Management challenges and the role of adjuvant chemotherapy in remnant gastric cancer: an analysis of 313 patients from the KEGG multicenter observational study.

BACKGROUND: Clinical findings and postoperative follow-up data on remnant gastric cancer (RGC) are limited due to its rarity. Additionally, the preoperative staging, radical surgery, and managing recurrence in RGC present significant clinical challenges. METHODS: We analyzed the clinicopathological findings, adjuvant chemotherapy, and patterns of postoperative recurrence of 313 consecutive patients who underwent curative surgery for RGC at 17 Japanese institutions. This study investigated the optimal management of RGC and the impact of adjuvant chemotherapy (AC) on recurrence-free survival (RFS). RESULTS: Pathological stages I, II, and III were observed in 55.9% (N = 175), 24.9% (N = 78), and 19.2% (N = 60) of the patients, respectively. The overall concordance rate between clinical and pathological T staging was 58.3%, with a clinical T4 sensitivity of 41.4% for diagnosing pathological T4. During the median follow-up period of 4.6 years, disease recurrence occurred in 24.3% of patients. Most recurrences (over 80%) occurred within 2.5 years, and 96.1% within 5 years after RGC surgery. Peritoneal recurrence was the most common in patients with advanced RGC, accounting for 14.1% in stage II and 28.3% in stage III. Multivariable regression analysis showed that AC was significantly associated with a longer RFS, with a hazard ratio of 0.45 (95% confidence interval: 0.26-0.76). CONCLUSIONS: Our study underscores the importance of early detection, accurate preoperative staging, and postoperative surveillance in managing advanced RGC cases. Despite some limitations, our findings indicate that AC may provide survival benefits comparable to those seen in primary gastric cancer.

Comparison of Minimally Invasive Surgery with Open Surgery for Remnant Gastric Cancer: A Multi-institutional Cohort Study.

BACKGROUND: Despite growing evidence of the effectiveness of minimally invasive surgery (MIS) for primary gastric cancer, MIS for remnant gastric cancer (RGC) remains controversial due to the rarity of the disease. This study aimed to evaluate the surgical and oncological outcomes of MIS for radical resection of RGC. PATIENTS AND METHODS: Patients with RGC who underwent surgery between 2005 and 2020 at 17 institutions were included, and a propensity score matching analysis was performed to compare the short- and long-term outcomes of MIS with open surgery. RESULTS: A total of 327 patients were included in this study and 186 patients were analyzed after matching. The risk ratios for overall and severe complications were 0.76 [95% confidence interval (CI): 0.45, 1.27] and 0.65 (95% CI: 0.32, 1.29), respectively. The MIS group had significantly less blood loss [mean difference (MD), -409 mL; 95% CI: -538, -281] and a shorter hospital stay (MD, -6.5 days; 95% CI: -13.1, 0.1) than the open surgery group. The median follow-up duration of this cohort was 4.6 years, and the 3-year overall survival were 77.9% and 76.2% in the MIS and open surgery groups, respectively [hazard ratio (HR), 0.78; 95% CI: 0.45, 1.36]. The 3-year relapse-free survival were 71.9% and 62.2% in the MIS and open surgery groups, respectively (HR, 0.71; 95% CI: 0.44, 1.16). CONCLUSIONS: MIS for RGC showed favorable short- and long-term outcomes compared to open surgery. MIS is a promising option for radical surgery for RGC.

Timing of real-time indocyanine green fluorescence visualization for lymph node dissection during laparoscopic colon cancer surgery.

PURPOSE: Although numerous studies have highlighted the potential value of indocyanine green (ICG) imaging in lymph node dissection of cancer surgery, its efficacy and optimal method remain to be clarified. This study aimed to investigate how lymphatic flow observation via ICG fluorescence could contribute to colon cancer surgery. METHODS: From October 2018 to March 2021, a total of 56 patients with colon cancer who underwent laparoscopic complete mesocolic excision with intraoperative ICG imaging were analyzed. Lymphatic flow was examined at the following time points following ICG injection: within 5 min, 30-60 min, and over 60 min. We also evaluated the distribution of ICG fluorescence per each vascular pedicle. RESULTS: Lymphatic flow was observed within 5 min following ICG injection in 6 cases (10.7%), and at 30-60 min following ICG injection in 43 cases (76.8%). ICG-stained vascular pedicles were variable especially in hepatic flexural, transverse, and splenic flexural colon cancer. Lymph node metastases were observed in 14 cases. Although metastatic lymph nodes were present only in the area along the ICG-stained vascular pedicles in 12 of the 14 cases, two patients exhibited lymph node metastasis in areas along the ICG-unstained vascular pedicles. ICG fluorescence was observed outside the standard range of lymph node dissection in 9 cases (20.9%: 9/43). Although addition of the proposed resection areas was made in 8 of these 9 cases, there was no pathologically positive lymph node. CONCLUSION: Real-time ICG fluorescence imaging of lymph nodes may improve the performance of laparoscopic colon cancer surgery, although its oncological benefit is not yet clear.

