Systematic review and meta-analysis of cost-effectiveness of minimally invasive versus open pancreatic resections

Background The systematic review is aimed to evaluate the cost-effectiveness of minimally invasive surgery (MIS) and open distal pancreatectomy and pancreaticoduodenectomy. Method The MEDLINE, CENTRAL, EMBASE, Centre for Reviews and Dissemination, and clinical trial registries were systematically searched using the PRISMA framework. Studies of adults aged ≥ 18 year comparing laparoscopic and/or robotic versus open DP and/or PD that reported cost of operation or index admission, and cost-effectiveness outcomes were included. The risk of bias of non-randomised studies was assessed using the Newcastle–Ottawa Scale, while the Cochrane Risk of Bias 2 (RoB2) tool was used for randomised studies. Standardised mean differences (SMDs) with 95% confidence intervals (CI) were calculated for continuous variables. Results Twenty-two studies (152,651 patients) were included in the systematic review and 15 studies in the meta-analysis (3 RCTs; 3 case-controlled; 9 retrospective studies). Of these, 1845 patients underwent MIS (1686 laparoscopic and 159 robotic) and 150,806 patients open surgery. The cost of surgical procedure (SMD 0.89; 95% CI 0.35 to 1.43; I2 = 91%; P = 0.001), equipment (SMD 3.73; 95% CI 1.55 to 5.91; I2 = 98%; P = 0.0008), and operating room occupation (SMD 1.17, 95% CI 0.11 to 2.24; I2 = 95%; P = 0.03) was higher with MIS. However, overall index hospitalisation costs trended lower with MIS (SMD − 0.13; 95% CI − 0.35 to 0.06; I2 = 80%; P = 0.17). There was significant heterogeneity among the studies. Conclusion Minimally invasive major pancreatic surgery entailed higher intraoperative but similar overall index hospitalisation costs. Supplementary Information The online version contains supplementary material available at 10.1007/s00423-023-03017-w.


Introduction
Surgical resection for pancreatic cancer by means of pancreaticoduodenectomy (PD) and distal pancreatectomy (DP) remains the primary modality of treatment.Traditional resection by open surgery is associated with high perioperative morbidity despite improvements in perioperative care and operative techniques [1,2].Minimally invasive approaches (MIS), including robotic and laparoscopic PD and DP, are being increasingly used in pancreatic surgery and are increasingly offered with a hypothesis that it may be associated with lower morbidity, less blood loss, improved surgical margins, and decreased length of hospital stay [3,4].The efficacy of both the approaches of MIS (robotic and laparoscopic) for major pancreatic resections is considered similar, and its role in DP is well established [4][5][6].
The learning curve of MIS for major pancreatoduodenectomies is considered long and remains a major barrier for

Inclusion and exclusion criteria
Studies of adults aged ≥ 18 year comparing laparoscopic and/or robotic versus open DP and/or PD that reported cost of operation or index admission and cost-effectiveness outcomes were included.Studies that included subjects aged < 18 years, or other major simultaneous surgeries in addition to DP or PD other than splenectomy, without separate reporting were excluded.Unpublished data, non-peerreviewed reports, and abstracts were also excluded.

Data extraction
Two authors independently screened titles and abstracts for full-text inclusion.Article full-texts were also reviewed by two authors independently with conflicts resolved by discussion.Data was extracted onto a prespecified template.Extracted outcomes included costs (cost of surgical procedure, defined as intraoperative costs; surgical instrument costs, operating room occupation costs, index hospitalisation costs, and cost-effectiveness).Quality-adjusted life year (QALY) is a measure of disease burden that incorporates quality and quantity of life.
There are different types of health economic evaluations, including cost-minimisation analysis (CMA), cost-effectiveness analysis (CEA), and cost-benefit analysis.CMA determines an intervention that is least expensive.CEA, including cost-utility analysis (CUA) and cost-consequence analysis, compares interventions that have common outcomes.CUA uses QALY to evaluate the benefit of quality of life and survival time gained against the cost [14].Incremental costeffectiveness ratio (ICER) is the difference in total costs (incremental costs) divided by an outcome measure (incremental effect) which provides the extra cost per unit outcome.CMA and ICER were extracted from studies, where reported.Subgroup analysis was performed where combined cost data were reported for laparoscopic and robotic subgroup ('Lap + Rob'), laparoscopy only ('Lap-only'), and robotic only ('Rob-only') groups.

