The Frequency of Specific KRAS Mutations, and Their Impact on Treatment Choice and Survival, in Patients With Metastatic Colorectal Cancer.

BACKGROUND: Patients with metastatic colorectal cancer (mCRC) and KRAS mutations have a poor prognosis, seemingly dependent on the location of the mutation. This multicenter, retrospective, cohort study assessed the frequency and prognostic value of specific KRAS mutation codon locations in mCRC patients, and survival outcomes in relation to treatment. MATERIALS AND METHODS: Data from mCRC patients treated in 10 Spanish hospitals between January 2011 and December 2015 were analyzed. The main objective was to investigate (1) the impact of KRAS mutation location on overall survival (OS), and (2) the effect of targeted treatment plus metastasectomy and primary tumor location on OS in patients with KRAS mutations. RESULTS: The KRAS mutation location was known for 337/2002 patients. Of these, 177 patients received chemotherapy only, 155 received bevacizumab plus chemotherapy, and 5 received anti-epidermal growth factor receptor therapy plus chemotherapy; 94 patients underwent surgery. The most frequent KRAS mutation locations were G12A (33.8%), G12D (21.4%), and G12V (21.4%). Compared with other locations, patients with a G12S mutation had the shortest median OS (10.3 [95% CI, 2.5-18.0] months). OS was longer in patients who underwent surgery versus those who did not, with a trend toward prolonged survival with bevacizumab (median OS 26.7 [95% CI, 21.8-31.7] months) versus chemotherapy alone (median OS 23.2 [95% CI, 19.4-27.0] months). CONCLUSION: These findings confirm that KRAS mutation location may predict survival outcomes in patients with mCRC, and suggest that pre-/post-operative bevacizumab plus metastasectomy provides survival benefits in patients with KRAS mutations.

Treatment with anticancer drugs for advanced pancreatic cancer: a systematic review.

BACKGROUND: Patients with advanced pancreatic cancer have a poor prognosis and high burden of cancer-related symptoms. It is necessary to assess the trade-off of clinical benefits and possible harms of treatments with anticancer drugs (TAD). This systematic review aims to compare the effectiveness of TAD versus supportive care or no treatment, considering all patient-important outcomes. METHODS: We searched PubMed, Embase, Cochrane Library, and Epistemonikos. Two reviewers performed selection, data extraction and risk of bias assessment. We assessed certainty of the evidence using the GRADE approach. RESULTS: We included 14 randomised controlled trials. Chemotherapy may result in a slight increase in overall survival (MD: 2.97 months (95%CI 1.23, 4.70)) and fewer hospital days (MD: -6.7 (-8.3, -5.1)), however, the evidence is very uncertain about its effect on symptoms, quality of life, functional status, and adverse events. Targeted/biological therapy may result in little to no difference in overall survival and a slight increment in progression-free survival (HR: 0.83 (95%CI 0.63, 1.10)), but probably results in more adverse events (RR: 5.54 (95%CI 1.24, 23.97)). The evidence is very uncertain about the effect of immunotherapy in overall survival and functional status. CONCLUSIONS: The evidence is very uncertain about whether the benefits of using treatment with anticancer drugs outweigh their risks for patients with advanced pancreatic cancer. This uncertainty is further highlighted when considering immunotherapy or a second line of chemotherapy and thus, best supportive care would be an appropriate alternative. Future studies should assess their impact on all patient-important outcomes to inform patients in setting their goals of care.

Efficacy and safety of trifluridine/tipiracil in older and younger patients with metastatic gastric or gastroesophageal junction cancer: subgroup analysis of a randomized phase 3 study (TAGS).

BACKGROUND: Trifluridine and tipiracil (FTD/TPI) demonstrated survival benefit vs placebo and manageable safety in previously treated patients with metastatic gastric/gastroesophageal junction cancer (mGC/GEJC) in the randomized, placebo-controlled, phase 3 TAGS study. This subgroup analysis of TAGS examined efficacy/safety outcomes by age. METHODS: In TAGS, patients with mGC/GEJC and ≥ 2 prior therapies were randomized (2:1) to receive FTD/TPI 35 mg/m2 or placebo, plus best supportive care. A preplanned subgroup analysis was performed to evaluate efficacy and safety outcomes in patients aged < 65, ≥ 65, and ≥ 75 years. RESULTS: Among 507 randomized patients (n = 337 FTD/TPI; n = 170 placebo), 55%, 45%, and 14% were aged < 65, ≥ 65, and ≥ 75 years, respectively. Overall survival hazard ratios for FTD/TPI vs placebo were 0.67 (95% CI 0.51-0.89), 0.73 (95% CI 0.52-1.02), and 0.67 (95% CI 0.33-1.37) in patients aged < 65, ≥ 65, and ≥ 75 years, respectively. Regardless of age, patients receiving FTD/TPI experienced improved progression-free survival and stayed longer on treatment than those receiving placebo. Among FTD/TPI-treated patients, frequencies of any-cause grade ≥ 3 adverse events (AEs) were similar across age subgroups (80% each), although grade ≥ 3 neutropenia was more frequent in older patients [40% (≥ 65 and ≥ 75 years); 29% (< 65 years)]; AE-related discontinuation rates did not increase with age [14% (< 65 years), 12% (≥ 65 years), and 12% (≥ 75 years)]. CONCLUSIONS: The results of this subgroup analysis show the efficacy and tolerability of FTD/TPI treatment regardless of age in patients with mGC/GEJC who had received 2 or more prior treatments.