Postoperative recurrence in locally advanced rectal cancer: how does neoadjuvant treatment affect recurrence pattern?

BACKGROUND: The treatment strategy for locally advanced rectal cancer (LARC) has recently expanded from total mesorectal excision to additional neoadjuvant chemoradiotherapy (nCRT) and/or systemic chemotherapy (NAC). Data on disease recurrence after each treatment strategy are limited. METHODS: Clinical stage II to III rectal cancer patients who underwent curative surgery between July 2005 and February 2021 were analyzed. The cumulative incidence and site of first recurrence were assessed. The median follow-up duration was 4.6 years. RESULTS: Among the 332 patients, we performed nCRT and NAC in 15.4% (N=51) and 14.8% (N=49), respectively. The overall recurrence rate was 23.5% (N=78). Although several differences in tumor stage or location were observed, there was no significant difference in the rate among the surgery alone (N=54, 23.3%), nCRT (N=11, 21.6%), and NAC (N=13, 26.5%) groups. In this cohort, the local recurrence rate (18.4%) was higher than the rate of distant metastasis in the NAC group (14.3%). All patients with recurrence in the nCRT group had distant metastases (N=11: one patient had distant and local recurrences simultaneously). For pathological stage 0-I, the recurrence rate was higher in the nCRT and NAC groups than in the surgery-alone group (nCRT, 10.0%; NAC, 15.4%; and surgery-alone, 2.0%). Curative-intent resection of distant-only recurrences significantly improved patients' overall survival (hazard ratio [95% confidence interval], 0.34 [0.14-0.84]), which was consistent even when stratified according to neoadjuvant treatment. Regardless of neoadjuvant treatment, >80% of recurrences occurred in the first 2.2 years, and 98.7% within 5 years after surgery. CONCLUSION: Regardless of neoadjuvant treatment, detecting distant metastases with intensive surveillance, particularly in the first 2 years after surgery, is important. Also, even if neoadjuvant treatment can downstage LARC to pathological stage 0-I, careful follow-up is needed.

Laparoscopic Versus Open Surgery for Locally Advanced Rectal Cancer: Five-Year Survival Outcomes in a Large, Multicenter, Propensity Score-Matched Cohort Study.