Risk of bias
The risk of bias of non-randomised studies was assessed using the Newcastle-Ottawa Scale [15], while the Cochrane Risk of Bias 2 (RoB2) tool was used for randomised studies [16] (Figure S2; Table S1).

Cost data
Cost data was converted to 2020 US dollars (USD) using a web-based tool (CCEMG-EPPI centre cost converter) [17] when the currency and price-year were different and were available.The costs were converted into the current-year cost of the country using the Gross Domestic Product Deflator Index, followed by conversion into USD for the year 2020.The purchasing power parity for the gross domestic product was used for the conversion rates.The latest reported date of the price year or date of last patient recruitment for surgery was used where price year was not stated.The amortised cost of robotic surgery was not included in meta-analysis.Willingness-to-pay threshold was calculated for ₤20,000 and ₤30,000, as per UK NICE guidelines, adjusted at 2020 price-year.Index hospitalisation cost was considered as the overall payment made towards the index hospital admission.

Statistical analysis
Review Manager 5.3 [18] (The Nordic Cochrane Centre, Copenhagen, Denmark) was used to perform meta-analyses of cost data.Standardised mean differences (SMDs) with 95% confidence intervals (CI) were calculated for continuous variables.The I 2 statistic was graded as low, moderate, and high heterogeneity when scores were < 30, 30-50, and ≥ 50% respectively [19].Medians were converted to mean estimates as per Higgins et al. [20].In cost-meta-analyses, where laparoscopic and robotic groups were reported Page 3 of 13 306 in separate arms, they were combined into a Lap + Rob group, which was reported as a subgroup analysis as per Higgins et al. [19].Funnel plots were visually assessed for publication bias (Figure S3).

Clinical characteristics
Patient age, gender, tumour characteristics, rates of previous abdominal surgery, and American Society of Anaesthesiologists (ASA) classification > 3 were comparable between MIS and open groups (Table 2).

Cost-effectiveness
Ricci et al. conducted cost-utility analysis in addition to CMA using EQ-5D derived QALY as a measure of effectiveness [37].They showed a mean difference in QALY was 0.2 ± 0.08 (P = 0.005), and total index hospitalisation cost was €1379 ± 919; P < 0.001), suggesting the greater cost of laparoscopic surgery was balanced by the improved benefit in QOL [37].The probability for laparoscopy being more cost-effective than open was higher at a willingness to pay above €5400 per QALY.The ICER was €5622 (₤5808 for 2020 price-year) per QALY gained.Van Hilst et al. were excluded from cost-effectiveness analysis as the mean cost difference was derived from total cost including time after discharge [23].

Laparoscopic versus robotic techniques
Rodriquez et al. reports higher costs associated with robotic surgery for cost of surgery, OR occupation, surgical instruments, but not overall index hospitalisation [8].Two studies also showed higher costs of OR occupation for MIS (robotic > laparoscopic > open), with laparoscopic surgery costing $338 more per patient [8,10].This was similar amongst non-meta-analysed studies that report greater instrument costs for MIS (robotic > laparoscopic [8]) compared to open by between 65 and 93% and greater costs per person [10,36,42] (Table S2).

Risk of bias
Observational studies overall had a low risk of bias, as most scored between 6 and 8 on the Newcastle-Ottawa quality assessment scale (Table 1).The included RCTs were overall associated with a high risk of bias largely due to outcome reporting [21][22][23].A summary of the risk of bias assessment can be found in Table S1 and Figure S2.Index hospitalisation was best reported in the lap subgroup and had enough studies to assess publication bias; see Figure S3.

