Prognostic Relevance of Primary Tumor Sidedness in Early-stage Colorectal Cancer: An Integrated Analysis of 4 Randomized Controlled Trials (JCOG2003A).

OBJECTIVE: The aim of this study was to determine the genuine prognostic relevance of primary tumor sidedness (PTS) in patients with early-stage colorectal cancer (CRC). BACKGROUND: The prognostic relevance of PTS in early-stage CRC remains a topic of debate. Several large epidemiological studies investigated survival only and did not consider the risk of recurrence so far. METHODS: Patients with stage II/III adenocarcinoma of the colon and upper rectum from 4 randomized controlled trials were analyzed. Survival outcomes were compared according to the tumor location: right-sided (cecum to transverse colon) or left-sided (descending colon to upper rectum). RESULTS: A total of 4113 patients were divided into a right-sided group (N=1349) and a left-sided group (N=2764). Relapse-free survival after primary surgery was not associated with PTS in all patients and each stage [hazard ratio (HR) adjusted =1.024 (95% CI: 0.886-1.183) in all patients; 1.327 (0.852-2.067) in stage II; and 0.990 (0.850-1.154) in stage III]. Also, overall survival after primary surgery was not associated with PTS in all patients and each stage [HR adjusted =0.879 (95% CI: 0.726-1.064) in all patients; 1.517 (0.738-3.115) in stage II; and 0.840 (0.689-1.024) in stage III]. In total, 795 patients (right-sided, N=257; left-sided, N=538) developed recurrence after primary surgery. PTS was significantly associated with overall survival after recurrence (HR adjusted =0.773, 95% CI: 0.627-0.954). CONCLUSIONS: PTS had no impact on the risk of recurrence for stage II/III CRC. Treatment stratification based on PTS is unnecessary for early-stage CRC.

Defining Benchmarks for Pelvic Exenteration Surgery: A Multicentre Analysis of Patients with Locally Advanced and Recurrent Rectal Cancer.

OBJECTIVE: To establish globally applicable benchmark outcomes for pelvic exenteration (PE) in patients with locally advanced primary (LARC) and recurrent rectal cancer (LRRC), using outcomes achieved at highly specialised centres. BACKGROUND DATA: PE is established as the standard of care for selected patients with LARC and LRRC. There are currently no available benchmarks against which surgical performance in PE can be compared for audit and quality improvement. METHODS: This international multicentre retrospective cohort study included patients undergoing PE for LARC or LRRC at 16 highly experienced centres between 2018 and 2023. Ten outcome benchmarks were established in a lower-risk subgroup. Benchmarks were defined by the 75th percentile of the results achieved at the individual centres. RESULTS: 763 patients underwent PE, of which 464 patients (61%) had LARC and 299 (39%) had LRRC. 544 patients (71%) who met predefined lower risk criteria formed the benchmark cohort. For LARC patients, the calculated benchmark threshold for major complication rate was ≤44%; comprehensive complication index (CCI): ≤30.2; 30-day mortality rate: 0%; 90-day mortality rate: ≤4.3%; R0 resection rate: ≥79%. For LRRC patients, the calculated benchmark threshold for major complication rate was ≤53%; CCI: ≤34.1; 30-day mortality rate: 0%; 90-day mortality rate: ≤6%; R0 resection rate: ≥77%. CONCLUSIONS: The reported benchmarks for PE in patients with LARC and LRRC represent the best available care for this patient group globally and can be used for rigorous assessment of surgical quality and to facilitate quality improvement initiatives at international exenteration centres.

Long-Term Outcomes of Additional Surgery After Endoscopic Resection Versus Primary Surgery for T1 Colorectal Cancer.

INTRODUCTION: There is considerable concern about whether endoscopic resection (ER) before additional surgery (AS) for T1 colorectal cancer (CRC) has oncologically potential adverse effects. Therefore, the aim of this study was to compare the long-term outcomes, including overall survival (OS), of patients treated with AS after ER vs primary surgery (PS) for T1 CRC using a propensity score-matched analysis from a large observational study. METHODS: This study investigated 6,105 patients with T1 CRC treated with either ER or surgical resection between 2009 and 2016 at 27 high-volume Japanese institutions, with those undergoing surgery alone included in the PS group and those undergoing AS after ER included in the AS group. Propensity score matching was used for long-term outcomes of mortality and recurrence analysis. RESULTS: After propensity score matching, 1,219 of 2,438 patients were identified in each group. The 5-year OS rates in the AS and PS groups were 97.1% and 96.0%, respectively (hazard ratio: 0.72, 95% confidence interval: 0.49-1.08), indicating the noninferiority of the AS group. Moreover, 32 patients (2.6%) in the AS group and 24 (2.0%) in the PS group had recurrences, with no significant difference between the 2 groups (odds ratio: 1.34, 95% confidence interval: 0.76-2.40, P = 0.344). DISCUSSION: ER before AS for T1 CRC had no adverse effect on patients' long-term outcomes, including the 5-year OS rate. ER is a viable first-line treatment option for endoscopically resectable T1 CRC.

Treatment Decision for Locally Resected T1 Colorectal Carcinoma-Verification of the Japanese Guideline Criteria for Additional Surgery Based on Long-Term Clinical Outcomes.