BACKGROUND: There is a paucity of evidence pertaining to long-term survival outcomes of laparoscopic versus open surgery for locally advanced rectal cancer. OBJECTIVE: This study aimed to evaluate the long-term survival outcomes of laparoscopic surgery for locally advanced rectal cancer and to investigate the recurrence pattern. DESIGN: This was a prospective analysis of a registered cohort. SETTINGS: This study was conducted at 69 institutions across Japan. PATIENTS: A total of 1500 patients with clinical stage II-III rectal cancer located below the peritoneal reflection between January 2010 and December 2011 were included. After propensity score matching, all eligible patients, including the matched patients registered in 2014, were prospectively followed up. MAIN OUTCOME MEASURES: Five-year relapse-free survival was the primary outcome. RESULTS: The median follow-up period was 5.6 years. Among the 964 matched patients, the 5-year relapse-free survival was 65.1% in the open group versus 63.5% in the laparoscopic group (HR 1.04; p = 0.71). Distant recurrences at rare sites, which were more frequently observed in the laparoscopic group, were significantly less salvaged (adjusted OR 0.74; p = 0.045). Postrecurrence 5-year overall survival was significantly better for patients who underwent salvage surgery than for those who did not; 55.3% vs 29.5% for patients with initial local recurrence ( p = 0.03) and 64.4% vs 30.7% for patients with distant recurrence alone ( p < 0.001). LIMITATIONS: Potential heterogeneity and influence of unknown confounding. CONCLUSIONS: Five-year follow-up data demonstrated that laparoscopic surgery for locally advanced rectal cancer was safely performed in terms of long-term prognosis. In addition, salvage surgery for recurrent lesions was associated with prolonged postrecurrence survival, both in patients with local and distant recurrence. However, recurrence at rare sites may require further investigation. See Video Abstract at http://links.lww.com/DCR/B793 . CIRUGA LAPAROSCPICA VERSUS CIRUGA ABIERTA EN CNCER DE RECTO LOCALMENTE AVANZADO RESULTADOS DE SUPERVIVENCIA A CINCO AOS EN UN ESTUDIO DE COHORTE DE GRAN MAGNITUD, MULTICNTRICO Y DE PAREAMIENTO POR PUNTAJE DE PROPENSIN: ANTECEDENTES:Existe una escasez de pruebas relacionadas con los resultados de supervivencia a largo plazo de la cirugía laparoscópica versus abierta para el cáncer de recto localmente avanzado.OBJETIVO:Este estudio tuvo como objetivo evaluar los resultados de supervivencia a largo plazo de la cirugía laparoscópica para el cáncer de recto localmente avanzado e investigar el patrón de recurrencia.DISEÑO:Fue un análisis prospectivo de una cohorte registrada.ENTORNO CLÍNICO:El estudio se llevó a cabo en 69 instituciones en todo Japón.PACIENTES:Se incluyó un total de 1500 pacientes con cáncer de recto en estadio clínico II-III ubicados por debajo de la reflección peritoneal, entre enero del 2010 y diciembre del 2011. Después del pareamiento por puntaje de propensión, se realizó un seguimiento prospectivo de todos los pacientes elegibles, incluidos los pacientes emparejados registrados en 2014.PRINCIPALES MEDIDAS DE VALORACIÓN:La supervivencia sin recaídas a cinco años fue el resultado primario.RESULTADOS:El período de seguimiento medio fue de 5,6 años. Entre los 964 pacientes emparejados, la supervivencia libre de recaída a 5 años fue del 65,1% en el grupo abierto frente al 63,5% en el grupo laparoscópico (cociente de riesgo 1,04; p = 0,71). Las recurrencias a distancia en sitios raros, que se observaron con mayor frecuencia en el grupo laparoscópico, tuvieron menor sobrevida (razón de posibilidades ajustada 0,74; p = 0,045). La supervivencia general a los 5 años después de la recidiva fue significativamente menor en los pacientes sometidos a una cirugía de rescate; 55,3% frente al 29,5% para los pacientes con recidiva local inicial ( p = 0,03) y 64,4% frente al 30,7% para los pacientes con recidiva a distancia sola ( p < 0,001).LIMITACIONES:Potencial heterogeneidad e influencia de factores de confusión desconocidos.CONCLUSIONES:El seguimiento a cinco años demostró que la cirugía laparoscópica para el cáncer de recto localmente avanzado es segura en términos de pronóstico a largo plazo. Además, la cirugía de rescate de las lesiones recurrentes se asoció con una mayor supervivencia posrecurrencia, tanto en pacientes con recurrencia local como a distancia. Sin embargo, la recurrencia en sitios raros puede requerir una mayor investigación. Consulte Video Resumen en http://links.lww.com/DCR/B793 . (Traducción- Dr. Ingrid Melo ).

Identification of high-risk stage I colon and rectal cancer patients: a retrospective analysis of a large Japanese cohort.

PURPOSE: Data regarding risk factors for recurrence in stage I colorectal cancer patients are limited. The aim of this study was to clarify the existence of a high-recurrence-risk population among stage I colorectal cancer patients. METHODS: This analysis included 7,539 stage I colorectal cancer patients treated between 1997 and 2012 at 24 leading hospitals in Japan. Risk factors for time to recurrence were evaluated using a Cox proportional hazards model, and a high-risk group for recurrence was identified. Prognostic outcomes of high-risk stage I colorectal cancer patients were compared with those of low-risk stage I and stage II patients. RESULTS: Multivariable analyses identified left-sided location (hazard ratio [HR]: 1.65, 95% confidence interval [CI]: 1.09-2.58), T2 tumors (HR: 1.80, 95% CI: 1.21-2.66), and lymphatic invasion (HR: 1.55, 95% CI: 1.05-2.28) as risk factors for recurrence in stage I colon cancer, and patients with these three risk factors were classified as high risk. For stage I rectal cancer, patients with poor differentiation (HR: 2.86, 95% CI: 1.21-5.69), T2 tumors (HR: 1.53, 95% CI: 1.07-2.23), and venous invasion (HR: 1.51, 95% CI: 1.08-2.13) were identified as high risk. The Kaplan-Meier analysis of cumulative recurrence rate and recurrence-free survival revealed that the high-risk stage I colorectal cancer patients have poorer clinical outcomes than the low-risk patients. CONCLUSION: Although stage I colorectal cancer patients generally have a favorable prognosis after curative surgery, poorer prognosis was observed in high-risk stage I colorectal cancer patients than in low-risk patients.

