Neoadjuvant Chemotherapy for Intrahepatic, Perihilar, and Distal Cholangiocarcinoma:a National Population-Based Comparative Cohort Study

IntroductionData supporting the utilization of neoadjuvant chemotherapy (NAC) in patients receiving resection for cholangiocarcinoma (CCA) remains uncertain. We aimed to determine whether NAC followed by resection improves long-term survival in intrahepatic (iCCA), perihilar (hCCA), and distal (dCCA) cholangiocarcinoma, analyzed separately.MethodsPatients undergoing surgery for iCCA, hCCA, and dCCA, receiving either none, NAC, or adjuvant chemotherapy (AC) from 2010 to 2016 were identified from the National Cancer Database (NCDB). Cox regression was performed to account for selection bias and to assess the impact of surgery alone (SA) versus either NAC or AC on overall survival (OS).ResultsThere were 9411 patients undergoing surgery for iCCA (n = 3772, 39.5%), hCCA (n = 1879, 20%), and dCCA (n = 3760, 40%). Of these, 10.6% (n = 399), 6.5% (n = 123), and 7.2% (n = 271) with iCCA, hCCA, and dCCA received NAC, respectively. On adjusted analyses, patients receiving NAC followed by surgery had significantly improved OS, compared to SA for iCCA (HR 0.75, CI95% 0.64-0.88, p < 0.001), hCCA (HR 0.72, CI95% 0.54-0.97, p = 0.033), and for dCCA (HR 0.65, CI95% 0.53-0.78, p < 0.001). However, sensitivity analyses demonstrated no differences in OS between NACs, followed by surgery or AC after surgery in iCCA (HR 1.19, CI95% 0.99-1.45, p = 0.068), hCCA (HR 0.83 CI95% 0.59-1.19, p = 0.311), and dCCA (HR 1.13 CI95% 0.91-1.41, p = 0.264).ConclusionsThis study associated NAC with increased OS for all CCA subtypes, even in patients with margin-negative and node-negative disease; however, no differences were found between NAC and AC. Our results highlight that a careful and interdisciplinary evaluation should be sought to consider NAC in CCA and warrant the need of larger studies to provide robust recommendation

Discovery of SMAD4 promoters, transcription factor binding sites and deletions in juvenile polyposis patients

Inactivation of SMAD4 has been linked to several cancers and germline mutations cause juvenile polyposis (JP). We set out to identify the promoter(s) of SMAD4, evaluate their activity in cell lines and define possible transcription factor binding sites (TFBS). 5′-rapid amplification of cDNA ends (5′-RACE) and computational analyses were used to identify candidate promoters and corresponding TFBS and the activity of each was assessed by luciferase vectors in different cell lines. TFBS were disrupted by site-directed mutagenesis (SDM) to evaluate the effect on promoter activity. Four promoters were identified, two of which had significant activity in several cell lines, while two others had minimal activity. In silico analysis revealed multiple potentially important TFBS for each promoter. One promoter was deleted in the germline of two JP patients and SDM of several sites led to significant reduction in promoter activity. No mutations were found by sequencing this promoter in 65 JP probands. The predicted TFBS profiles for each of the four promoters shared few transcription factors in common, but were conserved across several species. The elucidation of these promoters and identification of TFBS has important implications for future studies in sporadic tumors from multiple sites, and in JP patients

Adjuvant radiotherapy improves long-term survival after resection for gallbladder cancer A population-based cohort study.