INTRODUCTION: To verify the value of the pathological criteria for additional treatment in locally resected pT1 colorectal carcinoma (CRC) which have been used in the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines since 2009. METHODS: We enrolled 4,667 patients with pT1 CRC treated at 27 institutions between July 2009 and December 2016 (1,257 patients with local resection alone [group A], 1,512 patients with additional surgery after local resection [group B], and 1,898 patients with surgery alone [group C]). All 5 factors of the JSCCR guidelines (submucosal resection margin, tumor histologic grade, submucosal invasion depth, lymphovascular invasion, and tumor budding) for lymph node metastasis (LNM) had been diagnosed prospectively. RESULTS: Any of the risk factors were present in 3,751 patients. The LNM incidence was 10.4% (95% confidence interval 9.4-11.5) in group B/C patients with risk factors, whereas it was 1.8% (95% confidence interval 0.4-5.3) in those without risk factors ( P < 0.01). In group A, the incidence of recurrence was 3.6% in patients with risk factors, but it was only 0.4% in patients without risk factors ( P < 0.01). The disease-free survival rate of group A patients classified as risk positive was significantly worse than those of groups B and C patients. However, the 5-year disease-free survival rate in group A patients with no risk was 99.6%. DISCUSSION: Our large-scale real-world multicenter study demonstrated the validity of the JSCCR criteria for pT1 CRC after local resection, especially regarding favorable outcomes in patients with low risk of LNM.

Long-term Outcome After Surgical Resection of Para-aortic Lymph Node Metastasis of Colorectal Cancer: A Multicenter Retrospective Study.

BACKGROUND: The significance of resection of para-aortic lymph node metastasis in colorectal cancer is controversial. OBJECTIVE: To clarify the prognosis of colorectal cancer after para-aortic lymph node metastasis resection. DESIGN: Multicenter retrospective study. SETTINGS: Thirty-six institutions in Japan participated in this study. Database and medical records at each institution were used for data collection. PATIENTS: Patients with resected and pathologically proven para-aortic lymph node metastasis of colorectal cancer between 2010 and 2015 were included. MAIN OUTCOME MEASURES: Overall survival after para-aortic lymph node metastasis resection, recurrence-free survival, and recurrence patterns after R0 resection of para-aortic lymph node metastasis. RESULTS: A total of 133 patients were included in the primary analysis population in this study. The 5-year overall survival rate (95% CI) was 41.0% (32.0-49.8), and the median survival (95% CI) was 4.1 (3.4-4.7) years. Independent prognostic factors for overall survival were the pathological T stage (pT4 vs pT1- 3, adjusted HR: 1.91, p = 0.006), other organ metastasis (present vs absent, adjusted HR: 1.98, p = 0.005), time to metastases (synchronous vs metachronous adjusted HR: 2.02, p = 0.02), and the number of para-aortic lymph node metastasis (3 or more vs less than 3, adjusted HR: 2.13, p = 0.001). The 5-year recurrence-free survival rate (95% CI) was 21.1% (13.5-29.7), with a median (95% CI) of 1.2 (0.9-1.4) years. The primary tumor location (left- vs right-sided colon, adjusted HR: 4.77, p = 0.01; rectum vs right-sided colon, adjusted HR: 5.27, p = 0.006), other organ metastasis (present vs absent, adjusted HR: 1.90, p = 0.03), number of para-aortic lymph node metastases (3 or more vs less than 3, adjusted HR: 2.20, p = 0.001), and hospital volume (less than 10 vs 10 or more, adjusted HR: 2.18, p = 0.02) were identified as independent prognostic factors for recurrence-free survival. Para-aortic lymph node recurrence was the most common at 33.3%. LIMITATIONS: Selection bias cannot be ruled out because of the retrospective nature of the study. CONCLUSIONS: Less than 3 para-aortic lymph node metastases were a favorable prognostic factor for overall and recurrence-free survival. However, para-aortic lymph node metastases were considered to be a systemic disease, and the significance of resection was limited. See Video Abstract . RESULTADO A LARGO PLAZO POSTERIOR A LA RESECCIN QUIRRGICA DE METSTASIS EN GANGLIOS LINFTICOS PARAARTICOS DE CNCER COLORRECTAL UN ESTUDIO RETROSPECTIVO MULTICNTRICO: ANTECEDENTES:La importancia de la resección de metástasis en los ganglios linfáticos paraaórticos (PALNM) en el cáncer colorrectal (CCR) es controvertida.OBJETIVO:Aclarar el pronóstico del CCR después de la resección PALNM.DISEÑO:Estudio retrospectivo multicéntrico.ENTORNO CLINICO:Treinta y seis instituciones en Japón participaron en este estudio.PACIENTES:Pacientes con PALNM de CCR resecado y patológicamente probado entre 2010 y 2015.FUENTES DE DATOS:Base de datos y registros médicos de cada institución.PRINCIPALES MEDIDAS DE RESULTADO:Supervivencia general (SG) después de la resección PALNM, supervivencia libre de recurrencia (SLR) y patrones de recurrencia después de la resección R0 de PALNM.RESULTADOS:Se incluyó un total de 133 pacientes en la población de análisis primario de este estudio. La tasa de SG a 5 años (intervalo de confianza [IC] del 95 %) fue del 41,0 % (32,0, 49,8) y la mediana de supervivencia (IC del 95 %) fue de 4,1 (3,4, 4,7) años. Los factores de pronóstico independientes para la SG fueron el estadio T patológico (pT4 vs. pT1-3, índice de riesgo ajustado [aHR]: 1,91, p = 0,006), metástasis en otros órganos (presente vs. ausente, aHR: 1,98, p = 0,005), tiempo hasta las metástasis (síncronas vs. metacrónicas, aHR: 2,02, p = 0,02) y número de PALNM (≥3 vs. <3, aHR: 2,13, p = 0,001). La tasa de SLR a 5 años (IC del 95%) fue del 21,1% (13,5, 29,7), con una mediana (IC del 95%) de 1,2 (0,9, 1,4) años. La ubicación del tumor primario (colon del lado izquierdo vs. derecho, aHR: 4,77, p = 0,01; recto vs. colon del lado derecho, aHR: 5,27, p = 0,006), metástasis en otros órganos (presente vs. ausente, aHR: 1,90, p = 0,03), el número de PALNM (≥3 vs. <3, aHR: 2,20, p = 0,001) y el volumen hospitalario (<10 vs. ≥10, aHR: 2,18, p = 0,02) se identificaron como independientes factores pronósticos del SLR. La recurrencia de los ganglios linfáticos paraaórticos fue la más común con un 33,3%.LIMITACIONES:No se puede descartar un sesgo de selección debido a la naturaleza retrospectiva del estudio.CONCLUSIONES:Menos de tres PALNM fue un factor pronóstico favorable tanto para la SG como para la SLR. Sin embargo, las PALNM se consideraron una enfermedad sistémica y la importancia de la resección fue limitada. (Traducción- Dr. Francisco M. Abarca-Rendon ).