High prevalence of clonal hematopoiesis-type genomic abnormalities in cell-free DNA in invasive gliomas after treatment.

Plasma cell-free DNA (cfDNA) is emerging as an important diagnostic tool in cancer. However, cfDNA alterations may differ from those in tissue and sometimes may reflect processes unrelated to the cancer, including clonal hematopoiesis (CH). We examined plasma cfDNA, tested by next-generation sequencing (NGS), for characterized alterations (excluding variants of unknown significance) in 135 patients with invasive glioma. Overall, 21% (28/135) had ≥1 alteration; 17% (23/135) had CH-type cfDNA mutations. Temozolomide (a mutagenic alkylating agent) with concurrent radiation therapy prior to blood draw was significantly associated with an increase in CH-type mutations, even after age, race/ethnicity, and WHO-grade were considered as confounders (odds ratio [95% confidence interval, CI] 8.98 [1.13-71.46]; P = .04; multivariable analysis). Further, of 18 patients with invasive glioma who had both cfDNA and tissue DNA NGS and had ≥1 cfDNA alteration, 16 (89%) had ≥1 cfDNA alteration not found in their tissue DNA, including CH-type alterations in genes such as TP53 (most common), ATM, GNAS, and JAK2. Altogether, 87% of cfDNA alterations (20/23) observed in the 18 patients were implicated in CH. Finally, examining all 135 patients, CH-type cfDNA mutations were an independent prognostic factor for shorter survival (hazard ratio [95% CI] 3.28 [1.28-8.40]; P = .01). These findings emphasize that not all characterized cfDNA alterations detected in patients with solid tumors are cancer-related. Importantly, in patients with invasive gliomas who have had prior temozolomide and radiation, CH-related alterations in cfDNA are frequent and correlate with poor outcomes.

Comprehensive genomic landscape and precision therapeutic approach in biliary tract cancers.

Biliary tract cancers have dismal prognoses even when cytotoxic chemotherapy is administered. There is an unmet need to develop precision treatment approaches using comprehensive genomic profiling. A total of 121 patients with biliary tract cancers were analyzed for circulating-tumor DNA (ctDNA) and/or tissue-based tumor DNA (tissue-DNA) using clinical-grade next-generation sequencing: 71 patients (59%) had ctDNA; 90 (74%), tissue-DNA; and 40 (33%), both. Efficacy of targeted therapeutic approaches was assessed based upon ctDNA and tissue-DNA. At least one characterized alteration was detected in 76% of patients (54/71) for ctDNA [median, 2 (range, 0-9)] and 100% (90/90) for tissue-DNA [median, 4 (range, 1-9)]. Most common alterations occurred in TP53 (38%), KRAS (28%), and PIK3CA (14%) for ctDNA vs TP53 (44%), CDKN2A/B (33%) and KRAS (29%) for tissue-DNA. In 40 patients who had both ctDNA and tissue-DNA sequencing, overall concordance was higher between ctDNA and metastatic site tissue-DNA than between ctDNA and primary tumor DNA (78% vs 65% for TP53, 100% vs 74% for KRAS and 100% vs 87% for PIK3CA [But not statistical significance]). Among 80 patients who received systemic treatment, the molecularly matched therapeutic regimens based on genomic profiling showed a significantly longer progression-free survival (hazard ratio [95%confidence interval], 0.60 [0.37-0.99]. P = .047 [multivariate]) and higher disease control rate (61% vs 35%, P = .04) than unmatched regimens. Evaluation of ctDNA and tissue-DNA is feasible in biliary tract cancers.

Lower Incidence of Postoperative Pulmonary Complications Following Robot-Assisted Minimally Invasive Esophagectomy for Esophageal Cancer: Propensity Score-Matched Comparison to Conventional Minimally Invasive Esophagectomy.