Completion Surgery in Unfavorable Rectal Cancer after Transanal Endoscopic Microsurgery: Does It Achieve Satisfactory Sphincter Preservation, Quality of Total Mesorectal Excision Specimen, and Long-term Oncological Outcomes?

BACKGROUND: Unfavorable adenocarcinoma after transanal endoscopic microsurgery requires "completion surgery" with total mesorectal excision. The literature on this procedure is very limited. OBJECTIVE: This study aims to assess the percentage of transanal endoscopic microsurgery that will require completion surgery. DESIGN: This is an observational study with prospective data collection and retrospective analysis from patients who were operated on consecutively. SETTINGS: The study was conducted at a single academic institution. PATIENTS: Patients undergoing transanal endoscopic microsurgery from June 2004 to December 2018 who later required total mesorectal excision were included. MAIN OUTCOME MEASURES: All the patients followed the same protocol: preoperative study, indication of transanal endoscopic microsurgery with curative intent, performance of transanal endoscopic microsurgery, and completion surgery indication 3 to 4 weeks after transanal endoscopic microsurgery. RESULTS: Seven hundred seventy-four patients underwent transanal endoscopic microsurgery, 622 with curative intent (group I: adenoma, 517; group II: adenocarcinoma, 105). Completion surgery was indicated in 64 of 622 (10.3%) patients: group I, 40 of 517 (7.7%) and group II, 24 of 105 (22.9%). After applying exclusion criteria, completion surgery was performed in 55 patients (8.8%). Abdominoperineal resection was performed in 23 (45.1%); the initial lesion was within 6 cm of the anal verge in 19 of these 23 (82.6%). The clinical morbidity rate (Clavien Dindo> II) was 3 of 51 (5.9%). Total mesorectal excision was graded as complete in 42 of 49 (85.7%). The circumferential resection margin was tumor-free in 47 of 50 (94%). Median follow-up was 58 months. Local recurrence was recorded in 2 of 51 (3.9%) and systemic recurrence was recorded in 7 of 51 (13.7%); 5-year disease-free survival was 86%. LIMITATIONS: The limitations are defined by the study's observational design and the retrospective analysis. CONCLUSION: The indication of completion surgery after transanal endoscopic microsurgery is low, but is higher in the indication of adenocarcinoma. Compared with initial total mesorectal excision, completion surgery requires a higher rate of abdominoperineal resection, but has similar postoperative morbidity, total mesorectal excision quality, and oncological results. See Video Abstract at http://links.lww.com/DCR/B423. CIRUGA COMPLEMENTARIA EN CNCER DE RECTO DESFAVORABLE DESPUS DE UNA TEM SE OBTIENE SATISFACTORIAMENTE PRESERVACIN DEL ESFNTER, CALIDAD DE MUESTRA DE ETM Y RESULTADOS ONCOLGICOS A LARGO PLAZO: ANTECEDENTES:El adenocarcinoma con evolución desfavorable luego de una de microcirugía endoscópica transanal (TEM) requiere "cirugía de finalización" con la excisión total del mesorecto. La literatura sobre este procedimiento es muy limitada.OBJETIVO:Evaluar el porcentaje de microcirugía endoscópica transanal que requerió cirugía completa.DISEÑO:Estudio observacional con recolección prospectiva de datos y análisis retrospectivo de pacientes operados consecutivamente.AJUSTES:El estudio se realizó en una sola institución académica.PACIENTES:Aquellos pacientes sometidos a microcirugía endoscópica transanal desde junio de 2004 hasta diciembre de 2018 que luego requirieron excisón toztal del mesorecto.PRINCIPALES MEDIDAS DE RESULTADO:Todos los pacientes siguieron el mismo protocolo: estudio preoperatorio, indicación de microcirugía endoscópica transanal con intención curativa, realización de microcirugía endoscópica transanal e indicación de cirugía complementaria 3-4 semanas después de la microcirugía endoscópica transanal.RESULTADOS:Setecientos setenta y cuatro pacientes fueron sometidos a microcirugía endoscópica transanal, 622 con intención curativa (grupo I, adenoma: 517, grupo II, adenocarcinoma: 105). la cirugía complementaria fué indicada en 64/622 (10.3%), grupo I: 40/517 (7.7%) y grupo II 24/105 (22.9%). Después de aplicar los criterios de exclusión, la cirugía complementaria se realizó en 55 pacientes (8,8%). La resección abdominoperineal fué realizada en 23 (45,1%); en 19 de estos casos 23 (82,6%) la lesión inicial se encontraba dentro los 6 cm del margen anal. La tasa de morbilidad clínica (Clavien-Dindo > II) fue de 3/51 (5,9%). La excisión total del mesorecto se calificó como completa en 42/49 (85,7%). El margen de resección circunferencial se encontraba libre de tumor en 47/50 (94%). La mediana de seguimiento fue de 58 meses. La recurrencia local se registró en 2/51 (3.9%) y la recurrencia sistémica en 7/51 (13.7%); La supervivencia libre de enfermedad a 5 años fue del 86%.LIMITACIONES:Todas definidas por el diseño observacional y el análisis retrospectivo del mismo.CONCLUSIÓN:La indicación de completar la cirugía después de una TEM es baja, pero es más alta cuando la indicación es por adenocarcinoma. En comparación con la excisión total del mesorecto inicial, la cirugía complementaria requiere una tasa más alta de resección abdominoperineal, pero tiene una morbilidad postoperatoria, una calidad de excisión total del mesorecto y resultados oncológicos similares. ConsulteVideo Resumen en http://links.lww.com/DCR/B423. (Traducción-Dr. Xavier Delgadillo).