Prognostic impact of primary tumour location after curative resection in Stage I-III colorectal cancer: a single-centre retrospective study.

OBJECTIVE: The relationship of tumour site with post-recurrence course and outcome after primary surgery in resectable colorectal cancer is unclear. This study investigated the prognostic impact of primary tumour location following radical resection without preoperative treatment in Stage I-III colorectal cancer. METHODS: We analyzed 3770 patients with Stage I-III colorectal cancer who underwent curative resection at our hospital during 2000-15. We defined the right-sided colon as the cecum, ascending colon and transverse colon, and the left-sided colon as the descending colon, sigmoid and rectosigmoid junction. Patients were divided into three groups according to tumour site: right-sided colon, left-sided colon and rectum. Endpoints were overall survival, recurrence-free survival by stage and survival after recurrence, respectively. RESULTS: The 5-year overall survival rates of patients with stage I left-sided colon cancer, right-sided colon cancer and rectal cancer were 98.2, 97.3 and 97.2%, respectively (P = 0.488). The 5-year overall survival rates of patients with Stage II left-sided colon cancer, right-sided colon cancer and rectal cancer were 96.2, 88.7 and 83.0, respectively (P = 0.070). The 5-year overall survival rates of patients with Stage III left-sided colon cancer, right-sided colon cancer and rectal cancer were 88.7, 83.0 and 80.2, respectively (P = 0.001). The 5-year recurrence-free survival rates of patients with Stage I left-sided colon cancer, right-sided colon cancer and rectal cancer were 95.1, 94.5 and 90.6% (P = 0.027). The 5-year recurrence-free survival rates of patients with Stage II left-sided colon cancer, right-sided colon cancer and rectal cancer were 85.2, 90.2 and 76.1%, respectively (P < 0.001). The 5-year recurrence-free survival rates of patients with Stage III left-sided colon cancer, right-sided colon cancer and rectal cancer were 75.3, 75.3 and 59.8%, respectively (P < 0.001). Right-sided colon cancer was significantly associated with better recurrence-free survival compared with left-sided colon cancer (HR 1.29, 95% CI 1.03-1.63; P = 0.025) and rectal cancer (HR 1.89, 95% CI 1.51-2.38; P < 0.001) after adjusting for clinical factors. Amongst patients with recurrence, right-sided colon cancer was significantly associated with poorer survival after recurrence compared with left-sided colon cancer (HR 0.68, 95% CI 0.48-0.97; P = 0.036), and showed a tendency towards poorer survival after recurrence compared with rectal cancer (HR 0.79, 95% CI 0.57-1.10; P = 0.164). CONCLUSIONS: In Stage I-III colorectal cancer without preoperative treatment, our results suggest that the three tumour sites (right-sided colon, left-sided colon or rectum) may have prognostic significance for recurrence-free survival and survival after recurrence, rather than sidedness alone.

Cost-effectiveness of surveillance intervals after curative resection of colorectal cancer.