BACKGROUND: Whether robot-assisted minimally invasive surgery (RAMIE) is more beneficial than conventional minimally invasive surgery (MIE) remains unclear. METHODS: In total, 165 consecutive patients with esophageal carcinoma who underwent esophagectomy between January 2015 and April 2020 were retrospectively assessed. A 1:1 propensity score matching analysis was performed to compare the short-term outcomes between RAMIE and conventional MIE. RESULTS: After matching, 45 patients were included in the RAMIE and conventional MIE groups. RAMIE had a significantly longer total operative time (708 vs. 612 min, P < 0.001) and thoracic operative time (348 vs. 285 min, P < 0.001) than conventional MIE. However, there were no significant differences in terms of oncological outcomes, such as R0 resection rate and number of resected lymph nodes. The overall postoperative morbidity (Clavien-Dindo [C-D] grade II or higher) rate of RAMIE and conventional MIE were 51% and 73% (P = 0.03), respectively, and the severe postoperative morbidity (C-D grade III or higher) rates were 11% and 29% (P = 0.04), respectively. The incidence rate of recurrent laryngeal nerve palsy was halved in RAMIE (7%) compared with conventional MIE (20%) (P = 0.06). Finally, the pulmonary complication rate (18%) was significantly lower in patients who underwent RAMIE than in those who underwent conventional MIE (44%) (P = 0.006). CONCLUSIONS: RAMIE was safe and feasible, even during the early period of its application at a specialized center. Moreover, it may be a promising alternative to conventional MIE, with better short-term outcomes, including significantly lower incidence of pulmonary complications.

Long-Term Outcomes of Laparoscopic Radical Gastrectomy for Highly Advanced Gastric Cancer: Final Report of a Prospective Phase II Trial (KUGC04).

BACKGROUND: This is the final report evaluating the long-term outcomes of a single-arm phase II clinical trial that demonstrated the short-term efficacy of laparoscopic gastrectomy (LG) for highly advanced gastric cancer (AGC) [KUGC04]. PATIENTS AND METHODS: Seventy-three patients with histologically confirmed gastric adenocarcinoma and diagnosed with clinical stage II or higher, who potentially underwent curative resection between August 2009 and November 2014, were prospectively enrolled. Long-term outcomes with 5-year progression-free survival (PFS) and 5-year overall survival (OS) were evaluated according to clinical or pathological stages. Recurrence and progression patterns were also investigated. These outcomes were compared with those of previous reports to assess the applicability of LG for highly advanced gastric cancer (HAGC). RESULTS: The median observation period of all surviving patients was 75.1 months. The 5-year PFS and 5-year OS of all patients was 47.4% and 54.4%, respectively. Clinical stage-specific 5-year PFS and 5-year OS was 75.0, 69.1, 53.9, 39.4, 40.0 and 9.1, and 75.0, 68.8, 61.5, 45.0, 60.0 and 27.3, respectively, in stages IIA, IIB, IIIA, IIIB, IIIC, and IV, respectively. Pathological stage-specific 5-year PFS and 5-year OS, including ypStage with preoperative chemotherapy, was 100, 80.0, 100, 62.5, 80.0, 51.3, 16.7, 22.2 and 12.5, and 100, 80.0, 100, 75.0, 80.0, 64.2, 25.0, 33.3 and 12.5, respectively, in stage X (no residual tumor with preoperative chemotherapy), IA, IB, IIA, IIB, IIIA, IIIB, IIIC, and IV, respectively. Recurrence or progression was observed in 30 patients (41.1%). CONCLUSION: LG for HAGC performed by experienced surgeons is safe and oncologically acceptable.

Prognostic Impact of Lateral Pelvic Node Dissection on the Survival of Patients in Low Rectal Cancer Subgroups Based on Lymph Node Size.