Phase II randomized trial of capecitabine with bevacizumab and external beam radiation therapy as preoperative treatment for patients with resectable locally advanced rectal adenocarcinoma: long term results.

BACKGROUND: Preoperative chemoradiotherapy with capecitabine is considered as a standard of care for locally advanced rectal cancer. The "Tratamiento de Tumores Digestivos" group (TTD) previously reported in a randomized Ph II study that the addition of Bevacizumab to capecitabine-RT conferred no differences in the pre-defined efficacy endpoint (pathological complete response). We present the follow-up results of progression-free survival, distant relapse-free survival, and overall survival data at 3 and 5 years. METHODS: Patients (pts) were randomized to receive 5 weeks of radiotherapy (45 Gy/25 fractions) with concurrent Capecitabine 825 mg/m2 twice daily, 5 days per week with (arm A) or without (arm b) bevacizumab (5 mg/kg once every 2 weeks). RESULTS: In our study, the addition of bevacizumab to capecitabine and radiotherapy in the neoadjuvant setting shows no differences in pathological complete response (15.9% vs 10.9%), distant relapse-free survival (81.0 vs 80.4 and 76.2% vs 78.2% at 3 and 5 years respectively), disease-free survival (75% vs 71.7 and 68.1% vs 69.57% at 3 and 5 years respectively) nor overall survival at 5-years of follow-up (81.8% vs 86.9%). CONCLUSIONS: the addition of bevacizumab to capecitabine plus radiotherapy does not confer statistically significant advantages neither in distant relapse-free survival nor in disease-free survival nor in Overall Survival in the short or long term. TRIAL REGISTRATION: EudraCT number: 2009-010192-24 . Clinicaltrials.gov number: NCT01043484 .

Is aflibercept an optimal treatment for wt RAS mCRC patients after progression to first line containing anti-EGFR?

PURPOSE: To determine the efficacy and safety data of aflibercept + FOLFIRI in wt RAS mCRC patients after progression to standard chemotherapy + anti-EGFR treatment. METHODS: Retrospective, observational study in real life conducted in wt RAS mCRC patients treated with FOLFIRI-aflibercept after progression to standard first line chemotherapy + anti-EGFR treatment. RESULTS: A total of 120 patients from 12 Spanish hospitals were enrolled. Median age is 60 years (62.5%/37.5%male/female). Primary tumor site is 24.1%/75.9% right/left-side colon, and 40.8% of patients had a prior resection. All patients had wild-type RAS tumors including 5% of patients with BRAF mutations and received anti-EGFR treatment. At the time aflibercept was initiated, ECOG PS is 0/1 in 96% of patients. Median number of FOLFIRI-aflibercept cycles is 12. Efficacy results: Overall response rate is 33%; progression-free survival (PFS) is 6.9 months (95%CI: 6.1-7.8). Primary tumor resection was the only significant variable related to PFS in the multivariate analysis. Median overall survival (OS) is 14.5 months (95%CI: 9.7-19.3). ECOG and number of metastatic sites were related to OS in multivariate analysis. About 54.1% of patients received a third-line therapy including TAS-102 (23%), regorafenib (18.5%), and capecitabine (9.2%). TOXICITY: Grade 3-4 toxicities were observed in 37.5% of the patients (hematologic 16.6%, hypertension 7.5%, asthenia 5.9%, and perforation 2.5%). Aflibercept dose was reduced in 18.3% of patients. CONCLUSIONS: The results show that patients with wt RAS mCRC who received an anti-EGFR as part of the first-line treatment achieved similar RR, PFS, OS, and toxicities to those reported in VELOUR trial. These results suggest that FOLFIRI-aflibercept after first-line treatment with anti-EGFR is an appropriated option for RAS wt mCRC.

Quality of life of patients with metastatic pancreatic adenocarcinoma initiating first-line chemotherapy in routine practice.

