Minimally Invasive Resection of Early Lung Cancers

Low-dose computed tomography (LDCT) screening decreases lung cancer mortality in high-risk individuals and has now been approved and adopted for lung cancer screening in the United States. As more LDCT lung cancer screening programs are implemented, more patients with early-stage lung cancer who could benefit from surgical intervention will be identified. Although lobectomy currently remains the standard of care for early-stage non–small-cell lung cancer (NSCLC), thoracic surgeons are increasingly adopting minimally invasive surgery via thoracoscopy as a viable-and perhaps even preferred-approach for select lung cancer resections. Video-assisted thoracic surgery (VATS) lobectomy has been associated with decreased perioperative morbidity, and similar rates of locoregional recurrence and cancer-free survival can be achieved compared with the standard open surgical procedure. However, as lung cancers are detected at earlier stages, the optimal extent of lung resection for long-term cure continues to be investigated. For patients with very small-sized lung tumors and indolent lesions, cancer-free survival may not necessarily be compromised by undergoing less invasive approaches that intentionally resect less lung tissue, such as sublobar resections (eg, segmentectomy and wedge resection). This review looks at the current data and guidelines for thoracoscopic resection of stage I NSCLC and discusses the potential for limited lung resection in patients with the disease.

Introduction

Surgery currently offers the greatest opportunity for long-term cure for early-stage lung cancer and remains the cornerstone of any multimodality approach to locally advanced disease. Open lobectomy has been the standard operation for lung cancer resection since the widespread acceptance of the 1995 Lung Cancer Study Group (LCSG) randomized study comparing open lobectomy with more limited pulmonary resection in stage I non–small-cell lung cancer (NSCLC; T1N0).[1] This landmark trial by Ginsberg et al demonstrated a 30% increase in mortality in the sublobar group and a statistically higher locoregional recurrence (P = .08) in the limited resection group. Although lobectomy has generally been accepted as the standard extent of resection required for NSCLC surgery, surgical leaders in the thoracic oncology community continue to vigorously debate the relative merits of using less invasive techniques for cancer resection, while also re-initiating discussions of sublobar resection in an era of screening detection of very small and peripheral lung cancers.

Minimally invasive lobectomy-predominantly the video-assisted thoracic surgery (VATS) approach-has achieved equipoise with open lobectomy in terms of safety and efficacy, and the role of VATS continues to expand. Furthermore, two important developments in lung cancer will challenge the thoracic surgery community to reconsider the role of more limited pulmonary resection using a minimally invasive approach. First, the US population has a longer life expectancy, and therefore the incidence of lung cancer in the elderly population will increase; and second, the provocative results of the National Lung Screening Trial (NLST) showed that low-dose computed tomography (LDCT) lung cancer screening irrefutably saves lives.[2] These two trends predict that patients with lung cancer will be older and diagnosed at an earlier stage, and will therefore most likely have a preference for less invasive surgical intervention.

VATS Lobectomy: Current Evidence for Outcomes in Lung Cancer Resection

Numerous reports have been published over the past decade that promote the benefits of using the VATS approach for lung cancer resection-benefits achieved without compromising oncologic efficacy. Early proponents argued that VATS offered less perioperative morbidity, shorter hospitalizations, and less surgical stress, with decreased serum levels of measured pro-inflammatory cytokines, implying an immunologic benefit in cancer survival over the traditional open thoracotomy.[3-7] However, most of these studies were criticized for selection bias because patients with smaller, peripheral tumors underwent VATS, whereas those patients with larger, more central tumors were resected using the traditional open approach.

In fact, there are few direct comparisons between VATS lobectomy and the open lobectomy approach for lung cancer resection. There have only been two small, randomized studies comparing VATS with open lobectomy. [8,9] Kirby et al randomly assigned 61 stage I lung cancer patients to either VATS or open lobectomy and found that postoperative air leaks were reduced in the VATS group, with no significant differences observed in operating time, intraoperative blood loss, duration of chest tube drainage, or length of hospital stay.[8] The other prospective study, by Sugi et al, randomized 100 patients with early-stage lung cancer and likewise found no significant differences between those patients who received VATS lobectomy and those who underwent open thoracotomy; 5-year survival after surgery was 90% in the VATS group and 85% in the open cohort (P = .74).[9] These two small randomized studies suggested that the results of the VATS procedure were comparable to the conventional open approach, but that VATS did not provide the purported improvement in early postoperative outcomes reported in multiple nonrandomized case series. The widespread acceptance of these studies was limited by the small numbers of patients enrolled, their single-center design, and the fact that they were conducted during the early VATS experience.

However, as the thoracoscopic approach to lung surgery gained popularity worldwide, a substantial body of literature accrued-including several large published studies and systematic reviews-promoting the benefits of the VATS lobectomy and comparing the VATS approach with open anatomic lung resection.[10-14] These studies have emphasized improvements in perioperative patient outcomes (presumably due to the limited chest wall trauma with the VATS approach), citing less pulmonary morbidity, shorter hospital lengths of stay, and less acute postsurgical pain, with improved immediate postoperative pulmonary function. The faster postsurgical recovery and return to baseline quality of life associated with the VATS lobectomy has also arguably implied quicker recovery for administration of adjuvant chemotherapy in those patients who require it.