BACKGROUND: Major guidelines consistently recommend 5 years of postoperative surveillance for patients with colorectal cancer. However, they differ in their recommendations for examination intervals and whether they should vary according to disease stage. Furthermore, there are no reports on the cost-effectiveness of the different surveillance schedules. The objective of this study is to identify the most cost-effective surveillance intervals after curative resection of colorectal cancer. METHODS: A total of 3701 patients who underwent curative surgery for colorectal cancer at the National Cancer Center Hospital were included. A cost-effectiveness analysis was conducted for the five surveillance strategies with reference to the guidelines. Expected medical costs and quality-adjusted life years after colorectal cancer resection were calculated using a state-transition model by Monte Carlo simulation. The incremental cost-effectiveness ratio per quality-adjusted life years gained was calculated for each strategy, with a maximum acceptable value of 43 500-52 200 USD (5-6 million JPY). RESULTS: Stages I, II and III included 1316, 1082 and 1303 patients, respectively, with 45, 140 and 338 relapsed cases. For patients with stage I disease, strategy 4 (incremental cost-effectiveness ratio $26 555/quality-adjusted life year) was considered to be the most cost-effective, while strategies 3 ($83 071/quality-adjusted life year) and 2 ($289 642/quality-adjusted life year) exceeded the threshold value. In stages II and III, the incremental cost-effectiveness ratio for strategy 3 was the most cost-effective option, with an incremental cost-effectiveness ratio of $18 358-22 230/quality-adjusted life year. CONCLUSIONS: In stage I, the cost-effectiveness of intensive surveillance is very poor and strategy 4 is the most cost-effective. Strategy 3 is the most cost-effective in stages II and III.

Real-world treatment costs of first-line treatment for metastatic colorectal cancer: a survey of the JCOG colorectal cancer study group.

BACKGROUND: Although treatment outcomes for metastatic colorectal cancer (mCRC) have dramatically improved over the past few decades, drug costs have also significantly increased. This study aimed to investigate which first-line treatment regimens for mCRC are actually used (frequency) in Japanese practice and at what cost. METHODS: We collected data on patients with mCRC who received first-line treatment at 37 institutions of the Japan Clinical Oncology Group Colorectal Cancer Study Group from July 2021 to June 2022, and calculated the cost of regimens. The cost per month of each regimen was estimated based on standard usage, assuming a patient with a weight of 70 kg and a body surface area of 1.8 m2. We categorized the regimens into very high-cost (≥1 000 000 Japanese yen [JPY]/month), high-cost (≥500 000 JPY/month), and others (<500 000 JPY/month). RESULTS: The study included 1880 participants, 24% of whom were ≥ 75 years. Molecular targeted containing regimens were received by 78% of the patients. The most frequently used regimen was the doublet regimen (fluoropyrimidine with either oxaliplatin or irinotecan) plus bevacizumab (43%), followed by doublet plus cetuximab or panitumumab (21%). The cost of molecular targeted drugs-containing regimens (ranging from 85 406 to 843 602 JPY/month) is much higher than that of only cytotoxic drug regimens (ranging from 17 672 to 51 004 JPY/month). About 16% received high-cost treatments that included panitumumab-containing regimens and pembrolizumab (17% of patients aged ≤74 years and 11% of patients aged ≥75 years). CONCLUSION: About 16% of mCRC patients received first-line treatment with regimens costing >500 000JPY/month, and molecular targeted drugs being the main drivers of cost.

Short- and long-term outcomes of surgical treatment for inguinal lymph node metastasis in rectal and anal canal adenocarcinoma.

AIM: The significance of lymphadenectomy and its indications in patients with inguinal lymph node metastasis (ILNM) of anorectal adenocarcinoma is unclear. This study aimed to clarify the surgical outcomes and prognostic factors of inguinal lymphadenectomy for ILNM. METHOD: This study included patients who underwent surgical resection for ILNM of rectal or anal canal adenocarcinoma with pathologically positive metastases between 1997 and 2011 at 20 participating centres in the Study Group for Inguinal Lymph Node Metastasis from Colorectal Cancer organized by the Japanese Society for Cancer of the Colon and Rectum. Clinicopathological characteristics and short- and long-term postoperative outcomes were retrospectively analysed. RESULTS: In total, 107 patients were included. The primary tumour was in the rectum in 57 patients (53.3%) and in the anal canal in 50 (46.7%). The median number of ILNMs was 2.34. Postoperative complications of Clavien-Dindo Grade III or higher were observed in five patients. The 5-year overall survival rate was 38.8%. Multivariate analysis identified undifferentiated histological type (P < 0.001), pathological venous invasion (P = 0.01) and pathological primary tumour depth T0-2 (P = 0.01) as independent prognostic factors for poor overall survival. CONCLUSION: The 5-year overall survival after inguinal lymph node dissection was acceptable, and it warrants consideration in more patients. Further larger-scale studies are needed in order to clarify the surgical indications.

Clinical utility of sarcopenia dynamics assessed by psoas muscle volume in patients with colorectal cancer.

