Combined robotic approach and enhanced recovery after surgery pathway for optimization of costs in patients undergoing proctectomy.

BACKGROUND: Enhanced recovery after surgery (ERAS) pathways are beneficial in proctocolectomy, but their impact on robotic low rectal proctectomy is not fully investigated. This study assessed the impact of an ERAS pathway on the outcomes and cost of robotic (RTME) versus laparoscopic (LTME) total mesorectal excision. METHODS: A retrospective review was performed of patients with rectal cancer in a single French tertiary centre for three yearly periods: 2011, LTME; 2015, RTME; and 2018, RTME with ERAS. Patient characteristics, operative and postoperative data, and costs were compared among the groups. RESULTS: A total of 220 consecutive proctectomies were analysed (71 LTME, 58 RTME and 91 RTME with ERAS). A prevalence of lower and locally advanced tumours was observed with RTME. The median duration of surgery increased with the introduction of RTME, but became shorter than that for LTME with greater robotic experience (226, 233 and 180 min for 2011, 2015 and 2018 respectively; P < 0·001). The median duration of hospital stay decreased significantly for RTME with ERAS (11, 10 and 8 days respectively; P = 0·011), as did the overall morbidity rate (39, 38 and 16 per cent; P = 0·002). Pathology results, conversion and defunctioning stoma rates remained stable. RTME alone increased the total cost by €2348 compared with LTME. The introduction of ERAS and improved robotic experience decreased costs by €1960, compared with RTME performed in 2015 without ERAS implementation. In patients with no co-morbidity, costs decreased by €596 for RTME with ERAS versus LTME alone. CONCLUSION: ERAS is associated with cost reductions in patients undergoing robotic proctectomy.

ANTECEDENTES: Las vías clínicas ERAS son beneficiosas en la proctocolectomía, pero su impacto en la proctectomía rectal baja robótica no se ha investigado exhaustivamente. El objetivo de este estudio fue evaluar el impacto de la vía clínica ERAS sobre los resultados y el coste de la proctectomía robótica (resección total del mesorrecto robótica, robotic total mesorectal excision, RTME) versus procedimientos laparoscópicos de resección total del mesorrecto (laparoscopic total mesorectal excision, LTME). MÉTODOS: Revisión retrospectiva de pacientes con cáncer de recto tratados en un único centro terciario francés durante un periodo de tres años: 1) 2011: resección total del mesorrecto laparoscópica (LTME); 2) 2015: TME robótica y 3) 2018: TME robótica plus ERAS. Se compararon las características de los pacientes, los datos operatorios y postoperatorios, y los costes entre subgrupos utilizando análisis estadísticos. RESULTADOS: Se analizaron 220 proctectomías consecutivas que incluían 71 LTME, 58 RTME y 91 RTME plus ERAS. Se observó un predominio de tumores inferiores y localmente avanzados en la RTME. La mediana del tiempo operatorio aumentó con la introducción de RTME, pero llegó a ser inferior que en la LTME con una mayor experiencia robótica (226, 233 y 180 minutos para los periodos 1, 2 y 3, respectivamente; P = 0,0001). La mediana de la estancia hospitalaria disminuyó significativamente con la RTME plus ERAS (11, 10 y 8 días; P = 0,01), así como la morbilidad global (40%, 38% y 16%; P = 0,002). Los resultados de la anatomía patológica, las tasas de conversión y de estomas de protección permanecieron estables. La RTME sola aumentó el coste total en €2.348 comparado con la LTME. La introducción de ERAS y una mejora en la experiencia robótica disminuyeron los costes en €1.960 versus RTME realizada en 2015 sin la implementación de ERAS. En pacientes sin comorbilidades, los costes disminuyeron en €1.196 con RTME plus ERAS versus LTME sola. CONCLUSIÓN: ERAS se asocia con reducciones de coste en la proctectomía robótica.

Late toxicities and clinical outcome at 5 years of the ACCORD 12/0405-PRODIGE 02 trial comparing two neoadjuvant chemoradiotherapy regimens for intermediate-risk rectal cancer.