BACKGROUND: Despite advances in surgery, radiotherapy, and chemotherapy, pancreatic adenocarcinoma often progresses rapidly and causes death. The physical decline of these patients is expected to impact their quality of life (QoL). Therefore, in addition to objective measures of effectiveness, the evaluation of health-related QoL should be considered a matter of major concern when assessing therapy outcomes. METHODS: Observational, prospective, multicenter study including patients with metastatic pancreatic adenocarcinoma who started first-line chemotherapy in 12 Spanish centers. Treatment and clinical characteristics were recorded at baseline. Patients' health-related quality of life, ECOG, and Karnofsky index were measured at baseline, at Days 15 and 30, and every four weeks up to 6 months of chemotherapy. Health-related quality of life was measured using the EORTC-QLQ-C30 and EQ-5D questionnaires. Other endpoints included overall survival and progression-free survival. RESULTS: The study sample included 116 patients (median age of 65 years). Mean (SD) scores for the QLQ-C30 global health status scale showed a significant increasing trend throughout the treatment (p = 0.005). Patients with either a Karnofsky index of 70-80 or ECOG 2 showed greater improvement in the QLQ-C30 global health status score than the corresponding groups with better performance status (p ≤ 0.010). Pain, appetite, sleep disturbance, nausea, and constipation significantly improved throughout the treatment (p < 0.005). Patients with QLQ-C30 global health status scores ≥50 at baseline had significantly greater overall survival and progression-free survival (p = 0.005 and p = 0.021, respectively). No significant associations were observed regarding the EQ-5D score. CONCLUSIONS: Most metastatic pancreatic adenocarcinoma patients receiving first-line chemotherapy showed an increase in health-related quality of life scores throughout the treatment. Patients with lower performance status and health-related quality of life at baseline tended to greater improvement. The EORTC QLQ-C30 scale allowed us to measure the health-related quality of life of metastatic pancreatic adenocarcinoma patients receiving first-line chemotherapy.

A phase 2 study of panitumumab with irinotecan as salvage therapy in chemorefractory KRAS exon 2 wild-type metastatic colorectal cancer patients.

BACKGROUND: Targeted agents are standard treatment for RAS wild-type metastatic colorectal cancer in the first- and second-line settings. This phase 2 study determined the benefit of targeting the epidermal growth factor receptor (EGFR) with panitumumab plus irinotecan in irinotecan-refractory patients. METHODS: KRAS exon-2 wild-type patients failing prior irinotecan received panitumumab (6 mg/kg) and irinotecan (180 mg/m²) every 2 weeks. The primary endpoint was the overall response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). KRAS exon-2 status was evaluated centrally, along with NRAS, BRAF mutations, epiregulin, amphiregulin, PTEN and EGFR copy number status, and correlated with efficacy. RESULTS: Sixty-one patients were treated. Among the 46 wild-type RAS patients, the ORR was 15.2% (seven partial responses), with median PFS of 3.8 months (95% CI 2.7-4.3) and median OS of 12.5 months (95% CI 6.7-15.9). Wild-type BRAF patients showed a 13.0% response rate. No significant correlations between response and baseline biomarker expression were identified. Common grade 3-4 adverse events were diarrhoea and rash (18.0% each), hypomagnesaemia and asthenia (8.2% each). CONCLUSIONS: The addition of panitumumab to irinotecan as salvage therapy is feasible but has limited activity in irinotecan-refractory metastatic colorectal cancer. No biomarkers predictive of response were identified.

Clinicopathological and Molecular Characterization of Metastatic Gastrointestinal Stromal Tumors with Prolonged Benefit to Frontline Imatinib.

BACKGROUND: Oncogenic KIT/PDGFRA signaling inhibition with imatinib achieves disease control in most patients with advanced/metastatic gastrointestinal stromal tumor (GIST), but resistance eventually develops after 20-24 months. Notably, a small subset of these patients obtain durable benefit from imatinib therapy. METHODS: We analyzed clinical, pathological, and molecular characteristics and long-term outcomes in patients with metastatic GIST treated with continuous daily dosing of frontline imatinib in a cohort of patients benefiting for ≥5 years. A control group was obtained from the national Spanish Group for Sarcoma Research database and used as comparator. RESULTS: Sixty-four imatinib long-term responders (LTRs) and 70 control cases were identified. Compared with controls, LTRs at baseline had better performance status (PS) 0-1 (100% vs. 81%), lower mitotic count (median, 8 vs. 15), and tumor burden (number of metastases, 3 vs. 7). KIT exon 11 was the only region found mutated in LTRs. LTRs achieved 34% complete responses and a median progression-free survival of 11 years, compared with 4% and 2 years, respectively, in the control cohort. Prognostic factors that independently predicted long-term benefit with imatinib were PS, number of metastases prior to imatinib, and response to imatinib. Fifteen LTR patients developed new side effects attributable to imatinib after ≥5 years of continuous treatment. No resistance mutations were found in metastatic samples from three patients progressing on imatinib. CONCLUSION: GISTs in LTRs are a distinctive entity with less aggressive behavior and marked sensitivity to KIT inhibition. Patients reaching 5 or more years on imatinib have a higher chance of remaining progression free over time. IMPLICATIONS FOR PRACTICE: This work demonstrates that clinical and inherent tumor characteristics define a subset of patients with gastrointestinal stromal tumor (GIST) with increased likelihood to achieve durable response to first-line imatinib therapy. Patients reaching ≥5 years on imatinib have a greater chance of remaining progression free over time, although the disease is unlikely to be cured. Imatinib is well tolerated for >5 years, and emergent toxicities are overall manageable. Resistance to imatinib emerging in patients with GISTs after long-term imatinib treatment does not involve polyclonal expansion of KIT secondary mutations.

