Cleaning the scope: have randomized clinical trials clarified the benefits of minimally invasive thoracic surgery for non-small cell lung cancer?—a narrative review

Introduction

The evolution towards minimally invasive approaches represents one of the most significant developments in thoracic surgery over the last two decades. A robust body of evidence is essential to provide a firm foundation for which future innovations can build upon. Randomized control trials (RCTs) are the gold standard for evaluating the effectiveness of new interventions. However, surgical trials pose unique methodological challenges including learning curve, equipoise, blinding, and the rapid evolution of surgical technique (1). Surgical innovation frequently occurs in the absence of robust, prospective evidence supporting clinical benefit—often when the surgical community has already become convinced of the interventions benefit (2). Even when cardiothoracic surgery clinical trials are performed, there is often concern regarding their methodological rigor (3-6). The Thoracic Surgical Oncology Group (TSOG), established in 2017, formed partly due to the paucity of Thoracic Surgical Oncology trials (7).

Recently, several clinical trials have been initiated which compare short- and long-term clinical outcomes in patients undergoing lobectomy by either video-assisted thoracic surgery (VATS) or robotic approaches (8-10). Quality of life (QOL) and cost effectiveness have also been in the focus of many trials. In this report review, we review select clinical trials in minimally invasive thoracic surgery and discuss oncologic efficacy, long-term survival, perioperative complications, postoperative pain, and QOL. We also discuss methodological concerns including approaches to blinding, the learning curve, and suggest future directions. We present this article in accordance with the Narrative Review reporting checklist (available at https://actr.amegroups.com/article/view/10.21037/actr-24-149/rc).

Methods

We identified English-language, prospective randomized clinical trials comparing minimally invasive and open surgery techniques for lung cancer resection. Keywords included “thoracotomy”, “video-assisted thoracic surgery”, “robot assisted thoracic surgery”, “lung cancer”, “lobectomy”, “surgical technique”, “clinical trials”, “randomized”, and “prospective” and all appropriate Boolean operators. Studies were identified through query of the Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, PubMed, Embase, and Google Scholar. Citation tracing was used to supplant this search strategy. We summarize features of trial design including design, randomization, accrual, and outcomes. We discuss the implications of study results and suggest further directions. To limit our discussion to clinical trials most likely to reflect contemporary practice, we review English-language, studies published between January 1^st, 2010–April 1^st, 2024 in the highest impact journals in medicine (The Lancet and The New England Journal of Medicine), surgery (JAMA Surgery and Annals of Surgery), oncology (Journal of Clinical Oncology and Lancet Oncology), and cardiothoracic surgery (The Journal of Thoracic and Cardiovascular Surgery and The Annals of Thoracic Surgery) (Table 1) (3). Trial design, blinding methodology, surgeon participation (single, multiple), intervention & control arms, participants (randomized/analyzed), and primary outcome were abstracted and are presented in Table 2.

Narrative/results

Minimally invasive approaches versus thoracotomy

Compared to traditional posterolateral thoracotomy, VATS has been associated with shorter length of stay, reduced narcotic requirement, improved shoulder function, and greater patient satisfaction in lung cancer resection. Multiple clinical trials have investigated this comparison (11-17). No trial to date has compared robotic-assisted thoracic surgery (RATS) with thoracotomy for lobectomy, and it is possible that such a study, at least in a conventional RCT format, would have equipoise. Three RCTs investigating lobectomy with VATS versus thoracotomy approaches met inclusion criteria and are discussed with key aspects of study design summarized in Table 2.

Bendixen et al.

Bendixen and colleagues performed an observer-blinded RCT of VATS (four-port) versus anterolateral thoracotomy (11). The study period was October 1^st, 2008 to August 20^th, 2014 and took place at a public university-based CT surgery department in Denmark. The pre-specified primary outcome was pain (acute and chronic) over the 12-month study period. Patients with stage I non-small cell lung cancer (NSCLC) and Eastern Cooperative Oncology Group (ECOG) performance status 0–1 were considered for inclusion. Pain was assessed via the numerical rating scale (NRS) six-times daily during the hospitalization and at 2, 4, 8, 12, 26, and 52 weeks after surgery. A total of 206 patients were ultimately enrolled and randomized with 201 patients included in final analysis (modified-intention-to-treat with exclusion of benign pathology). The authors identified improved pain control in the VATS group postoperatively and throughout the 52-week study period (P<0.0001). A strength of this investigation was the standardization and description of concomitant interventions most likely to affect the primary outcome, namely analgesia, which was scheduled and identical between groups. However, as was described at the time of publication, universal epidural placement, particular in stage I patients, does not reflect contemporary clinical practice then or now (which the authors suggest was necessary for masking). A further strength was the use of universal postoperative dressings as well as the exclusion of the surgeon from post-operative decision making. Both strategies represent important efforts to target potential biases that may affect primary and secondary outcomes. Unfortunately, excluding surgeons from post-operative decision making is not likely to reflect common practice, and may affect the relevance of their findings.