BACKGROUND: Lateral pelvic node (LPN) dissection (LPND) is considered a promising technique for treating low rectal cancer; however, there is insufficient evidence of its prognostic value. Using centrally reviewed preoperative pelvic magnetic resonance (MR) images, this study aimed to find the patient population who has benefited from LPND. PATIENTS AND METHODS: MR images of patients from 69 institutes with stage II-III low rectal cancer were reviewed by experienced radiologists. Recurrence-free survival (RFS), overall survival (OS), and short-term outcomes were measured. RESULTS: In total, 731 preoperative MR images were reviewed (excluding patients with short-axis LPN ≥ 10 mm). Of these, 322 underwent total mesorectum excision (TME) without LPND (non-LPND group), and 409 underwent TME with LPND (LPND group). Preoperative treatment was performed for 40% and 25% of patients in the non-LPND and LPND groups, respectively. The incidence of postoperative complications was higher in the LPND group (44.5%) than in the non-LPND group (33.2%; P = 0.002). Among patients with LPNs < 5 mm, OS and RFS curves were not significantly different between the groups. Among patients with LPNs ≥ 5 mm, the LPND group had significantly higher 5-year OS and RFS than the non-LPND group (OS: 81.9% versus 67.3%; RFS: 69.4% versus 51.6%). On multivariate analysis of LPN ≥ 5 mm cases, LPND was independently associated with RFS. CONCLUSIONS: Despite the high incidence of postoperative complications, this study showed the prognostic impact of LPND on low rectal cancer patients with LPNs (≥ 5 mm, < 10 mm short axis) measured by experienced radiologists. Trial registration UMIN-ID: UMIN000013919.

Temporal and spatial effects and survival outcomes associated with concordance between tissue and blood KRAS alterations in the pan-cancer setting.

We investigated the impact of time interval, primary vs. metastatic biopsy site, variant allele fraction (VAF) and histology on concordance of KRAS alterations in tissue vs. circulating tumor DNA (ctDNA), and association of concordance with survival. Blood and tissue were evaluated by next-generation sequencing in 433 patients with diverse cancers. Altogether, 101 patients (23.3%) had KRAS alterations: 56, ctDNA (12.9%); 81, tissue (18.7%); and 36, both (8.3%). The overall blood and tissue concordance rate for KRAS alterations was 85%, but was mainly driven by the large negative/negative subset. Therefore, specificity of one test for the other was high (88.1-94.3%), while sensitivity was not high (44.4-64.3%) and was lower still in patients with >6 vs. ≤2 months between blood and tissue sampling (31.0-40.9% vs. 51.2-84.0%; p = 0.14 time interval-dependent sensitivity of blood for tissue; p = 0.003, tissue for blood). Positive concordance rate for KRAS alterations was 57.1% vs. 27.4% (colorectal vs. noncolorectal cancer; p = 0.01), but site of biopsy (primary vs. metastatic) and VAF (%ctDNA) was not impactful. The presence of KRAS alterations in both tests was independently associated with shorter survival from diagnosis (hazard ratio, 1.72; 95% confidence interval, 1.04-2.86) and from recurrent/metastatic disease (1.70; 1.03-2.81). Positive concordance of KRAS alterations between ctDNA and tissue was negatively affected by a longer time period between blood and tissue sampling and was higher in colorectal cancer than in other malignancies. The presence of KRAS alterations in both tests was an independent prognostic factor for poor survival.

Prognostic implications of RAS alterations in diverse malignancies and impact of targeted therapies.

RAS alterations are often found in difficult-to-treat malignancies and are considered "undruggable." To better understand the clinical correlates and coaltered genes of RAS alterations, we used targeted next-generation sequencing (NGS) to analyze 1,937 patients with diverse cancers. Overall, 20.9% of cancers (405/1,937) harbored RAS alterations. Most RAS-altered cases had genomic coalterations (95.3%, median: 3, range: 0-51), often involving genes implicated in oncogenic signals: PI3K pathway (31.4% of 405 cases), cell cycle (31.1%), tyrosine kinase families (21.5%) and MAPK signaling (18.3%). Patients with RAS-altered versus wild-type RAS malignancies had significantly worse overall survival (OS; p = 0.02 [multivariate]), with KRAS alterations, in particular, showing shorter survival. Moreover, coalterations in both RAS and PI3K signaling or cell-cycle-associated genes correlated with worse OS (p = 0.004 and p < 0.0001, respectively [multivariate]). Among RAS-altered patients, MEK inhibitors alone did not impact progression-free survival (PFS), while matched targeted therapy against non-MAPK pathway coalterations alone showed a trend toward longer PFS (vs. patients who received unmatched therapy) (HR: 0.79, 95% CI: 0.61-1.03, p = 0.07). Three of nine patients (33%) given tailored combination therapies targeting both MAPK and non-MAPK pathways achieved objective responses. In conclusion, RAS alterations correlated with poor survival across cancers. The majority of RAS alterations were accompanied by coalterations impacting other oncogenic pathways. MEK inhibitors alone were ineffective against RAS-altered cancers while matched targeted therapy against coalterations alone correlated with a trend toward improved PFS. A subset of the small number of patients given MEK inhibitors plus tailored non-MAPK-targeting agents showed responses, suggesting that customized combinations warrant further investigation.