BACKGROUND: Sarcopenia affects the postoperative prognosis of patients with colorectal cancer (CRC). Recently, it has become possible to measure psoas volume from computed tomography images, and an index called psoas volume index (PVI) has been reported. However, it is unclear whether the dynamics of PVI before and after surgery is associated with clinical outcomes after CRC surgery. This study aimed to evaluate the association between pre- and postoperative PVI dynamics and clinical outcomes after CRC surgery. METHODS: This study analyzed 1115 patients diagnosed with primary CRC and operated on for treatment between January 2014 and December 2017. Sarcopenia was defined as PVI below the lowest tertile in the preoperative assessment for each sex. The overall population was divided into four groups according to the dynamics of sarcopenia from preoperative to postoperative: group 1 (pre-to postoperative sarcopenia), group 2 (preoperative nonsarcopenia to postoperative sarcopenia), group 3 (pre-to postoperative nonsarcopenia), and group 4 (pre-to postoperative nonsarcopenia). RESULTS: Based on pre- and postoperative sarcopenia dynamics, 343 patients (29.7%) were classified into group 1, 105 patients (9.1%) into group 2, 42 patients (3.6%) into group 3, and 665 patients (57.6%) into group 4. Comparison of overall survival (OS) by the Kaplan-Meier method showed that Group 2 tended to have the worst prognosis (p = 0.007). Multivariate analysis showed an increased OS risk in Group 2 in sarcopenia dynamics (Hazard ratio: 2.103, 95% CI: 1.202-3.681, p = 0.009). CONCLUSIONS: Sarcopenia dynamics using PVI is an independent prognostic predictor of OS in patients with CRC.

Lateral node metastasis in low rectal cancer as a hallmark to predict recurrence patterns.

BACKGROUND: Lateral node metastasis confers a poor prognosis in rectal cancer. Several multidisciplinary treatments have been proposed with favorable outcomes. However, appropriate neoadjuvant/adjuvant treatments or follow-up plans based on information about the probable recurrence site have not been specified. We aimed to clarify the distinctive features of recurrence patterns for lateral node-positive low rectal cancer according to the lateral and mesorectal lymph node status. METHODS: We retrospectively analyzed 508 patients with stage III low rectal cancer who underwent lateral node dissection. We investigated the impact of lateral and mesorectal lymph node status on site-specific recurrence rates and patient survival. RESULTS: Analyses for relapse-free survival revealed the prognostic impact of lateral node positivity in stage III low rectal cancer (p < 0.0001). Lateral node-positive patients exhibited higher risk of overall recurrence, local recurrence, and recurrence in extra-regional nodes than lateral node-negative patients (p < 0.0001, p = 0.001, and p < 0.0001, respectively). However, lateral node positivity was not statistically associated with a hematogenous recurrence rate. In lateral node-positive patients, both tumor-node-metastasis (TNM)-N status and number of lateral nodes involved were revealed as significant prognostic factors (p < 0.0001, both). In addition, the number of lateral nodes involved could be a discriminatory indicator of probabilities of local recurrence and recurrence in extra-regional nodes (p = 0.02, and p < 0.0001, respectively). CONCLUSIONS: Lateral node-positive low rectal cancer exhibits higher local recurrence and extra-regional node recurrence rates that correlate with the number of lateral nodes involved.

RAS mutation associated with short surgically controllable period in colorectal liver metastases: a retrospective study.

BACKGROUND: The prognostic implications of the RAS status in colorectal cancer liver metastasis (CRLM) remain unclear. This study investigated the prognostic significance of RAS status after curative hepatectomy, focusing on surgical controllability. METHODS: This retrospective study included liver-only CRLM patients who underwent the first hepatectomy between 2015 and 2022 at the National Cancer Center Hospital. Recurrence-free survival (RFS), surgically controllable period (SCP), and overall survival (OS) were compared between RAS wild-type (RAS-wt) and mutant (RAS-mt) patients. Multivariate analyses were conducted to identify independent prognostic factors for each outcome and independent risk factors for less than 1 year SCP. RESULTS: A total of 150 patients were evaluated, comprising 63 patients with RAS-mt status. There was no significant difference in RFS between RAS-mt and RAS-wt (7.00 vs. 8.03 months, p = 0.48). RAS-mt patients exhibited worse SCP (11.80 vs.21.13 months, p < 0.001) and OS (44.03 vs. 70.03 months, p < 0.001) compared to RAS-wt. Multivariate analysis identified RAS-mt as an independent prognostic factor for both OS (hazard ratio [HR]: 3.37, p < 0.001) and SCP (HR: 2.20, p < 0.001), and as an independent risk factor for less than 1 year of SCP (odds ratio, 2.31; p = 0.03). CONCLUSIONS: CRLM with RAS mutations should be considered for strict surgical indications with preoperative chemotherapy and thorough examination, considering the possibility of short SCP.

Optimizing smartphone psychotherapy for depressive symptoms in patients with cancer: Multiphase optimization strategy using a decentralized multicenter randomized clinical trial (J-SUPPORT 2001 Study).

AIM: Patients with cancer experience various forms of psychological distress, including depressive symptoms, which can impact quality of life, elevate morbidity risk, and increase medical costs. Psychotherapy and pharmacotherapy are effective for reducing depressive symptoms among patients with cancer, but most patients prefer psychotherapy. This study aimed to develop an efficient and effective smartphone psychotherapy component to address depressive symptom. METHODS: This was a decentralized, parallel-group, multicenter, open, individually randomized, fully factorial trial. Patients aged ≥20 years with cancer were randomized by the presence/absence of three cognitive-behavioral therapy (CBT) skills (behavioral activation [BA], assertiveness training [AT], and problem-solving [PS]) on a smartphone app. All participants received psychoeducation (PE). The primary outcome was change in the patient health questionnaire-9 (PHQ-9) total score between baseline and week 8. Secondary outcomes included anxiety. RESULTS: In total, 359 participants were randomized. Primary outcome data at week 8 were obtained for 355 participants (99%). The week 8 PHQ-9 total score was significantly reduced from baseline for all participants by -1.41 points (95% confidence interval [CI] -1.89, -0.92), but between-group differences in change scores were not significant (BA: -0.04, 95% CI -0.75, 0.67; AT: -0.16, 95% CI -0.87, 0.55; PS: -0.19, 95% CI -0.90, 0.52). CONCLUSION: As the presence of any of the three intervention components did not contribute to a significant additive reduction of depressive symptoms, we cannot make evidence-based recommendations regarding the use of specific smartphone psychotherapy.