VIOLET trial (video-assisted thoracoscopic lobectomy versus conventional open lobectomy for lung cancer trial)

The VIOLET trial enrolled 503 participants with a primary outcome of QOL and incorporated longitudinal follow up to assess long-term oncologic efficacy with improved QOL and oncologic outcomes, including upstaging to pN2 disease after the procedure, uptake of adjuvant treatment, and overall and progression-free survival (13). The primary outcome was physical function at five-weeks as assessed by the European Organization for Research and Treatment of Cancer core health-related quality of life questionnaire (QLQ-C30). Participants 16 years or older with suspected or confirmed lung cancer (cT1-3) and regional lymph node involvement (cN0-1) amenable to either VATS or open lobectomy were considered for inclusion. Patients were informed only of their surgery prior to discharge after they were asked to confirm which intervention, they thought they had received. VATS and Thoracotomy approach including, total port sites, varied and was left to surgeon preference. Lymph node assessment was protocolized according to IASLC guidelines (18). QOL questionnaires employed included the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-LC13, and EuroQol 5-Dimension 5-Level (EQ-5D-5L) self-report questionnaires. Adjustments for multiplicity for QOL outcomes was performed (19). Other measures of clinical efficacy included prolonged incisional pain (defined as the need for analgesia more than 5 weeks after random assignment). Of the 502 participants, 436 patients received their allocated treatment. Mean age of participants was 69 (SD 8.8) years, and 249 (49.5%) were men. Analyses were intention-to-treat. Participants who underwent VATS had significantly better physical functioning as assessed by the primary outcome measure (QLQ-C30) at five weeks (P<0.05). Oncologic outcomes including lymph node station harvest were equivalent.

The protocol, which was shared a priori, declared a single objective endpoint i.e., physical functioning as assessed by QLQ-C30, identified a clinically significant threshold for difference, and performed an appropriate sample size calculation. There are several other laudable features of trial design. It is a multi-center study, which represents a cross section of community and academic medical centers. It was a phased study, in which phase 1 served to optimize recruitment practice and acted as a qualitative laboratory to develop best practices in patient education, communication, and study accrual. In this way, the study served to strengthen the overall infrastructure for future randomized clinical trials in the UK. A subgroup analysis was planned a priori to investigate concomitant aspects of patient care related to QOL and pain control (paravertebral block vs. intercostal block) (20).

Interestingly, the authors reported that only 51.2% of patients who received VATS and 45.74% of patients who received thoracotomy were able to correctly guess their surgical approach. In other words, more than half of the patients who underwent thoracotomy—which requires a much larger incision and often involves muscle dividing, rib spreading, and rib fracture—thought they underwent minimally invasive surgery. Though the patients did not have a point of reference, it does suggest that they were comfortable enough to believe that their incisions must have been less invasive. The finding does support the relative effectiveness of their short-term blinding period and helps contextualize the relatively modest benefit of VATS over Thoracotomy in postoperative pain control.

Long et al.

Finally, a non-inferiority multicenter RCT in China from 2008 to 2014 studied 425 patients randomized to either VATS or axillary thoracotomy found VATS to be associated with less intraoperative blood loss and comparable short-term oncologic outcomes, including lymph node yield (12). Length of hospital stay was not statistically shorter (14 days in VATS versus 15 days in thoracotomy; P>0.05). The long length of hospitalization in this study reflects local practice patterns with early admission to complete preoperative evaluation and workup. Thus, the LOS benefit is unlikely to be apparent in this context. As we have previously suggested, blood loss may reflect the reason for the thoracotomy (e.g., intraoperative emergency, complicated anatomy, advanced disease), and was not a direct consequence of the surgery itself. As such, even in the RCT setting, review of the baseline characteristics of study groups and consideration for intention-to-treat to treat analysis (i.e., in cases of conversion) is essential to ensure to the integrity of randomization and generalizability (21).