Lauren subtypes of advanced gastric cancer influence survival and response to chemotherapy: real-world data from the AGAMENON National Cancer Registry.

BACKGROUND: The choice of chemotherapy in HER2-negative gastric cancer is based on centre's preferences and adverse effects profile. No schedule is currently accepted as standard, nor are there any factors to predict response, other than HER2 status. We seek to evaluate whether Lauren type influences the efficacy of various chemotherapies and on patient overall survival (OS). METHODS: We have conducted a multicenter study in 31 hospitals. The eligibility criteria include diagnosis of stomach or gastroesophageal junction adenocarcinoma, HER2 negativity, and chemotherapy containing 2-3 drugs. Cox proportional hazards regression adjusted for confounding factors, with tests of 'treatment-by-histology' interaction, was used to estimate treatment effect. RESULTS: Our registry contains 1303 tumours analysable for OS end points and 730 evaluable for overall response rate (ORR). A decrease in ORR was detected in the presence of a diffuse component: odds ratio 0.719 (95% confidence interval (CI), 0.525-0.987), P=0.039. Anthracycline- or docetaxel-containing schedules increased ORR only in the intestinal type. The diffuse type displayed increased mortality with hazard ratio (HR) of 1.201 (95% CI, 1.054-1.368), P=0.0056. Patients receiving chemotherapy with docetaxel exhibited increased OS limited to the intestinal type: HR 0.65 (95% CI, 0.49-0.87), P=0.024, with no increment in OS for the subset having a diffuse component. With respect to progression-free survival (PFS), a significant interaction was seen in the effect of docetaxel-containing schedules, with better PFS limited to the intestinal type subgroup, in the comparison against any other schedule: HR 0.65 (95% CI, 0.50-0.85), P=0.015, and against anthracycline-based regimens: HR 0.64 (95% CI, 0.46-0.88), P=0.046. CONCLUSIONS: As a conclusion, in this registry, Lauren classification tumour subtypes predicted survival and responded differently to chemotherapy. Future clinical trials should stratify effect estimations based on histology.

Metabolomic Analysis of Gastric Cancer Progression within the Correa's Cascade Using Ultraperformance Liquid Chromatography-Mass Spectrometry.

Gastric cancer (GC) is among the most common cancers worldwide. Gastric carcinogenesis is a multistep and multifactorial process beginning with chronic gastritis induced by Helicobacter pylori (H. pylori) infection. This process is often described via a sequence of events known as Correas's cascade, a stepwise progression from nonactive gastritis, chronic active gastritis, precursor lesions of gastric cancer (atrophy, intestinal metaplasia, and dysplasia), and finally adenocarcinoma. Our aim was to identify a plasma metabolic pattern characteristic of GC through disease progression within the Correa's cascade. This study involved the analysis of plasma samples collected from 143 patients classified in four groups: patients with nonactive gastritis and no H. pylori infection, H. pylori infected patients with chronic active gastritis, infected or noninfected patients with precursor lesions of gastric cancer, and GC. Independent partial least-squares-discriminant binary models of UPLC-ESI(+)-TOFMS metabolic profiles, implemented in a decision-directed acyclic graph, allowed the identification of tryptophan and kynurenine as discriminant metabolites that could be attributed to indoleamine-2,3-dioxygenase upregulation in cancer patients leading to tryptophan depletion and kynurenine metabolites generation. Furthermore, phenylacetylglutamine was also classified as a discriminant metabolite. Our data suggest the use of tryptophan, kynurenine, and phenylacetylglutamine as potential GC biomarkers.

Hybrid NOTES: TEO for transanal total mesorectal excision: intracorporeal resection and anastomosis.

BACKGROUND: Laparoscopic surgery for rectal TME achieves better patient recovery, lower morbidity, and shorter hospital stay than open surgery. However, in laparoscopic rectal surgery, the overall conversion rate is nearly 20%. Transanal TME combined with laparoscopy, known as Hybrid NOTES, is a less invasive procedure that provides adequate solutions to some of the limitations of rectal laparoscopy. Transanal TME via TEO with technical variants (intracorporeal resection and anastomosis, TEO review of the anastomosis) attempts to standardize and simplify the procedure. METHOD: Prospective observational study was used describe and assess the technique in terms of conversion to open surgery, overall morbidity, surgical site infection and hospital stay. The sample comprised consecutive patients diagnosed with rectal tumor less than 10 cm from the anal verge who were candidates for low anterior resection using TME (except T4). Demographic, surgical, postoperative, and pathological variables were analyzed, as well as morbidity rates. RESULTS: From September 2012 to August 2014, 32 patients were included. The conversion rate was 0%. Overall morbidity was 31.3%, SSI rate was 9.4%, and mean hospital stay was 8 days. Oncological radical criteria were achieved with pathological parameters of 94% of complete TME and a median circumferential margin of 13 mm. CONCLUSION: The introduction of technical variants of TEO for transanal resection can facilitate a procedure that requires extensive experience in transanal and laparoscopic surgery. Studies of sphincter function, quality of life, and long-term oncological outcome are now necessary.