Genomic landscape and its prognostic significance in stage III colorectal cancer: JCOG1506A1, an ancillary of JCOG0910.

Large-scale genomic sequencing of colorectal cancers has been reported mainly for Western populations. Differences by stage and ethnicity in the genomic landscape and their prognostic impact remain poorly understood. We investigated 534 Japanese stage III colorectal cancer samples from the Phase III trial, JCOG0910. Targeted-capture sequencing of 171 potentially colorectal cancer-associated genes was performed, and somatic single-nucleotide variants and insertion-deletions were determined. Hypermutated tumors were defined as tumors with MSIsensor score >7 and ultra-mutated tumors with POLE mutations. Genes with alterations associated with relapse-free survival were analyzed using multivariable Cox regression models. In all patients (184 right-sided, 350 left-sided), mutation frequencies were TP53, 75.3%; APC, 75.1%; KRAS, 43.6%; PIK3CA, 19.7%; FBXW7, 18.5%; SOX9, 11.8%; COL6A3, 8.2%; NOTCH3, 4.5%; NRAS, 4.1%; and RNF43, 3.7%. Thirty-one tumors were hypermutated (5.8%; 14.1% right-sided, 1.4% left-sided). Modest associations were observed: poorer relapse-free survival was seen with mutant KRAS (hazard ratio 1.66; p = 0.011) and mutant RNF43 (2.17; p = 0.055), whereas better relapse-free survival was seen with mutant COL6A3 (0.35; p = 0.040) and mutant NOTCH3 (0.18; p = 0.093). Relapse-free survival tended to be better for hypermutated tumors (0.53; p = 0.229). In conclusion, the overall spectrum of mutations in our Japanese stage III colorectal cancer cohort was similar to that in Western populations, but the frequencies of mutation for TP53, SOX9, and FBXW7 were higher, and the proportion of hypermutated tumors was lower. Multiple gene mutations appeared to impact relapse-free survival, suggesting that tumor genomic profiling can support precision medicine for colorectal cancer.

A comprehensive appraisal of HER2 heterogeneity in HER2-amplified and HER2-low colorectal cancer.

BACKGROUND: This study aimed to elucidate the clinicopathological and molecular features of HER2-amplified and HER2-low colorectal cancers (CRCs). We also characterised HER2 expression statuses in CRCs focusing on their intratumoral heterogeneity and alterations in metastatic lesions to establish practical HER2 status assessment. METHODS: We evaluated 1009 CRCs for HER2 expression and HER2 amplification by immunohistochemistry and FISH, respectively, and correlated the results to clinicopathological and molecular data. For HER2-positive tumours, HER2 expression in metastatic lesions was also assessed. RESULTS: Twenty-five HER2-amplified (2.5%) and 46 HER2-low tumours (4.6%) were identified. HER2-amplified tumours consistently lacked a mucinous component and HER2-low tumours tended to be in the right colon, but no other clinicopathological features were noted. KRAS, NRAS or BRAF mutations were detected in only two HER2-amplified tumours (8%), whereas 23 HER2-low tumours (50%) had one of these mutations. Most HER2-amplified and HER2-low tumours showed a homogeneous or mosaic HER2 expression pattern and a clustered heterogeneous expression pattern was rather rare. HER2 expression was maintained in most metastatic lesions in both HER2-amplified (93%) and HER2-low tumours (81%). CONCLUSIONS: These results suggest that biopsy-based assessment of primary lesions is appropriate for the identification of CRC patients eligible for systemic HER2-targeted therapy.

Effect of Biologics on the Risk of Advanced-Stage Inflammatory Bowel Disease-Associated Intestinal Cancer: A Nationwide Study.

INTRODUCTION: The aim of this study was to evaluate the effect of biologics on the risk of advanced-stage inflammatory bowel disease (IBD)-associated intestinal cancer from a nationwide multicenter data set. METHODS: The medical records of patients with Crohn's disease (CD) and ulcerative colitis (UC) diagnosed with IBD-associated intestinal neoplasia (dysplasia or cancer) from 1983 to 2020 were included in this study. Therapeutic agents were classified into 3 types: biologics, 5-aminosalicylic acid, and immunomodulators. The pathological cancer stage was compared based on the drug used in both patients with CD and UC. RESULTS: In total, 1,042 patients (214 CD and 828 UC patients) were included. None of the drugs were significantly associated with cancer stage in the patients with CD. In the patients with UC, an advanced cancer stage was significantly associated with less use of biologics (early stage: 7.7% vs advanced stage: 2.0%, P < 0.001), 5-aminosalicylic acid, and immunomodulators. Biologic use was associated with a lower incidence of advanced-stage cancer in patients diagnosed by regular surveillance (biologics [-] 24.5% vs [+] 9.1%, P = 0.043), but this was not the case for the other drugs. Multivariate analysis showed that biologic use was significantly associated with a lower risk of advanced-stage disease (odds ratio = 0.111 [95% confidence interval, 0.034-0.356], P < 0.001). DISCUSSION: Biologic use was associated with a lower risk of advanced IBD-associated cancer in patients with UC but not with CD. The mechanism of cancer progression between UC and CD may be different and needs to be further investigated.