VATS versus RATS

Technical limits of VATS may make fine nodal or vascular dissection more challenging. Such intrinsic elements include limitations in maneuverability (i.e., straight rigid instruments in a rigid chest wall), motion reversal and amplification, six-degrees of freedom, lack of three-dimensional appreciation. RATS has been suggested to overcome these technical limitations while providing the benefits of a minimally invasive approach. Existing platforms lack haptic feedback; however, other potential advantages included improved dexterity, better ergonomics, and tremor control. These advantages may reduce the rate of conversion to thoracotomy and therefore translate the benefits of pain control and QOL demonstrated in previous investigations comparing thoracotomy and VATS. These important considerations formed the basis of RCTs investigating QOL outcomes between minimally invasive thoracic surgical approaches. Two RCTs meeting inclusion criteria and are discussed in this section (Table 2).

RAVAL trial (robotic-assisted vs. video-assisted lobectomy trial)

The RAVAL trial is a multi-center, international trial two-phase trial, which randomized participants to robotic portal lobectomy with 4 arms (RPL-4) versus VATS-lobectomy (9). Participants are blinded to the type of surgical approach until the completion of the trial. Patients age 18 years and older with clinical stage I, II or IIIa NSCLC deemed appropriate candidates for lobectomy were considered for inclusion. The primary objective was health-related QOL (HRQOL) at 12 weeks. In cases of conversion, the patient remained in their study group under an intention-to-treat analysis.

This study was the first multi-center trial of minimally invasive thoracic surgical interventions to attempt participant blinding throughout the course of the investigation. QOL outcome measures and pain are especially vulnerable as they depend on patient’s subjective experience (22). Indeed, RAVAL investigators document the enthusiasm and favorable expectations that the Canadian population has towards robotic surgeries, and the uptake of RATS among surgeons reflects a mutual enthusiasm from the provider perspective (23). In Canada and other countries with similar health systems, access to robotic technology may be limited until the value of the intervention can be demonstrated to incremental cost effective ratio (ICER) threshold, the basis of which is formed by health utility assessment.

This investigation was therefore subject to significant threat of bias—among them performance bias and reporting bias. Participant and observer blinding is a logical approach to address this issue, which was incorporated into the trial design. However, according to the trial protocol and published findings, little attempts were made to ensure high quality participant blinding. The investigators note that the operating room setup between VATS and RATS were similar and that the four port incisions for both approaches could be dressed in a similar fashion. However, in most hospitals, the room setup and technical requirements for RATS and VATS are very different and the presence of a robotic console and patient cart can be easily recognized. Moreover, no attempt was made to address the quality of blinding such as with the Bang Blinding Index or any questionnaire to our knowledge. In their short-term results, the authors did disclose there were six cases of accidental unblinding, all from the RATS arm and through accidental disclosure by the clinical team. The investigators found improved health utility scores in patients undergoing RATS compared to VATS at 12 weeks. This was assessed by the EQ-5D-5L. There was a trend towards increased conversion in the VATS group relative to RATS but this did not reach statistical significance (15.66% versus 7.41%; P=0.10).

RVlob trial (robotic-assisted versus video-assisted thoracoscopic lobectomy trial)

The RVlob trial was a single-center open label study which randomized 363 participants to four-port robotic-assisted lobectomy (RAL) versus uniportal thoracoscopic-assisted lobectomy (VAL) with 320 patients ultimately enrolled (8). The reasons for exclusion were withdrawal of consent (10/43, 23.3%), pathology other than NSCLC on frozen section (28/43, 65.1%), and intraoperative change in surgical plan (5/43, 11.6%). The study period was May 2017 to May 2020. Patients were considered for inclusion if they were deemed appropriate candidates for lobectomy without a defined clinical stage. Patients were excluded if greater than 80 years old. The primary endpoints were 3-year overall survival (OS) rate and the extent of lymph node dissection. The trial was a non-inferiority design with the primary outcome for lymph node harvest defined as a difference in total lymph node yield with a non-inferiority margin of 0.5. The mean difference was 1.27 (0.06, 2.48) favoring RATS. As the lower confidence interval does not exceed the non-inferiority margin, the study results are inconclusive regarding the non-inferiority of each approach. RVlob also investigated non-inferiority of OS in a 3-year time frame with a 5% difference in survival as the non-inferiority threshold (8). Recently published data from this trial demonstrated non-inferiority for RATS versus VATS (24).