In a comparison of VATS lobectomy and thoracotomy, Whitson et al collected 39 studies, with a total of 3,114 VATS patients and 3,256 thoracotomy patients, and found statistically significant decreased chest tube duration (P = .025) and hospitalization (P = .016), and improved 4-year postresection survival (P = .003) in the VATS group.[13] A similar review published in 2009 by Yan et al also suggested that the VATS approach had more favorable outcomes than open lobectomy. These authors analyzed 21 comparative studies of VATS and open resection and found no overall difference in postoperative morbidity (defined as prolonged air leaks, arrhythmia, and pneumonia) or mortality with VATS, but did find improvement in systemic recurrence and long-term mortality.[14]

Large inpatient databases have also been used to compare VATS with open lobectomy and to determine whether a VATS approach can be used safely in appropriately selected patients. The discharge records of 13,619 patients who underwent lobectomy by either thoracotomy (n = 12,860) or VATS (n = 759) between 2004 and 2006 were analyzed by Gopaldas et al, who reported that there were no differences in rates of in-hospital mortality, lengths of stay, or postoperative complications between the similarly matched-cohorts.[15] Another recent study, this one using the 2007–2009 Surveillance, Epidemiology and End Results (SEER)-Medicare database, also concluded that VATS resection for lung cancer could be performed with similar, if not less morbidity than open lobectomy. In this propensity-matched study by Paul et al, the investigators found that in-hospital mortality, length of stay, and postoperative complications (arrhythmias, pneumonia/sepsis, need for ventilation, and atelectasis) were equivalent or occurred less frequently in the VATS group compared with the thoracotomy group.[16] Interestingly, in a cost analysis study, Farjah et al compared the 90-day total costs of VATS lobectomy to the costs associated with open lobectomy for lung cancer using a national insurance claims database and found that the costs for the VATS group were nearly $3,500 less than for the open lobectomy group. This cost difference was largely due to the increased percentage of prolonged hospitalization (> 14 days from surgery to discharge) after surgery in the open lobectomy group.[17]

These propensity-matched studies and large meta-analyses had their limitations, however, including lack of correction for important variables, such as surgeon experience/expertise, and nuances of tumor characteristics not accounted for in staging (ie, peripheral rather than central location). A noteworthy study by Farjah et al illustrated the relevance of taking into account such confounders when evaluating the safety and efficacy of VATS.[18] The authors analyzed nearly 13,000 patients with lung cancer who underwent either open or VATS resection and found that those who received VATS had smaller-sized tumors compared with patients who underwent open conventional resection; however, early 30-day mortality was similar overall, and further subset analysis of this cohort suggested that when VATS was performed by low-volume surgeons or at low-volume hospitals, the procedure was associated with higher risk of early death. In addition, the development of streamlined patient management pathways concurrent with the implementation of VATS procedures was another unmeasured impact that confounded the differences in outcomes, making it unclear as to whether the procedure, the management pathway, or the surgeon choosing the procedure was the dominant or important determinant.

Although the accumulated body of evidence suggests that VATS lobectomy for early NSCLC can be safely performed with minimal, and arguably less procedural morbidity, the oncologic equivalence of this approach compared with the gold standard of thoracotomy has been justifiably scrutinized.[19] Central to this issue has been the thoroughness of mediastinal lymph node dissection and subsequent accuracy of lung cancer staging. The lack of contemporary multicenter, prospective, randomized controlled trials limits the evaluation of the oncologic efficacy of VATS in retrospective studies. A number of single-institution experiences with VATS resection have suggested that fewer mediastinal lymph nodes have been examined compared with the open approach, thereby potentially understaging patients with early-stage lung cancer who might have benefited from adjuvant therapy if they had been accurately staged.[20-22] Denlinger et al found in their relatively early VATS experience that significantly fewer mediastinal lymph node samples were obtained with the VATS approach compared with thoracotomy (7.1 samples vs 8.9 samples; P = .029); notably, fewer N2 nodes (particularly station 7) and N2 stations were sampled in the VATS group.[20] Other recently published retrospective single-institution studies have found similar results.[21,22] Lee et al used propensity score matching to retrospectively compare patients with early-stage lung cancer who underwent surgical resection by VATS or by thoracotomy and discovered that those patients who underwent VATS had fewer N2 lymph nodes (5.7 nodes vs 8.5 nodes; P = .001) and N2 stations (1.9 stations vs 2.4 stations; P < .001) evaluated.[22] Merritt et al found that in early-stage lung cancer patients with clinical N0 disease, fewer total lymph nodes were evaluated in the matched group of VATS patients compared with the open lobectomy group, and a greater percentage of open lobectomy patients were upstaged from clinical N0 to N1/N2 stage.[21] Similar conclusions have been reached using large databases to evaluate the thoroughness of mediastinal lymph node evaluation by VATS lobectomy. Licht et al analyzed the Danish Lung Cancer Registry from 2007–2011 and found significantly greater nodal upstaging in patients with clinical stage I NSCLC who underwent open lobectomy compared with those who underwent VATS lobectomy. N1 upstaging was 13.1% in the open group compared with 8.1% in the VATS group; N2 upstaging was also higher in the open lobectomy group (11.5% vs 3.8%).[23] Corroborating this finding, Boffa et al used the Society of Thoracic Surgery thoracic surgical database from 2001–2010 and found that among the 11,531 patients who underwent resection for clinical stage I lung cancer, N0 to N1 upstaging was significantly lower (6.7% vs 9.3%; P < .001) in the VATS group compared with those who underwent open resection.[24] Despite the significant statistical differences reported in these studies with regard to the number of lymph nodes and nodal stations evaluated in VATS resection vs open resection for early-stage lung cancer, significant differences in rates of disease-free or overall survival have not been reported in them.[21-24] A recent propensity-matched analysis comparing VATS with open lobectomy using contemporary SEER-Medicare data found that overall survival, disease-free survival, and cancer-specific survival at 3 years of follow-up were not statistically different between the two groups; in fact, in this database study, more lymph nodes were examined in the VATS group than in the open lobectomy group (mean number of nodes examined: 19.9 vs 17.6; P = .0327; median number of nodes examined: 10 vs 9, P = .0004).[16]