Targeting fusions for improved outcomes in oncology treatment.

BACKGROUND: Fusions are increasingly pursued as oncology therapeutic targets. The current study evaluated differences in outcomes for fusion versus nonfusion targets. METHODS: Outcomes were compared for patients with fusions versus those with other alterations for US Food and Drug Administration-approved single agents (from package inserts) and for patients treated at the University of California at San Diego. RESULTS: A total of 28 drugs approved by the US Food and Drug Administration (6189 patients) were included in the analysis. The median response rate was 68% versus 50% for fusions versus nonfusion matches (odds ratio [OR], 1.67; P < .0001); solid tumor therapies had an OR of 2.07 (P < .0001) and hematologic therapies had an OR of 3.35 (P < .0001) for fusion versus nonfusion targets. The University of California at San Diego analysis included 79 patients in whom fusions were treated of the 2455 patients screened. Patients matched to fusions were found to have a longer median progression-free survival (PFS) (11.6 months; 95% CI, 4.0-35.4 months) compared with those unmatched to fusions (4.9 months; 95% CI, 3.5-8.8 months) (P = .034). Patients with fusions matched to other alterations present in the tumor had a median PFS that was indistinguishable from that of those patients with fusions who were treated with unmatched therapy (4.0 months vs 5.0 months; P = .75). CONCLUSIONS: Significantly higher response rates and a longer PFS were observed when targeting fusions compared with nonfusions. The observations reported in the current study suggest that fusions are important targets and that additional studies are needed to confirm that optimized therapy may require targeting fusions, even in the presence of other alterations.

Attrition of Patients on a Precision Oncology Trial: Analysis of the I-PREDICT Experience.

BACKGROUND: Precision oncology uses molecular profiling of tumors to identify biomarker-tailored therapies for patients in the hope of improving outcomes. Typically, only a minority of patients receives evaluable matched treatment. This study explored the reasons for attrition on a precision medicine trial. MATERIALS AND METHODS: Study participants were 190 adult patients who consented to the I-PREDICT (Investigation of molecular Profile-Related Evidence Determining Individualized Cancer Therapy) trial. Patients had metastatic and/or unresectable incurable malignancies. Patients who were not evaluable were analyzed. RESULTS: Of consented patients, 44% were not evaluable. Men were twice as likely to be not evaluable as women. Prominently, 45% of patients who were not evaluable dropped off because of death, hospice referral, or decline in organ function. CONCLUSION: Health deterioration of consented patients is a significant barrier to being evaluable on the I-PREDICT trial. These data suggest that patients are enrolled on precision oncology trials too late in their disease course or with excessive disease burden.

Prognostic impact of the combination of neutrophil-to-lymphocyte ratio and Glasgow prognostic score in colorectal cancer: a retrospective cohort study.

PURPOSE: Although neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte count, and Glasgow prognostic score (GPS) are well-known prognostic markers in cancer, their prognostic importance is still controversial. We evaluated the prognostic value of NLR, PLR, monocyte count, and GPS in colorectal cancer (CRC). METHOD: We retrospectively evaluated 448 CRC patients undergoing curative resection. We compared overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS) between dichotomized groups by the optimal cutoff point. Univariate and multivariate analyses were applied to identify prognostic factors. RESULT: High NLR, high monocyte count, and high GPS exhibited significantly worse prognosis in OS, CSS, and DFS compared with low NLR, low monocyte count, and low GPS, respectively. In contrast, PLR was not significantly associated with OS, CSS, and DFS. The univariate and multivariate analyses indicated that poor OS was significantly associated with age ≥ 69 and high NLR; that poor CSS was significantly associated with age ≥ 69, M factor, high CA19-9, adjuvant chemotherapy, and high GPS; and that poor DFS was significantly associated with venous invasion, high NLR, and high GPS. When 448 patients were classified into three groups based on NLR and GPS, there was a significant difference in OS, CSS, and DFS between all the three groups. Patients with NLR ≥ 2.05 and GPS = 1/2 exhibited remarkably poorer prognosis, whereas those with both NLR < 2.05 and GPS = 0 exhibited remarkably better prognosis. CONCLUSION: Combination of NLR and GPS can be a novel scoring system to effectively stratify outcome in CRC.