BACKGROUND: Outcome of intermediate risk rectal cancer may be improved by the addition of oxaliplatin during 5-fluoruracil concomitant neoadjuvant chemoradiotherapy. The purpose of this study is to analyze the main clinical results of the ACCORD12 trial (NCT00227747) in rectal cancer after 5 years of follow-up. PATIENTS AND METHODS: Inclusion criteria were as follows: rectal adenocarcinoma accessible to digital examination staged T3-T4 Nx M0 (or T2 Nx distal anterior rectum). Two neoadjuvant chemoradiotherapy regimens were randomized: CAP45 (RT 45 Gy + capecitabine) and CAPOX50 (RT 50 Gy + capecitabine and oxaliplatin). Main end point was sterilization of the operative specimen. Acute and late toxicities were prospectively analyzed with dedicated questionnaires. RESULTS: Between November 2005 and July 2008, 598 patients were included in the trial. After a median follow-up of 60.2 months, there was no difference between treatment arms in multivariate analysis either for disease-free survival or overall survival (OS) [P = 0.9, hazard ratio (HR)=1.02; 95% confidence interval (CI), 0.76-1.36 and P = 0.3, HR = 0.87; 95% CI, 0.66-1.15, respectively]. There was also no difference of local control in univariate analysis (P = 0.7, HR = 0.92; 95% CI, 0.51-1.66). Late toxicities were acceptable with 1.6% G3 anal incontinence, and <1% G3 diarrhea, G3 rectal bleeding, G3 stenosis, G3-4 pain, G3 urinary incontinence, G3 urinary retention and G3 skeletal toxicity. There was a slight increase of erectile dysfunction over time with a 63% rate of erectile dysfunction at 5 years. There was no significant statistical difference for these toxicities between treatment arms. CONCLUSIONS: The CAPOX50 regimen did not improve local control, disease-free survival and overall survival in the ACCORD12 trial. Late toxicities did not differ between treatment arms.

FOXO3a and the MAPK p38 are activated by cetuximab to induce cell death and inhibit cell proliferation and their expression predicts cetuximab efficacy in colorectal cancer.

BACKGROUND: Cetuximab, a monoclonal antibody against EGFR used for the treatment of colorectal cancer (CRC), is ineffective in many patients. The aim of this study was to identify the signalling pathways activated by cetuximab in CRC cells and define new biomarker of response. METHODS: We used in vitro, in vivo models and clinical CRC samples to assess the role of p38 and FOXO3a in cetuximab mechanism of action. RESULTS: We show that cetuximab activates the MAPK p38. Specifically, p38 inhibition reduced cetuximab efficacy on cell growth and cell death. At the molecular level, cetuximab activates the transcription factor FOXO3a and promotes its nuclear translocation via p38-mediated phosphorylation, leading to the upregulation of its target genes p27 and BIM and the subsequent induction of apoptosis and inhibition of cell proliferation. Finally, we found that high FOXO3a and p38 expression levels are associated with better response rate and improved outcome in cetuximab-treated patients with CRC harbouring WT KRAS. CONCLUSIONS: We identify FOXO3a as a key mediator of cetuximab mechanism of action in CRC cells and define p38 as its activator in this context. Moreover, high FOXO3a and p38 expression could predict the response to cetuximab in patients with CRC harbouring WT KRAS.

Preclinical validation of AXL receptor as a target for antibody-based pancreatic cancer immunotherapy.

AXL receptor tyrosine kinase (RTK) is implicated in proliferation and invasion of many cancers, particularly in pancreatic ductal adenocarcinoma (PDAC), for which new therapeutic options are urgently required. We investigated whether inhibition of AXL activity by specific monoclonal antibodies (mAbs) is efficient in limiting proliferation and migration of pancreatic cancer cells. Expression of AXL was evaluated by immunohistochemistry in 42 PDAC. The AXL role in oncogenesis was studied using the short hairpin RNA approach in a pancreatic carcinoma cell line. We further generated antihuman AXL mAbs and evaluated their inhibitory effects and the AXL downstream signaling pathways first in vitro, in a panel of pancreatic cancer cell lines and then in vivo, using subcutaneous or orthotopic pancreatic tumor xenografts. AXL receptor was found expressed in 76% (32/42) of PDAC and was predominantly present in invasive cells. The AXL-knockdown Panc-1 cells decreased in vitro cell migration, survival and proliferation, and reduced in vivo tumor growth. Two selected anti-AXL mAbs (D9 and E8), which inhibited phosphorylation of AXL and of its downstream target AKT without affecting growth arrest-specific factor 6 (GAS6) binding, induced downexpression of AXL by internalization, leading to an inhibition of proliferation and migration in the four pancreatic cancer cell lines studied. In vivo, treatment by anti-AXL mAbs significantly reduced growth of both subcutaneous and orthotopic pancreatic tumor xenografts independently of their KRAS mutation status. Our in vitro and preclinical in vivo data demonstrate that anti-human AXL mAbs could represent a new approach to the pancreatic cancer immunotherapy.