Medico-economic impact of thoracoscopy versus thoracotomy in lung cancer: multicentre randomised controlled trial (Lungsco01)

Lung cancer (LC) remains a major health problem with an estimated 130,180 deaths in 2022 in the US, which makes it the leading cause of cancer death in both sexes [1]. For early-stage LC, surgery remains the cornerstone of management and results in better overall survival [2]. Lobectomy with mediastinal lymph node dissection is therefore recommended in order to limit the risk of local recurrence [3]. However, lobectomy is associated with a high proportion of postoperative complications, especially respiratory complications, ranging from 12% in the analysis of the American Society of Thoracic Surgeons database, around 15% in the French National Epithor database, to 30% in a recent study using the SEER database [4‐6]. Moreover, as reported by Stéphan et al., postoperative respiratory complications are associated with increases in mortality and length of stay in the intensive care or surgical ward, which has an effect on health system spending [7].

During the last decade, the use of video-assisted thoracoscopic surgery (VATS) lobectomy for LC has grown considerably. In France, the use of VATS jumped from 12% of lobectomies in 2012 to 48% in 2017 [8].

Recommendations from the American College of Chest Physicians in 2013 and the European Society of Medical oncology in 2014 suggest that VATS lobectomy be performed depending on the experience of the surgeon and for tumors of any stage [2, 3]. These recommendations are based on meta-analyses from the last decade, which indicated that VATS resulted in shorter hospital stays and fewer postoperative complications such as atelectasis or pneumonia [9‐14]. However, the data used to formulate these recommendations were of poor quality. There are few randomized controlled trials (RCTs) in the literature evaluating the benefits of VATS compared to open thoracotomy for LC. In fact, only Bendixen et al., in a trial involving 206 patients, found that there was a benefit regarding postoperative pain and quality of life during the first year of follow-up in favor of VATS versus open thoracotomy [15].

To date, only four RCTs comparing complications and overall survival following VATS lobectomy or open thoracotomy for the treatment of lung cancer have been published in English [16‐19]. The authors did not find VATS to be more beneficial than open thoracotomy except for intraoperative blood loss and median time of surgery. There were no benefits in terms of postoperative complications, mortality or length of hospital stay.

More recently, Bendixen et al. reported the results of the cost-utility analysis of VATS lobectomy performing a RCT including 103 patients in each group. They highlighted that VATS lobectomy was a cost-effective alternative to open thoracotomy for stage I LC [20].

The medico-economic literature on this subject is poor, which is why a medico-economic study is now needed to determine whether the costs induced by VATS are offset by the reduction in postoperative complications. This paper presents the results of a large RCT assessing the medico-economic impact of VATS lobectomy when compared with open thoracotomy in the French context.

The primary aim of this study was to evaluate the cost-effectiveness and the cost-utility impacts of VATS lobectomy when compared with open thoracotomy for the management of non-small cell lung cancer (NSCLC). These medico-economic analyses were performed at 30 days after surgery. The secondary aim was to evaluate the cost-effectiveness and cost-utility impacts at 3 months after surgery.

Lungsco01 is an open two-arm parallel RCT comparing lobectomy or segmentectomy performed by VATS with lobectomy or segmentectomy using thoracotomy for the treatment of LC. As specified in the published study protocol, the study involved French thoracic surgery departments that had already performed more than 50 VATS lobectomies [21]. The number of patients in each of the treatment groups was calculated and planned to be equal (300 patients in each arm), with a ratio of 1:1 and a stratification by centre since the different practices of each team may have an impact on the judgement criterion [21]. The list of randomised patients was divided into blocks of 12 to obtain balanced groups. Randomisation was available after patients had met the inclusion criteria [21].

Two hundred and sixty-two patients were assessed for eligibility and signed consent to participate in the study from July 29, 2016 to November 24, 2020. One hundred and thirty-one patients were randomised to the VATS group, 128 to the thoracotomy group, and 3 were not randomized (Fig. 1). Ten centres participated in the study.