BACKGROUND Data supporting routine use of adjuvant radiotherapy (RT) compared to without RT (noRT) for gallbladder cancer (GBC) is unclear. This study aimed to determine whether RT improves long-term survival following resection for GBC. METHODS Patients receiving resection for GBC followed by RT from 2004 to 2016 were identified from the National Cancer Database (NCDB). Patients with survival <6 months were excluded to account for immortal time bias. Propensity score matching (PSM) and Cox regression was performed to account for selection bias and analyze impact of RT on overall survival. RESULTS Of 7514 (77%) noRT and 2261 (23%) RT, 2067 noRT and 2067 RT patients remained after PSM. After matching, RT was associated with improved survival (median: 26.2 vs 21.5 months, p < 0.001), which remained after multivariable adjustment (HR: 0.82, CI: 0.76-0.89, p < 0.001). On multivariable interaction analyses, this benefit persisted irrespective of nodal status: N0 (HR: 0.84, CI: 0.77-0.93), N1 (HR: 0.77, CI: 0.68-0.88), N2/N3 (HR: 0.56, CI: 0.35-0.91), margin status: R0 (HR: 0.85, CI: 0.78-0.93), R1 (HR: 0.78, CI: 0.68-0.88) and use of adjuvant chemotherapy (AC) (HR: 0.67, CI: 0.57-0.79). Benefit with RT were also seen in patients with T2 - T4 disease and in patients undergoing simple and extended cholecystectomy. CONCLUSION RT following resection was associated with improved survival in this study, even in margin-negative and node-negative disease. These findings may suggest addition of RT into multimodality therapy for GBC

Cost-effectiveness of Maintenance Capecitabine and Bevacizumab for Metastatic Colorectal Cancer

Key Points Question For metastatic colorectal cancer, what is the incremental cost-effectiveness of adding capecitabine and bevacizumab maintenance treatment after standard induction chemotherapy? Findings This economic evaluation study finds that compared with observation, capecitabine and bevacizumab maintenance therapy adds average per-patient benefits of 0.14 quality-adjusted life-years (QALYs), with incremental costs of $105 217 and an incremental cost-effectiveness ratio of$725 601 per QALY. To reduce the cost to $59 039 per unadjusted life-year (median household income) total drug costs must be reduced from$6173 to $452 per 3-week chemotherapy cycle. Meaning High US drug prices represent the best target for improving the cost-effectiveness of capecitabine and bevacizumab maintenance therapy for metastatic colorectal cancer, which is not currently cost-effective. Go to: Abstract Importance Unregulated drug prices increase cancer therapy costs. After induction chemotherapy, patients with metastatic colon cancer can receive maintenance capecitabine and bevacizumab therapy based on improved progression-free survival, but whether this treatment’s cost justifies its benefits has not been evaluated in the United States. Objective This study sought to determine the influence of capecitabine and bevacizumab drug prices on cost-effectiveness from a Medicare payer’s perspective. Design, Setting, and Participants The incremental cost-effectiveness of capecitabine and bevacizumab maintenance therapy was determined with a Markov model using a quality-of-life penalty based on outcomes data from the CAIRO phase 3 randomized clinical trial (RCT), which included 558 adults in the Netherlands with unresectable metastatic colorectal cancer who had stable disease or better following induction chemotherapy. The outcomes were modeled using Markov chains to account for patients who had treatment complications or cancer progression. Transition probabilities between patient states were determined, and each state’s costs were determined using US Medicare data on payments for capecitabine and bevacizumab treatment. Deterministic and probabilistic sensitivity analyses identified factors affecting cost-effectiveness. Main Outcomes and Measures Life-years gained were adjusted using CAIRO3 RCT quality-of-life data to determine quality-adjusted life-years (QALYs). The primary end point was the incremental cost-effectiveness ratio, representing incremental costs per QALY gained using a capecitabine and bevacizumab maintenance regimen compared with observation alone. Results Markov model estimated survival and complication outcomes closely matched those reported in the CAIRO3 RCT, which included 558 adults (n = 197 women, n = 361 men; median age, 64 and 63 years for patients in the observation and maintenance therapy groups, respectively) in the Netherlands with unresectable metastatic colorectal cancer who had stable disease or better following induction chemotherapy. Incremental costs for a 3-week maintenance chemotherapy cycle were$6601 per patient. After 29 model iterations corresponding to 60 months of follow-up, mean per-patient costs were $105 239 for maintenance therapy and$21.10 for observation. Mean QALYs accrued were 1.34 for maintenance therapy and 1.20 for observation. The incremental cost-effectiveness ratio favored maintenance treatment, at an incremental cost of $725 601 per QALY. The unadjusted ratio was$438 394 per life-year. Sensitivity analyses revealed that cost-effectiveness varied with changes in drug costs. To achieve an incremental cost-effectiveness ratio of less than $59 039 (median US household income) per unadjusted life-year would require capecitabine and bevacizumab drug costs to be reduced from$6173 (current cost) to $452 per 3-week chemotherapy cycle. Conclusions and Relevance Antineoplastic therapy is expensive for payers and society. The price of capecitabine and bevacizumab maintenance therapy would need to be reduced by 93% to make it cost-effective, a finding useful for policy decision making and payment negotiations

Survival benefit of adjuvant chemotherapy following neoadjuvant therapy and oesophagectomy in oesophageal adenocarcinoma.