Correlation between recurrence-free survival and overall survival after upfront surgery for resected colorectal liver metastases.

BACKGROUND: The role of recurrence-free survival (RFS) as a valid surrogate endpoint for overall survival (OS) in patients who underwent upfront surgery for colorectal liver metastases remains uncertain. The aim of the study was to compare the two survival measures in a nationwide cohort of upfront resected colorectal liver metastasis. METHODS: Data from patients with colorectal liver metastases without extrahepatic metastases who underwent curative surgery for liver metastases were retrieved from the Japanese nationwide database (data collection 2005-2007 and 2013-2014). RFS, OS, and survival after recurrence were estimated using the Kaplan-Meier method. The correlation (ρ) between RFS and OS was assessed using the rank correlation method combined with iterative multiple imputation, to account for censoring. As a secondary analysis, the correlation was evaluated according to adjuvant chemotherapy regimen. In sensitivity analysis, the pairwise correlation between RFS and OS was calculated. RESULTS: A total of 2385 patients with colorectal liver metastases were included. In the primary analysis, there was a moderately strong correlation between RFS and OS (ρ = 0.73, 95 per cent c.i. 0.70 to 0.76). The strength of the correlation was similar regardless of the adjuvant treatment regimen (oxaliplatin plus 5-fluorouracil: ρ = 0.72, 0.67 to 0.77; 5-fluorouracil alone: ρ = 0.72, 0.66 to 0.76; observation: ρ = 0.74, 0.69 to 0.78). The mean(s.d.) pairwise correlation coefficient between 3-year RFS and 5-year OS was 0.87(0.06). CONCLUSION: In surgically treated patients with colorectal liver metastases, there was a moderately strong correlation between RFS and OS, which was unaffected by the treatment regimen. Further validation using a trial-level analysis is required.

Nomogram as a novel predictive tool for lymph node metastasis in T1 colorectal cancer treated with endoscopic resection: a nationwide, multicenter study.

BACKGROUND AND AIMS: Since 2009, the Japanese Society for Cancer of the Colon and Rectum guidelines have recommended that tumor budding and submucosal invasion depth, in addition to lymphovascular invasion and tumor grade, be included as risk factors for lymph node metastasis (LNM) in patients with T1 colorectal cancer (CRC). In this study, a novel nomogram was developed and validated by usirge-scale, real-world data, including the Japanese Society for Cancer of the Colon and Rectum risk factors, to accurately evaluate the risk of LNM in T1 CRC. METHODS: Data from 4673 patients with T1 CRC treated at 27 high-volume institutions between 2009 and 2016 were analyzed for LNM risk. To prepare a nonrandom split sample, the total cohort was divided into development and validation cohorts. Pathologic findings were extracted from the medical records of each participating institution. The discrimination ability was measured by using the concordance index, and the variability in each prediction was evaluated by using calibration curves. RESULTS: Six independent risk factors for LNM, including submucosal invasion depth and tumor budding, were identified in the development cohort and entered into a nomogram. The concordance index was .784 for the clinical calculator in the development cohort and .790 in the validation cohort. The calibration curve approached the 45-degree diagonal in the validation cohort. CONCLUSIONS: This is the first nomogram to include submucosal invasion depth and tumor budding for use in routine pathologic diagnosis based on data from a nationwide multi-institutional study. This nomogram, developed with real-world data, should improve decision-making for an appropriate treatment strategy for T1 CRC.

Impact of correlations between prioritized outcomes on the net benefit and its estimate by generalized pairwise comparisons.

Benefit-risk balance is gaining interest in clinical trials. For the comprehensive assessment of benefits and risks, generalized pairwise comparisons are increasingly used to estimate the net benefit based on multiple prioritized outcomes. Although previous research has demonstrated that the correlations between the outcomes impact the net benefit and its estimate, the direction and magnitude of this impact remain unclear. In this study, we investigated the impact of correlations between two binary or Gaussian variables on the true net benefit values via theoretical and numerical analyses. We also explored the impact of correlations between survival and categorical variables on the net benefit estimates based on four existing methods (Gehan, Péron, Gehan with correction, and Péron with correction) in the presence of right censoring via simulation and application to actual oncology clinical trial data. Our theoretical and numerical analyses revealed that the true net benefit values were impacted by the correlations in various directions depending on the outcome distributions. With binary endpoints, this direction was governed by a simple rule with a threshold of 50% for a favorable outcome. Our simulation showed that the net benefit estimates based on Gehan's or Péron's scoring rule could be substantially biased in the presence of right censoring, and that the direction and magnitude of this bias were associated with the outcome correlations. The recently proposed correction method greatly reduced this bias, even in the presence of strong outcome correlations. The impact of correlations should be carefully considered when interpreting the net benefit and its estimate.