Of the two strategies, VATS was found to be more expensive, and it did not result in cost reductions in the post-surgical period at 30 days or at 3 months. Like in other RCTs, we did not show significant benefits for VATS in terms of post-operative complications or mortality [16‐19]. However, the cost-utility analysis showed that VATS resulted in a slight but significant higher number of QALYs at 30 days after surgery (given a calculated ICER of €19,162/QALY). The bootstrap analysis revealed a 64% probability of efficiency at this time horizon for VATS, at a widely-accepted willingness-to-pay threshold of €25,000/QALY [32] (and only 34% at 3 months).

This trial is the first prospective multicentre RCT to assess the medico-economic impact of VATS compared with open thoracotomy for the management of NSCLC in France. To our knowledge, only one other cost-utility study by Bendixen et al. has been published to date comparing the two strategies [20]. This Danish study was performed in parallel to a clinical RCT between 2008 and 2014, including 103 VATS and 103 thoracotomies. Similar to our study, Bendixen et al. observed significantly better QALYs after VATS at 30 days (+ 0.07 QALY at 4 weeks, p-value: 0.008) and higher, but not significantly, QALYs at 3 months (+ 0.02 at 12 weeks, p-value = 0.162). As in our study, QALYs were assessed using EQ-5D-3L® and were imputed in case of missing data. However, they found lower overall costs per patient operated by VATS (- €4,267), and 84.3% of the bootstrapped cost-utility pairs were located in the bottom-right quadrant of the CU-plane, meaning lower costs and more QALYs following VATS. The probability of VATS being cost-effective was 95% at DKK 50,000/QALY (€6,720/QALY) according the acceptability curve. However, there were some differences between our studies: theirs was monocentric, designed for the first 12 months following surgery, from the perspective of healthcare services, and included additional costs (consultations with general practitioners, physiotherapists, psychologists, and chiropractors, and prescription drugs). Another more recent publication from 2021 comparing cost and effectiveness between VATS and open lobectomy in China concluded that hospitalization costs were similar for the two strategies, but that there were lower post-surgical costs and higher effectiveness for VATS [13]. However, this study was monocentric and retrospective, and did not present incremental medico-economic ratios. Its results cannot be compared with ours due to differences in defined costs and effectiveness criteria (blood transfusion rate, lung infection rate and post-operative LOS). Regarding the only cost differential between the two strategies, a recent systematic literature review reported that for 19 of 20 studies analysed up to 2020, VATS was associated with higher operative costs [33]. In 17 of them, this cost was significantly counterbalanced by other costs that were lower in VATS compared to thoracotomy during and after discharge. Finally, 10 studies found lower total costs for VATS, 7 found similar total costs, and 3 found higher total costs despite the lower hospitalization costs. Here again, comparisons between these studies and with our results remain difficult. In addition to the fact that the majority of these studies were retrospective and single-centre, the main difference lies in the methodology used for cost evaluation (the choice of perspective, time horizon, expenditure items, and unit costs) and in the characteristics of the included population and the surgeons (when information was available) [33].