BACKGROUND The evidence assessing the additional benefits of adjuvant chemotherapy (AC) following neoadjuvant therapy (NAT; i.e. chemotherapy or chemoradiotherapy) and oesophagectomy for oesophageal adenocarcinoma (EAC) are limited. This study aimed to determine whether AC improves long-term survival in patients receiving NAT and oesophagectomy. METHODS Patients receiving oesophagectomy for EAC following NAT from 2004 to 2016 were identified from the National Cancer Data Base (NCDB). To account for immortality bias, patients with survival ≤3 months were excluded to account for immortality bias. Propensity score matching (PSM) and Cox regression was performed to account for selection bias and analyze impact of AC on overall survival. RESULTS Overall, 12,972 (91%) did not receive AC and 1,255 (9%) received AC. After PSM there were 2,485 who did not receive AC and 1,254 who did. After matching, AC was associated with improved survival (median: 38.5 vs 32.3 months, p < 0.001), which remained after multivariable adjustment (HR: 0.78, CI: 0.71-0.87). On multivariable interaction analyses, this benefit persisted in subgroup analysis for nodal status: N0 (HR: 0.85, CI: 0.69-0.96), N1 (HR: 0.66, CI: 0.56-0.78), N2/3 (HR: 0.80, CI: 0.66-0.97) and margin status: R0 (HR: 0.77, CI: 0.69-0.86), R1 (HR: 0.60, CI: 0.43-0.85). Further, patients with stable disease following NAT (HR: 0.60, CI: 0.59-0.80) or downstaged (HR: 0.80, CI: 0.68-0.95) disease had significant survival benefit after AC, but not patients with upstaged disease. CONCLUSION AC following NAT and oesophagectomy is associated with improved survival, even in node-negative and margin-negative disease. NAT response may be crucial in identifying patients who will benefit maximally from AC, and thus future research should be focused on identifying molecular phenotype of tumours that respond to chemotherapy to improve outcomes

Adjuvant chemotherapy for perihilar cholangiocarcinoma: A population-based comparative cohort study.

BACKGROUND Data supporting routine use of adjuvant chemotherapy (AC) compared to no AC (noAC) for perihilar cholangiocarcinoma (hCCA) is unclear. This study aimed to determine whether AC improves long-term survival following resection for hCCA. METHODS Patients receiving resection for hCCA followed by AC or no AC from 2010 to 2016 were identified from the National Cancer Database (NCDB). Propensity score matching (PSM) and Cox regression was performed to account for selection bias and analyze impact of AC on overall survival. RESULTS Of 924 (56%) noAC and 719 (44%) AC, 320 noAC and 320 AC patients remained after PSM. After matching, AC was associated with improved survival (median: 28.2 vs 19.9 months, p < 0.001), which remained after multivariable adjustment (HR: 0.61, CI: 0.50-0.75, p < 0.001). On multivariable interaction analyses, the benefit of AC over no AC persisted irrespective of nodal status: N0 (HR: 0.62, CI: 0.41-0.92, p = 0.019), N1 (HR: 0.52, CI: 0.36-0.75, p = 0.001), N2 (HR: 0.31, CI: 0.11-0.90, p = 0.032), Nx (HR: 0.22, CI: 0.09-0.55, p = 0.001) and margin status: R0 (HR: 0.74, CI: 0.57-0.97, p = 0.026), R1 (HR: 0.31, CI: 0.21-0.47, p < 0.001). Stratified analysis by nodal, margin and AC status demonstrated consistent results. CONCLUSION AC following resection for hCCA was associated with improved survival in this study, even in margin-negative and node-negative disease. These findings suggest incorporation of AC into multimodality therapy for hCCA in all cases, where appropriate