Prognostic Factors of Bone Metastases From Colorectal Cancer in the Era of Targeted Therapy.

BACKGROUND: Various prognostic factors have been reported for bone metastases from different primary tumor sites. However, bone metastases from colorectal cancer are very rare, and the prognostic factors have not been investigated in detail. OBJECTIVE: This study aimed to identify prognostic factors of bone metastases from colorectal cancer. DESIGN: This is a retrospective cohort study using data from a prospectively collected database. SETTINGS: This study was conducted at a single tertiary care cancer center in Japan. PATIENTS: Patients who developed bone metastases from colorectal cancer during the study period among all patients who received initial treatment for colorectal cancer at our hospital between 2005 and 2016 (n = 4538) were included. MAIN OUTCOME MEASURES: Overall survival after diagnosis of bone metastases from colorectal cancer was the main outcome measure. RESULTS: Ninety-four patients developed bone metastases during the study period. The 5-year overall survival rate was 11.0%. Multivariable analysis identified the following independent risk factors associated with poor prognosis: ≥70 years of age at diagnosis of bone metastases (HR, 2.48; 95% CI, 1.24-4.95; p < 0.01), curative surgery not performed as initial treatment (HR, 2.54; 95% CI, 1.24-5.19; p = 0.01), multiple bone metastases (HR, 2.44; 95% CI, 1.30-4.57; p < 0.01), albumin level <3.7 g/dL (HR, 3.80; 95% CI, 1.95-7.39; p < 0.01), CEA ≥30 ng/mL (HR, 1.94; 95% CI, 1.09-3.46; p = 0.02), and less than 3 chemotherapy options remaining at diagnosis of bone metastases (HR, 2.83; 95% CI, 1.51-5.30; p < 0.01). The median survival times for patients with 0-2, 3, and 4-6 risk factors were 25.0, 8.8, and 4.3 months, respectively. LIMITATIONS: The main limitation is the single-center, retrospective design of this study. CONCLUSIONS: Our results may facilitate multidisciplinary decision-making in patients with bone metastases from colorectal cancer. See Video Abstract at http://links.lww.com/DCR/B930 . FACTORES PRONSTICOS DE LAS METSTASIS SEAS DEL CNCER COLORRECTAL EN LA ERA DE LA TERAPIA DIRIGIDA: ANTECEDENTES:Se han reportado varios factores pronósticos para las metástasis óseas de diferentes sitios de tumores primarios. Sin embargo, las metástasis óseas del cáncer colorrectal son muy raras y los factores pronósticos no se han investigado en detalle.OBJETIVO:Identificar los factores pronósticos de las metástasis óseas del cáncer colorrectal.DISEÑO:Estudio de cohorte retrospectivo utilizando datos de una base de datos recolectada prospectivamente.ENTORNO CLINICO:Un solo centro oncológico de atención terciaria en Japón.PACIENTES:Se seleccionaron pacientes que desarrollaron metástasis óseas de cáncer colorrectal durante el período de estudio entre todos los pacientes que recibieron tratamiento inicial para el cáncer colorrectal en nuestro hospital entre 2005 y 2016 (n = 4538).MEDIDA DE RESULTADO PRINCIPAL:Supervivencia general después del diagnóstico de metástasis óseas por cáncer colorrectal.RESULTADOS:Noventa y cuatro pacientes desarrollaron metástasis óseas, lo que representa el 2,0% de todos los pacientes con cáncer colorrectal que comenzaron el tratamiento durante el período de estudio. La tasa de supervivencia global a 5 años fue del 11,0 %. El análisis multivariable identificó los siguientes factores de riesgo independientes asociados con mal pronóstico: edad ≥70 años al momento del diagnóstico de metástasis óseas (hazard ratio 2,48, CI del 95 % 1,24-4,95, p < 0,01), cirugía curativa no realizada como tratamiento inicial (hazard ratio 2,54, CI 95 % 1,24-5,19, p = 0,01), metástasis óseas múltiples (hazard ratio 2,44, CI del 95 % 1,30-4,57, p < 0,01), nivel de albúmina <3,7 g/dL (hazard ratio 3,80, CI del 95 % 1,95 -7,39, p < 0,01), antígeno carcinoembrionario ≥30 ng/mL (hazard ratio 1,94, CI del 95 % 1,09-3,46, p = 0,02) y menos de 3 opciones de quimioterapia restantes al momento del diagnóstico de metástasis óseas (hazard ratio 2,83, 95 % CI 1,51-5,30, p < 0,01). La mediana de los tiempos de supervivencia para los pacientes con 0-2, 3 y 4-6 factores de riesgo fue de 25,0, 8,8 y 4,3 meses, respectivamente.LIMITACIONES:Diseño retrospectivo de un solo centro.CONCLUSIÓN:Nuestros resultados pueden facilitar la toma de decisiones multidisciplinares en pacientes con metástasis óseas de cáncer colorrectal. Consulte Video Resumen en http://links.lww.com/DCR/B930 . (Traducción- Dr. Francisco M. Abarca-Rendon ).