Evaluation of efficacy and safety markers in a phase II study of metastatic colorectal cancer treated with aflibercept in the first-line setting.

BACKGROUND: Aflibercept (ziv-aflibercept) is an anti-angiogenic agent recently approved in combination with FOLFIRI for the treatment of metastatic colorectal cancer (mCRC) patients previously treated with oxaliplatin. Despite heterogeneity in response to aflibercept, no biomarkers for efficacy or adverse effects have been identified. Here we present biomarker data from the randomised phase II AFFIRM trial assessing aflibercept in combination with mFOLFOX6 first line in mCRC. METHODS: Ninety-six somatic mutations in key oncogenic drivers of mCRC and 133 common single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) pathway genes were analysed, and 27 plasma markers measured at baseline, during and after treatment. We assessed correlations of these three classes of biomarkers with progression-free survival (PFS) and adverse events (AEs). RESULTS: Somatic mutations identified in KRAS, BRAF, NRAS, PIK3CA and PIK3R1 did not significantly correlate with PFS (multiple testing-adjusted false discovery rate (FDR) or multiple testing-adjusted FDR>0.3). None of the individual SNPs correlated with PFS (multiple testing-adjusted FDR>0.22), but at the gene level variability in VEGFB significantly correlated with PFS (multiple testing-adjusted FDR=0.0423). Although none of the plasma markers measured at baseline significantly correlated with PFS, high levels of circulating IL8 at baseline together with increased levels of IL8 during treatment were significantly associated with reduced PFS (multiple testing-adjusted FDR=0.0478). No association was found between biomarkers and AEs. CONCLUSIONS: This represents the first biomarker study in mCRC treated with aflibercept. High IL8 plasma levels at baseline and subsequent increases in IL8 were associated with worse PFS, suggesting that IL8 may act as a potentially predictive biomarker of aflibercept treatment outcome.

A randomized phase II study of capecitabine-based chemoradiation with or without bevacizumab in resectable locally advanced rectal cancer: clinical and biological features.

BACKGROUND: Perioperatory chemoradiotherapy (CRT) improves local control and survival in patients with locally advanced rectal cancer (LARC). The objective of the current study was to evaluate the addition of bevacizumab (BEV) to preoperative capecitabine (CAP)-based CRT in LARC, and to explore biomarkers for downstaging. METHODS: Patients (pts) were randomized to receive 5 weeks of radiotherapy 45 Gy/25 fractions with concurrent CAP 825 mg/m(2) twice daily 5 days per week and BEV 5 mg/kg once every 2 weeks (3 doses) (arm A), or the same schedule without BEV (arm B). The primary end point was pathologic complete response (ypCR: ypT0N0). RESULTS: Ninety pts were included in arm A (44) or arm B (46). Grade 3-4 treatment-related toxicity rates were 16% and 13%, respectively. All patients but one (arm A) proceeded to surgery. The ypCR rate was 16% in arm A and 11% in arm B (p =0.54). Fifty-nine percent vs 39% of pts achieved T-downstaging (arm A vs arm B; p =0.04). Serial samples for biomarker analyses were obtained for 50 out of 90 randomized pts (arm A/B: 22/28). Plasma angiopoietin-2 (Ang-2) levels decreased in arm A and increased in arm B (p <0.05 at all time points). Decrease in Ang-2 levels from baseline to day 57 was significantly associated with tumor downstaging (p =0.02). CONCLUSIONS: The addition of BEV to CAP-based preoperative CRT has shown to be feasible in LARC. The association between decreasing Ang-2 levels and tumor downstaging should be further validated in customized studies. TRIAL REGISTRY: Clinicaltrials.gov identifier NCT01043484. Trial registration date: 12/30/2009.

Variability in microRNA recovery from plasma: Comparison of five commercial kits.

Numerous studies have indicated that microRNAs (miRNAs) are present and stable in multiple biological fluids, suggesting a great potential as biomarkers for molecular diagnostics and prognostics. Variations in the amount of starting material and isolation method to obtain miRNA may introduce bias and contribute to quantification errors. Given these concerns, we compared five commercially available kits for serum/plasma miRNA isolation to determine whether the plasma miRNA profile varies with the isolation method. We isolated miRNAs in blood plasma from colorectal cancer patients and healthy donors with five commercially available kits: Exiqon, Norgen, Macherey-Nagel, Qiagen, and Zymo Research. First, we assessed the robustness of the RNA isolation process and the quality of isolated miRNAs with the miRCURY microRNA QC PCR Panel (Exiqon), which contains six RNA spike-ins for quality control of RNA isolation (UniSp2, -4, and -5), complementary DNA (cDNA) synthesis (UniSp6 and cel-miR-39-3p), and polymerase chain reaction (PCR) amplification (UniSp3). This panel also includes circulating human miR-103, miR-191, miR-23a, and miR-451. Second, to evaluate the variability in miRNA profiling in relation to the extraction method, we analyzed plasma levels of candidate miRNA biomarkers for colorectal cancer (miR-18a, miR-21, and miR-29a). To determine PCR efficiencies per amplicon and per sample, we used LinRegPCR software. We found that all isolation methods were suitable for extracting miRNA from plasma samples and that all had similar Cq values in the three steps analyzed: RNA isolation, cDNA synthesis, and quantitative reverse transcription (qRT)-PCR. However, although the PCR replicates were excellent, the intersample variability of the spike-ins was unsatisfactorily high and all kits yielded suboptimal PCR efficiencies for some amplicons. Overall, our results underline the great difficulties involved in measuring miRNAs in plasma. The use of spike-ins is critical to control technical factors that affect final miRNA levels. We recommend that researchers investigating circulating miRNAs verify the PCR efficiency for each amplicon because quantification may be influenced by sample and PCR components.