Discussion
This systematic review and meta-analysis evaluated the available evidence on the costs and cost-effectiveness of MIS and open major pancreatic surgery.Cost of surgical procedure, cost of surgical instruments, and operating room costs significantly favoured open surgery; however, the overall cost of index hospitalisation was comparable between open surgery and MIS.The reasons for reduced hospitalisation are not detailed and could be because of advantages in reduced length of stay or the operator bias.
Cost of surgical instruments was significantly more expensive for MIS than open surgery despite the exclusion of the cost of purchase and maintenance of robotic equipment.This is similar in other areas with established robotic surgical practice such as prostatectomy where costs of surgical supplies and OR occupation are higher with MIS compared to open prostatectomy, despite excluding amortised cost and reduced operative time [43,44].The requirement for additional equipment such as laparoscopic and robotic electrosurgical instruments and needle drivers may be a key contributor to these raised costs [45,46].Childers and Maggard-Gibbons found that instrument and accessory costs of robotics across gynaecological, urological, and general surgeries were around $1866 per procedure [47], whereas equipment for non-robotic surgery is relatively inexpensive.Our findings show that robotic surgery had the highest costs, followed by laparoscopic then open, confirming the results of a recent meta-analysis comparing robotic and laparoscopic DP [48,49].
Despite significantly greater costs of MIS for DP and PD, overall cost of index hospitilisation was comparable in the laparoscopic and robotic subgroup.Higher operative costs of MIS may be compensated by lower costs outside of the OR.This is likely related to decreased length of hospital stay and reduced recovery times [50,51].Previous meta-analysis found a laparoscopic approach to DP reduced length of stay by 3.8 days (P < 0.01) compared to open [52].Abu Hilal et al. [53] showed similar findings: lower postoperative costs with laparoscopic compared to open DP (− £5547, P = 0.006) resulting in an overall reduction in hospitalisation cost of £4737 (P = 0.197).Similarly, Fingerhut et al. compared laparoscopic vs open DP [54] and showed higher operative but lower postoperative costs resulting in cost-equipoise between both approaches.
The current study found that MIS is associated with an incremental cost of €5622 per QALY gained.This meets the threshold adapted by the NHS in the UK of £20,000 and £30,000 per QALY for recommending treatments [55].MIS had a 100% probability of being cost-effective when the threshold value for an additional gain of QALY was £20,000.As experience with MIS increases and the availability of robotic surgery increases, the cost-effectiveness may further improve and may justify its use in the healthcare systems that are interested in delivering equitable and sustainable value-based healthcare.
There are several limitations of the included studies in this review.Most studies were case-controlled and three were RCTs.There was also a high level of heterogeneity between studies, potentially due to the studies being conducted across 6 countries where costs vary between hospitals and healthcare systems.Because of this, the applicability of the average cost of MIS and open surgery may have limited transferability into individual healthcare settings [56].Reporting the resection of proximal and distal pancreatic resections with different operative complexity and outcomes also adds to the heterogeneity.To minimise bias due to this heterogeneity, we decided to use SMD to measure effect sizes.Two of the studies had high heterogeneity; a sensitivity analysis performed has not changed the overall results of meta-analyses [37,38].Direct cost assessment, as done in this review, does not account for indirect benefits such as earlier return to normal activities including and loss of productivity [57].This study also does not account for the training costs associated with the significant learning curve associated with laparoscopic and robotic surgery [58].The small sample size of most studies also necessitates further research to detect differences between MIS and open surgery.Also, the overall number of robotic procedures is small and will need future larger studies.The similar overall cost of index hospitalisation suggests minimally invasive pancreatic surgery is no worse than open approaches.However, only one included study analysed the ICER of laparoscopic DP, and further studies are required to evaluate the cost-effectiveness of the MIS approach to pancreatic surgery.Given the smaller volumes in the minimally invasive cohort, the authors discussed and opted to keep the laparoscopic and robotic options together.There is a need to perform costanalysis of robotic surgery separately as the data evolves and the procedure gets established.Publication bias was evident in the laparoscopic-only subgroup analysis of index hospitalisation costs.Hence, the results from this analyses have to be interpreted with much caution.The authors believe that the limitations of this review would highlight the drawbacks and help in the development of appropriate methodology for future studies.
In conclusion, this systematic review and meta-analysis found that MIS approaches are associated with higher procedural costs but may have similar overall index hospitalisation costs compared to open pancreatic surgery.

Fig. 4
Fig. 4 Comparison of index hospitalisation costs

Table 2
Clinical characteristics of patients included undergoing minimally invasive or open major pancreatic surgery

Table 3
Summary of economic evaluation in each study USD US dollar, CE cost-effectiveness analysis, CMA cost-minimisation analysis, CUA cost-utility analysis * Time to functional recovery /QALY/ICER measured against total cost until after discharge (i.e.outpatients and emergency room)