), 25.3% (n = 92), and 4.7% (n = 17), respectively. The average length of the GTH was 8.5 mm, ranging from 2 to 30 mm. CONCLUSIONS: This is the first multicenter study with a large sample by which the GTH was classified based on laparoscopic intraoperative observation. Variations in the GTH were classified into four types based on the number of colic drainage veins (right colic, superior right colic, middle colic, accessory middle colic, and ileocolic veins), among which the right colic vein was the most common. The length of the GTH was relatively short, and thus might carry a risk of bleeding. Further clinical data should be correlated with the characteristics of the GTH.

Signet ring cell component in pretreatment biopsy predicts pathological response to preoperative chemoradiotherapy in rectal cancer.

PURPOSE: Neoadjuvant therapy is routinely used in the management of locally advanced rectal cancer. This study aimed to evaluate the predictive value of pathological parameters in tumor response after treatment. METHODS: We reviewed the hematoxylin-eosin slides from pretreatment biopsies of 150 rectal cancer patients who received preoperative chemoradiotherapy (PCRT) at Sun Yat-sen University Cancer Center between May 2013 and June 2016. Pathological and clinical parameters were both studied. The tumor response after chemoradiotherapy was evaluated using the tumor regression grade (TRG). Logistic regression was used to evaluate the relevance between these parameters and tumor response. RESULTS: Complete tumor response (TRG0 and pCR) to PCRT was identified in 40 (26.7%) patients. The pCR rate was 93.33% (14 of 15) in cases with signet ring cell component versus 19.26% (26 of 135) in those without signet ring cell component (p < 0.001). Four cases with signet ring cell component were evaluated as clinical complete response (cCR), all of whom also achieved pCR; in contrast, only 9 of 15 (60%) cCR cases without signet ring cell achieved pCR. CONCLUSION: Our data suggest that the signet ring cell component in pretreatment biopsies may be a potential predictor of tumor response to PCRT in rectal cancer. This suggests patients with clinical complete response are more suitable for a wait-and-watch approach.