The present study has several limitations. Only the hospital perspective was considered insofar as only hospital resources consumed were available based on the data collected in the e-CRF. In this perspective, in order to calculate the production cost per stay as recommended in medico-economic guidelines [28, 30], the DRG were retrospectively determined based on individual information available in the e-CRF, and with the expertise of the medical information department of the Dijon University Hospital. While the initial stays necessarily had the same DRG root (04C02: “Major surgery on the thorax”) for which we had only to determine a level of severity (04C021: “Major surgery on the thorax, level 1” to 04C024: “Major surgery on the thorax, level 4”), those for other re-hospitalisations had to be determined. Moreover, though the production costs per DRG are available in the ENCC, these remain average costs, calculated from 70 representative establishments in France, with the disadvantage of lacking precision on inter-individual variability [34]. However, the ENCC average costs per DRG are recognized as being close to opportunity cost and relevant for economic analyses [34]. The calculation of production costs per stay in the voluntary sample of the 70 hospitals participating in the ENCC follows a common methodology based on the principle of full costs, obtained by allocating expenses to analysis sections and to individual stays according to allocation keys. The national benchmark of the ENCC is presented according to two cost scales, one for public establishments and one for private for-profit establishments. A detailed analysis of costs is available, making them transferable [34]. Then, since the Lungsco01 trial included a micro-costing study based on fifty randomised patients to evaluate the real production cost of VATS and thoracotomy procedures [26], the average surgery cost values obtained were applied to all patients in the trial according to their arm of randomisation, but without adjustment for individual operative time and for individual consumables used. Indeed, the e-CRF was not designed to collect all resources consumed in the operating room for all patients in the trial (except for those included in the micro-costing). However, it is well recognized that a micro-costing study implies a large amount of work that cannot be done on a larger number of patients, but it is the most accurate approach for estimating the real cost of in-hospital healthcare interventions [26, 35]. The fact that the analysis was conducted in the context of a randomized trial allowed comparisons between the two groups and limited potential biases [26]. Another limitation is the number of patients randomized in the study. While the protocol planned to include 600 patients (300 per group), calculated on the basis of the primary clinical endpoint, only 259 patients were finally randomised, demonstrating the major difficulties in carrying out a RCT of this size in thoracic surgery. Another limitation is that the time horizon was 3 months after surgery, not allowing for any potential longer-term effects. However, this can be justified by the fact that neither of the two procedures is likely influence late outcomes (beyond 90 days). Finally, there were missing responses for the EQ-5D-3L® even though it was administered face-to-face. Unfortunately, missing data are a frequent issue in medico-economic analyses within randomised clinical trials. QALYs were thus imputed using the recommended multiple imputation method [36].

Nonetheless, this study has several strengths. This is the first multicentre RCT in France to prospectively evaluate the cost-utility impact of VATS versus open thoracotomy in the management of NSCLC, considering costs from the initial stay and patient follow-up (re-admissions), and utility (QALYs). The centres were required to have performed 50 VATS procedures to be included in the study, thus limiting biases linked to the experience of the surgeons performing VATS. The costing methodology used conforms to the methodological recommendations of health economists [35] and the Haute Autorité de Santé (HAS) [28], in terms of DRG-adjusted approach for the initial stays and of combination of micro-costing and gross-costing approaches. While micro-costing identifies and measures the resources consumed by the innovative intervention, gross-costing estimates the cost items that can be valued using standard costs (ex: for readmissions related to complications). Finally, our study is one of the few studies that takes ‘utility’ into consideration, though it is a particularly important dimension for medico-economic studies in lung cancer [15, 37‐40].

Today, the results of medico-economic studies are considered to be a tool for authorities whose mission is to inform public decision-making on the allocation of health resources (ex: decisions regarding reimbursement). Currently, the procedure of lobectomy or segmentectomy by VATS is valorised through act GFFA009 (Pulmonary lobectomy, by thoracotomy, with preparation by thoracoscopy), whose valuation (838.75 €) is insufficient considering the real cost of VATS surgery (3,876.49 €). In our context, the revaluation of VATS should take into account the acceptability threshold of willingness-to-pay that will be set by decision-makers in terms of acceptable supplemental costs per additional QALY gained. Other additional criteria could also be taken into consideration, depending on the decision-making context. For example, multi-criteria decision analysis (MCDA) could also be relevant since it provides information on a wider range of outcomes including physical functioning, psychological well-being, person-centeredness, access to care, and financial affordability [41]. Research comparing MCDA and a cost-utility analysis is needed. Good communication between researchers and decision-makers will be an important part of identifying the most suitable approach [41].

Given our results, the economic efficiency of VATS at a willingness-to-pay threshold of €25,000/QALY remains fragile at 30 days (64% probability). The economic efficiency is not established beyond that time horizon. However, the acceptability curves given will allow decision-makers to judge the probability of efficiency of this technology depending on other WTP thresholds.