Discussion

Lymphadenectomy

A purported advantage of RATS technology is ease of ability in carrying out the fine dissection necessary for high quality lymph node dissection. At the time of VATS introduction, this was one of the suggested weaknesses of the new technology. In the aforementioned trials of VATS versus thoracotomy, VATS was found to have similar oncologic efficacy in that lymph node harvest and rate of upstaging were equivalent. Lymph node yield was also a secondary endpoint in the RAVAL and ROMAN trials, which found RATS to be associated with higher lymph node yield; although, no difference in rate of nodal upstaging was found (10). It is important to note that in all these trials standardization of lymph node sampling or lymphadenectomy was not strictly defined or monitored. More importantly, differences in total lymph node harvests were influenced by the quantity of N1 lymph nodes for which pathologic assessment of the specimen plays a significant role. As a result, the number of N1 nodes is less likely to be influenced by surgical approach in lobectomy since the specimen is removed in both cases. These questions are the subject of an ongoing trial (NCT06252129) (25).

Additionally, the significance of total lymph node yield, separate from rate of nodal upstaging, is of questionable clinical significance. This is particularly true in the era of neo-adjuvant and adjuvant immunotherapy for which additional lymph node resection beyond sampling may in fact produce worse oncologic outcomes (26). Future reports should aim to identify a more clinically relevant endpoint and seek to standardize methods including pathologic assessment as well as control for lymph node fragmentation which may result from robotic instrumentation.

Postoperative pain and QOL

The thoracotomy incision can be among the largest in surgery. Adequate perioperative analgesia is recommended both for minimizing discomfort and downstream pulmonary sequelae. Acute and chronic pain following thoracotomy is well described with the potential for long-term impairment of QOL. This is known as post-thoracotomy pain syndrome (PTPS) (27). Impairment of shoulder function is also a recognized consequence of traditional posterolateral thoracotomy, which is unsurprising given the division of multiple muscle layers (28). Multiple refinements of the thoracotomy incision have been devised in the effort to reduce associated morbidity without apparent effect (28). Meta-analysis of these efforts have demonstrated only marginal gains in select physical domains—for example, an improvement in internal shoulder rotation (P>0.05) while pain scores were largely equivocal both in the acute and chronic settings (29).

These findings suggest the surgical morbidity, at least as it relates to pain, is largely driven by the degree of rib spreading, which may be even greater in muscle sparing approaches to accommodate limitations in exposure. This was investigated in Bendixen et al. in which anterior thoracotomy with sparing of the latissimus dorsi was compared to four-port VATS approaches. Perioperative pain and QOL (as assessed by the EQ5D) were greater in the VATS group at one year. More patients in the thoracotomy group reported moderate-to-severe pain (NRS ≥3) during the 52-week of follow up (P<0.05).

The VIOLET trial used more tailored assessments of QOL, including QLQ-LC13, a lung cancer specific quality instrument and a separate assessment of chronic incisional pain, which was demonstrably greater in the thoracotomy group (59.6% in the VATS group, 72.3% of the participants in the open surgery group; P<0.05). In all trials, there was the missed opportunity to assess chronic pain in a focused manner such as with a neuropathic pain scale as well as the impact on shoulder function. Of note, since the initiation/publication of the VIOLET trial, the QLQ-LC13 instrument has been recently updated to include surgery specific questions as well as the side effects of targeted- and immunotherapy.

Future trials in minimally invasive surgery should make use of these well validated global scales with consideration of data capture of well-known chronic complications and impaired shoulder function, which are more likely to be a consequence of surgical intervention. Such studies should consider subgroup assessments of perioperative analgesia, anesthesia, rehabilitation, and physical therapy protocols as part of an overall ERAS strategy (20,30-32). As targeted- and immunotherapy are increasingly being utilized, as part of an overall multi-modal strategy in early stage lung cancer, focused attention should be given to their impact on QOL.

Given that rib spreading is minimized in both RATS and VATS groups, one may argue that attempts to ascertain a clinically meaningful difference in pain or QOL is somewhat misguided. The proposed mechanism as delineated in the RAVEL trial protocol is reduced rate of conversion to thoracotomy in select patient subgroups [high body mass index (BMI), larger tumor size] (33,34). As mentioned earlier, the conversion rate favored RATS (7.41% vs. 15.66%; P=0.10) but did not reach significance (34). HRQOL was similar across the study group in the study period in the RVlob Trial. A single statistically significant finding of pain at four weeks was noted in the single PORT VATS group (35). Conversion rates were similar between study groups. The authors comment that this may be explained by the degree of instrument torquing necessary in uniportal VATS.