Open versus Laparoscopic Surgery for Advanced Low Rectal Cancer: A Large, Multicenter, Propensity Score Matched Cohort Study in Japan.

BACKGROUND: Laparoscopic surgery for rectal cancer is widely performed all over the world and several randomized controlled trials have been reported. However, the usefulness of laparoscopic surgery compared with open surgery has not been demonstrated sufficiently, especially for the low rectal area. OBJECTIVE: The aim of this study was to investigate the hypothesis that laparoscopic primary tumor resection is safe and effective when compared with the open approach for locally advanced low rectal cancer. PATIENTS AND METHODS: Data from patients with clinical stage II to III low rectal cancer below the peritoneal reflection were collected and analyzed. The operations were performed from 2010 to 2011. Short-term outcomes and long-term prognosis were analyzed with propensity score matching. RESULTS: Of 1608 cases collated from 69 institutes, 1500 cases were eligible for analysis. The cases were matched into 482 laparoscopic and 482 open cases. The mean height of the tumor from the anal verge was 4.6 cm. Preoperative treatment was performed in 35% of the patients. The conversion rate from laparoscopic to open surgery was 5.2%. Estimated blood loss during laparoscopic surgery was significantly less than that during open surgery (90 vs 625 mL, P < 0.001). Overall, the occurrence of complications after laparoscopic surgeries was less than that after open surgeries (30.3% vs 39.2%, P = 0.005). Three-year overall survival rates were 89.9% [95% confidence interval (95% CI) 86.7-92.4] and 90.4% (95% CI 87.4-92.8) in the laparoscopic and open groups, respectively, and no significant difference was seen between the 2 groups. No significant difference was observed in recurrence-free survival (RFS) between the 2 groups (3-year RFS: 70.9%, 68.4 to 74.2 vs 71.8%, 67.5 to 75.7). CONCLUSION: Laparoscopic surgery could be considered as a treatment option for advanced, low rectal cancer below the peritoneal reflection, based on the short-term and long-term results of this large cohort study (UMIN-ID: UMIN000013919).

A New Prediction Model for Local Recurrence After Curative Rectal Cancer Surgery: Development and Validation as an Asian Collaborative Study.

BACKGROUND: Local recurrence is one of the remaining problems in rectal and rectosigmoid cancer, and it is sometimes difficult to treat. OBJECTIVE: This study aimed to explore various factors that are highly related to local recurrence and to develop a new prediction model for local recurrence after curative resection. DESIGN: This is a retrospective cohort study SETTINGS:: This study was conducted at 2 academic hospitals in Japan and Korea. PATIENTS: A total of 2237 patients with stage I to III rectal and rectosigmoid cancer who underwent a curative operation with a negative circumferential margin were selected. INTERVENTIONS: Surgical treatment was the intervention. MAIN OUTCOME MEASURES: Local recurrence was the primary outcome measure. RESULTS: A total of 1232 patients were selected, and rectosigmoid cancer with rare local recurrence (2/221) was excluded. A different set of 792 patients with rectal cancer were chosen for validation. Multivariate analysis showed the following factors as significant for local recurrence: poorly differentiated tumor (HR, 11.2; 95% CI, 4.5-28.0), tumor depth (HR, 5.0), lymph node metastasis (HR, 4.1), operative procedure (HR, 3.2), postoperative complications (HR, 2.9), tumor location (HR, 2.6), and CEA level (HR, 2.4); a new prediction score was created by using these factors. A poorly differentiated tumor was assigned 2 points, and all other factors were assigned 1 point each. Patients who scored more than 5 points (n = 21) were judged as "high risk," with a 2-year local recurrence rate of 66.5%. The new predictive model could also separate the patients into different risk groups in the validation set. The high-risk group had higher recurrence rates than medium- and low-risk groups (2-year local recurrence rate: 41%, 15%, and 2.1%). LIMITATIONS: This study was limited by its retrospective nature and potential for selection bias. CONCLUSIONS: Seven factors were shown to be significantly correlated with the local recurrence of rectal cancer, and the usefulness of this new prediction model was demonstrated. See Video Abstract at http://links.lww.com/DCR/A429.