Preoperative chemotherapy in patients with intermediate-risk rectal adenocarcinoma selected by high-resolution magnetic resonance imaging: the GEMCAD 0801 Phase II Multicenter Trial.

BACKGROUND: The need for preoperative chemoradiation or short-course radiation in all T3 rectal tumors is a controversial issue. A multicenter phase II trial was undertaken to evaluate the efficacy and safety of neoadjuvant capecitabine and oxaliplatin combined with bevacizumab in patients with intermediate-risk rectal adenocarcinoma. METHODS: We recruited 46 patients with T3 rectal adenocarcinoma selected by magnetic resonance imaging (MRI) who were candidates for (R0) resection located in the middle third with clear mesorectal fascia and who were selected by pelvic MRI. Patients received four cycles of neoadjuvant capecitabine and oxaliplatin combined with bevacizumab (final cycle without bevacizumab) before total mesorectal excision (TME). In case of progression, preoperative chemoradiation was planned. The primary endpoint was overall response rate (ORR). RESULTS: On an intent-to-treat analysis, the ORR was 78% (n = 36; 95% confidence interval [CI]: 63%-89%) and no progression was detected. Pathologic complete response was observed in nine patients (20%; 95% CI: 9-33), and T downstaging was observed in 48%. Forty-four patients proceeded to TME, and all had R0 resection. During preoperative therapy, two deaths occurred as a result of pulmonary embolism and diarrhea, respectively, and one patient died after surgery as a result of peritonitis secondary to an anastomotic leak (AL). A 13% rate of AL was higher than expected. The 24-month disease-free survival rate was 75% (95% CI: 60%-85%), and the 2-year local relapse rate was 2% (95% CI: 0%-11%). CONCLUSION: In this selected population, initial chemotherapy results in promising activity, but the observed toxicity does not support further investigation of this specific regimen. Nevertheless, these early results warrant further testing of this strategy in an enriched population and in randomized trials.

SEOM-GEMCAD-TTD clinical guidelines for the adjuvant treatment of colon cancer (2023).

Colorectal cancer (CRC) has a 5-year overall survival rate of over 60%. The decrease in the rate of metastatic disease is due to screening programs and the population's awareness of healthy lifestyle. Similarly, advancements in surgical methods and the use of adjuvant chemotherapy have contributed to a decrease in the recurrence of resected disease. Before evaluating a patient's treatment, it is recommended to be discussed in a multidisciplinary tumor board. In stage II tumors, the pathologic characteristics of poor prognosis must be known (T4, number of lymph nodes analyzed less than 12, lymphovascular or perineural invasion, obstruction or perforation, poor histologic grade, presence of tumor budding) and it is mandatory to determine the MSI/MMR status for avoiding administering fluoropyridimidines in monotherapy to patients with MSI-H/dMMR tumors. In stage III tumors, the standard treatment consists of a combination of fluoropyrimidine (oral or intravenous) with oxaliplatin for 6 months although the administration of CAPOX can be considered for 3 months in low-risk tumors. Neoadjuvant treatment is not consolidated yet although immunotherapy is achieving very good preliminary results in MSI-H patients. The use of ctDNA to define the treatment and monitoring of resected tumors is only recommended within studies. These guidelines are intended to help decision-making to offer the best management of patients with non-metastatic colon cancer.

How appropriate is treating patients diagnosed with advanced esophageal cancer with anticancer drugs? A multicenter retrospective cohort Spanish study.

AIM: To assess the appropriateness of systemic oncological treatments (SOT) provided to patients diagnosed with advanced esophageal cancer (EC) across a group of participating hospitals. METHODS: Multicenter, retrospective cohort study in five Spanish hospitals including newly confirmed advanced EC cases between July 1, 2014, and June 30, 2016, with a 5-year follow-up. RESULTS: We identified 157 patients fulfilling the inclusion criteria (median age: 65 years, 85.9% males). Most patients, 125 (79.6%) were treated at least with one active treatment, and 33% received two or more lines of SOT. The 1-, 2- and 5-year overall survival rates were 30.3% [95%CI: 23.8, 38.7], 14.0% [95%CI: 9.3, 21.0], and 7.1% [95% CI: 3.8, 13.1] respectively, and the median survival time 8 months (95% CI: 6, 19) for stages IIIb IIIc and 7 months (95% CI: 5, 9) for stage IV. Clinical stage, receiving more than one line of SOT, and treatment with radiotherapy accelerated the time to death (0.4, 0.9-, and 0.8-times shorter survival respectively, p < 0.05). Better performance status (ECOG < 2) extended survival time by 2.2 times (p = 0.04). Age < 65 years (OR 9.4, 95% CI 3.2, 31.4, p < 0.001), and being treated in one particular hospital (OR 0.2, 95% CI 0.0, 0.8, p < 0.01) were associated with the administration of two or more lines of SOT. Altogether, 18.9% and 9.0% of patients received chemotherapy in the last four and two weeks of life, respectively. Moreover, 2.5% of patients were prescribed a new line of chemotherapy during the last month of life. The proportion of all patients who did not have access to palliative care reached 29.3%, and among those who had access to it, 34.2% initiated it in the last month of life. CONCLUSION: A high proportion of advanced EC patients receive many treatments not based on sound evidence and they do not benefit enough from palliative care services. The most accepted appropriateness indicators point out that some of the analyzed patients could have been overtreated. This study provides important insights into the quality of care provided to advanced EC, and furthermore, for giving valuable insight and opportunities for improvement.