It’s possible that RATS may offer an advantage in reducing conversion rates in select patient populations, such as in high BMI patients as the RAVEL investigators suggest. An important future direction will be clarifying this result in patients who have undergone neo-adjuvant systemic therapy. In parallel, consideration should also be given to the relationship between early-recovery after surgery protocols and minimally invasive surgical approaches (36). A statistically significant difference in conversion rate in a RCT would clearly establish a clinical benefit of RATS over VATS.

A notable statistically significant finding across both RVlob and RAVEL trials was the greater intraoperative blood loss observed in the VATS group, 150 vs. 50 mL in the case of the RAVEL trial (P=0.0002). Patients who underwent VATS were more likely to have two chest tubes in place post-surgery (12.05% vs. 3.70%; P=0.05) perhaps secondary to bleeding. Insertion of a second chest tube may be associated with greater postoperative pain and is also perhaps a driver of the observations in difference in QOL.

Learning curve

Defining an operational definition of learning curve in surgery has been fraught. In a recent review and meta-analysis outcome measures included mean console and dock time, blood loss, chest tube duration, length of hospital stay and total lymph nodes removed (37). Issues in the present literature included limited proctorship, absence of long-term survival data, variability in provider experience with previous minimally invasive approaches. In all randomized clinical trials a minimum case requirement was in place. Over half of all lobectomies are now robotic assisted and there is less concern that technical performance may limit comparisons (38).

Health economics

Economic analyses of VATS versus thoracotomy have consistently demonstrated the cost effectiveness of minimally invasive approaches compared to open including the cost analysis of the RCT performed by Bendixen et al. (39). Cost savings was attributable to decreased length of stay and readmission in the VATS cohort. These postoperative findings were also demonstrated in the VIOLET trial (13).

The cost of robotic surgery is multifactorial and attributed to the capital investment, higher instrument cost per case, and finally operative time. One micro-costing analysis suggested the cost difference was driven principally by the cost of consumables and secondarily by the capital cost and increased operative time/staff cost in approximately equal portions (40). Predictably, the relative cost effectiveness of RATS has been shown to improve with procedure volume and decreased operating time (41). Operative time has been the focus of recent analyses for resource utilization (42).

The regulatory standards for new devices in the United States, such as for the da Vinci surgical system, generally rely upon clinical safety rather than clinical benefit or cost-effectiveness. As such, robotic surgery has largely evolved in the absence of robust prospective clinical data supporting its relative benefit. In other countries, new technology or interventions are appraised based on an incremental cost effective ratio (ICER).

The RAVAL trial aimed to evaluate the cost effectiveness of robotic lobectomy. Health Utility scores were calculated from the Canadian EQ-5D-5L value set. The incremental cost per quality-adjusted life year (QALY) of RPL-4 relative to VATS-lobectomy was calculated at the 12-month time point. Direct and indirect methods were calculated using a microcosting method previously described (9). The incremental cost was $14,925.62/QALY gained (95% CI: $6,843.69, $23,007.56) relative to VATS-lobectomy, well below the threshold employed in most nations (43). However, as previously discussed the challenge of blinding participant in this domain may make it difficult to ascertain differences in clinical outcomes subject to significant bias such as QOL making it challenging to establish a theoretical cost-effectiveness or cost-equivalency for RATS by the methods described.

Limitations and future directions

This review is not intended to be exhaustive but to describe the major RCTs investigating minimally invasive approaches for lobectomy. Our review is intended to identify pitfalls in previous RCTs and identify future directions. RCTs comparing multi-port and uniport approaches between and among VATS and RATS represent an important future direction but are beyond the scope of this review.

Conclusions

We document the evolution of randomized clinical trials for lobectomy in Thoracic Surgery. We identify opportunities to improve the quality of future randomized clinical trials of minimally invasive surgical approaches in thoracic oncology. Methodological issues, including the approaches to patient blinding and the lack of standardized assessment of lymphadenectomy, make it difficult to draw definitive conclusions from published RCTs comparing RATS to VATS. We suggest the use of the more specific survey instruments for pain and QOL (e.g., QLQ-LC13 with surgery subscale, neuropathic pain scales). We suggest the development of standardized guideline for the assessment, measurement, and identification of clinically relevant research outcomes related to lymph node assessment.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://actr.amegroups.com/article/view/10.21037/actr-24-149/rc

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-149/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-149/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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