Date Published: February 28, 2019
Publisher: Public Library of Science
Author(s): Alison Bradley, Robert Van Der Meer, Sunil Krishnan.
Neoadjuvant therapy has emerged as an alternative treatment strategy for potentially resectable pancreatic cancer. In the absence of large randomized controlled trials offering a direct comparison, this study aims to use Markov decision analysis to compare efficacy of traditional surgery first (SF) and neoadjuvant treatment (NAT) pathways for potentially resectable pancreatic cancer.
An advanced Markov decision analysis model was constructed to compare SF and NAT pathways for potentially resectable pancreatic cancer. Transition probabilities were calculated from randomized control and Phase II/III trials after comprehensive literature search. Utility outcomes were measured in overall and quality-adjusted life months (QALMs) on an intention-to-treat basis as the primary outcome. Markov cohort analysis of treatment received was the secondary outcome. Model uncertainties were tested with one and two-way deterministic and probabilistic Monte Carlo sensitivity analysis.
SF gave 23.72 months (18.51 QALMs) versus 20.22 months (16.26 QALMs). Markov Cohort Analysis showed that where all treatment modalities were received NAT gave 35.05 months (29.87 QALMs) versus 30.96 months (24.86QALMs) for R0 resection and 34.08 months (29.87 QALMs) versus 25.85 months (20.72 QALMs) for R1 resection. One-way deterministic sensitivity analysis showed that NAT was superior if the resection rate was greater than 51.04% or below 75.68% in SF pathway. Two-way sensitivity analysis showed that pathway superiority depended on obtaining multimodal treatment in either pathway.
Whilst NAT is a viable alternative to traditional SF approach, superior pathway selection depends on the individual patient’s likelihood of receiving multimodal treatment in either pathway.
Outcomes for pancreatic cancer remain poor despite advances in surgical technique and adjuvant treatment [1,2]. Early complete surgical resection is the only potentially curative treatment, with surgery followed by adjuvant therapy becoming the standard of care for resectable pancreatic cancer . Up to 50% of patients fail to receive adjuvant therapy due to: post-operative complications, early metastases nullifying the potential benefits of high-risk surgery, and reduced performance status [4,5]. Neoadjuvant therapy (NAT) has emerged as an alternative to traditional surgery-first (SF) approach. Postulated benefits include: avoiding futile surgery by identifying aggressive tumour types, eliminating micrometastesis, multimodal treatment completion and increased R0 resection rates [6,7].
50 phase II/III studies met the inclusion criteria and were included in the NAT arm of the model, 4 of which were randomized. 9 of these studies offered comparison with upfront surgery. For the SF pathway 15 studies were RCTs, 10 of which offered comparison between adjuvant regimes, 5 of which offered comparison between adjuvant therapy and surgery only. 16 cohort studies were also included in the SF pathway to offer comparison across outcomes of resection rates, R0 resection, and rates of receiving adjuvant therapy (Table 1). Probability estimates and ranges and quality of life utilities are displayed in Table 2.
The role of NAT in treatment of pancreatic cancer is an ongoing area of debate . Markov decision analysis is a powerful tool offering analysis of complex medical decisions therefore this study provides important interim analysis and contributes to only three existing studies that utilize evidence-based Markov decision-analysis to compare NAT and SF pathways [9,13,14]. Our analysis showed that SF pathway gave an additional 3.5 months (2.25 QALMs) but neither pathway was conclusively superior. Markov cohort analysis of outcomes where multimodal treatment was received in both pathways (resection in NAT and adjuvant therapy in SF) demonstrated superior outcomes with NAT pathway. One-way sensitivity analysis showed that NAT was superior on in intention-to-treat basis if the probability of resection in the NAT pathway was above 51.04%. Base-case probability of resection in NAT pathway was 41%. This could represent NAT pathway allowing time to filter out more aggressive tumours, hence avoiding futile, expensive and high-risk surgery [6,7]. Conversely critics of NAT would argue that this indicates loosing the window of resectability [6,7]. Critics of NAT have also raised concerns that it could increase post-operative complications, a claim not substantiated in our analysis, which is also corroborated by previous studies [9,14].
In the absence of large multicenter RCTs, this study utilizes best currently available evidence in a Markov decision analysis model to provide an important interim source of information [13,14] to inform the ongoing debate regarding best treatment for potentially resectable pancreatic cancer. On an intention-to-treat basis conclusive superiority of either pathway could not be concluded. However, Markov cohort analysis demonstrated superiority of NAT pathway if multimodal treatment was received. This highlights three important future directions for research: 1) cost-effectiveness analysis of NAT versus SF pathways 2) assessment of treatment pathways of resectable only cases hence offering a true like-for-like comparison and 3) developing methods of personalized predictive statistical modeling to provide individualized predictions of outcomes across competing treatment pathways to support shared clinical decision-making.