Real-world study on microsatellite instability and mismatch repair deficiency testing patterns among patients with metastatic colorectal cancer in Spain.

PURPOSE: Clinical practice guidelines recommend that all patients with metastatic colorectal cancer (mCRC) should be tested for mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H). We aimed to describe the dMMR/MSI-H testing practice in patients with mCRC in Spanish centers. METHODS: Multicenter, observational retrospective study that included patients newly diagnosed with mCRC or who progressed to a metastatic stage from early/localized stages. RESULTS: Three hundred patients were included in the study from May 2020 through May 2021, with a median age of 68 years, and two hundred twenty-five (75%) had stage IV disease at initial diagnosis; two hundred eighty-four patients received first-line treatment, and dMMR/MSI-H testing was performed in two hundred fifty-one (84%) patients. The results of the dMMR/MSI-H tests were available in 61 (24%) of 251 patients before the diagnosis of metastatic disease and in 191 (81%) of 236 evaluable patients for this outcome before the initiation of first-line treatment. Among the 244 patients who were tested for dMMR/MSI-H with IHC or PCR, 14 (6%) were MMR deficient. The most frequent type of first-line treatment was the combination of chemotherapy and biological agent, that was received by 71% and 50% of patients with MMR proficient and deficient tumors, respectively, followed by chemotherapy alone, received in over 20% of patients in each subgroup. Only 29% of dMMR/MSI-H tumors received first-line immunotherapy. CONCLUSION: Our study suggests that a high proportion of patients with mCRC are currently tested for dMMR/MSI-H in tertiary hospitals across Spain. However, there is still room for improvement until universal testing is achieved. TRIAL REGISTRATION: Not applicable.

Nab-Paclitaxel plus Gemcitabine and FOLFOX in Metastatic Pancreatic Cancer.

BACKGROUND: Sequential nab-paclitaxel plus gemcitabine followed by modified FOLFOX-6 (oxaliplatin, leucovorin, and 5-fluorouracil) (nab-P/Gem-mFOLFOX) showed a good safety and clinical profile in metastatic pancreatic ductal adenocarcinoma (mPDAC) in the phase I SEQUENCE trial. METHODS: The safety and efficacy of sequential nab-P/Gem-mFOLFOX was compared with standard nab-paclitaxel plus gemcitabine (nab-P/Gem) as first-line treatment in a multi-institutional, randomized, open-label, phase II trial in patients with untreated mPDAC. We randomly assigned patients in a 1:1 ratio to receive nab-P/Gem on days 1, 8, and 15 followed by mFOLFOX on day 29 of a 6-week cycle (experimental group) or nab-P/Gem on days 1, 8, and 15 of a 4-week cycle (control group). The primary end point was the 12-month overall survival rate. RESULTS: A total of 157 patients were randomly assigned: 78 to nab-P/Gem-mFOLFOX and 79 to nab-P/Gem. Patients receiving nab-P/Gem-mFOLFOX had a 12-month overall survival of 55.3% (95% confidence interval [CI], 44.2 to 66.5) versus 35.4% (95% CI, 24.9 to 46) in the control group (P=0.02). Similarly, the 24-month survival was 22.4% (95% CI, 13 to 31.8) with nab-P/Gem-mFOLFOX versus 7.6% (95% CI, 1.8 to 13.4) with control treatment. The median overall survival was 13.2 months (95% CI, 10.1 to 16.2) with nab-P/Gem-mFOLFOX and 9.7 months (95% CI, 7.5 to 12) with nab-P/Gem (hazard ratio for death, 0.68; 95% CI, 0.48 to 0.95). The safety profile showed a higher incidence of grade 3 or higher neutropenia (35 of 76 vs. 19 of 79 patients, P=0.004), grade 3 or higher thrombocytopenia (18 of 78 vs. 6 of 79 patients, P=0.007), and two treatment-related deaths (2.6%) with nab-P/Gem-mFOLFOX compared with none with control treatment. CONCLUSIONS: Sequential nab-P/Gem-mFOLFOX showed a significantly higher 12-month survival when compared with the standard nab-P/Gem treatment; this came with greater treatment toxicity. (Funded by Celgene; EuCT number, 2014-005350-19; ClinicalTrials.gov number, NCT02504333.)