Although the short-term benefits of VATS lobectomy over open lobectomy seem well established, albeit by retrospective low-level nonrandomized studies, it is less clear whether there are intermediate to long-term benefits for the minimally invasive approach. Rates of VATS lobectomy have increased substantially; VATS was performed in only 1% of patients in 1994, but this had increased to 9% by 2002.[18] The Society of Thoracic Surgeons National General Thoracic Database includes a demographic that is skewed toward academic and higher-volume thoracic surgery centers in the United States; this database shows a 32% rate of VATS lobectomy use by 2006.[25] However, it is evident that a substantial number of surgeons are not adopting VATS lobectomy, or are rarely using the procedure. This may be a result of skepticism about the degree and magnitude of benefit conferred by VATS, concern about safety or efficacy, difficulty in acquiring and mastering the technical skills of VATS lobectomy-or likely a combination of these factors.

Weighing the cumulative evidence from the past decade evaluating the oncologic efficacy of VATS lobectomy in early NSCLC treatment, the current recommendations by the National Comprehensive Cancer Network (NCCN) and the American College of Chest Physicians (ACCP) for stage I NSCLC propose that VATS lobectomy is not inferior to open lobectomy when performed at experienced centers in appropriately selected patients.[26,27] More importantly, regardless of the selected method, a systematic approach to lymph node evaluation for accurate cancer staging is paramount when making decisions regarding multimodality treatment requirements. NCCN guidelines recommend N1 and N2 lymph node resection and mapping during curative surgery, with a minimum of three different N2 stations sampled.[28]

Also implicit in the NCCN and ACCP recommendations are important caveats to consider when choosing VATS for lung cancer resection. Tumor location and size should be factors when deciding whether VATS is appropriate for lobectomy; however, institutional and surgeon-specific considerations should be taken into account in addition to the technical criteria for selecting patients wisely for VATS lobectomy. VATS lobectomies for early-stage lung cancer resection are more likely to be performed at large academic centers with higher surgical volume, by dedicated thoracic surgeons who are actively involved in a multidisciplinary approach to lung cancer management. Examining the SEER-Medicare database, Farjah et al found that among the 19,745 evaluated patients who had undergone pulmonary resection for lung cancer, only 32% of the surgeries were performed by dedicated general thoracic surgeons; 24% of the lung cancer resections were performed by general surgeons, who are typically exposed to fewer thoracic surgeries in the course of their training and have limited experience and formal training in thoracoscopic approaches to anatomic lung resection. More importantly, this factor affected outcomes: lung cancer patients treated by dedicated general thoracic surgeons had an 11% lower hazard ratio for death compared with those patients treated by general surgeons.[28] Other investigators have found similar outcomes regarding the impact of surgeon-specialty on lung cancer outcomes after resection.[29-31] Since center-specific outcomes and surgeon experience contributed to the positive outcomes reported in the contemporary VATS lobectomy literature, the decision to perform a VATS lobectomy in an individual diagnosed with early-stage NSCLC must take these factors into account.[32]

Less Invasive Thoracic Surgery: Its Role in an Aging Population

NSCLC remains a disease that is especially common in the elderly; two-thirds of NSCLC patients are older than 65 years, with an average age at diagnosis of 70 years.[33] By 2030, US citizens over the age of 80 are projected to comprise 5% of the population, and it is estimated that there will be a significant increase in the number of persons with early-stage NSCLC in this population, many of whom will have associated comorbidities.[34] Historically, surgeons were reluctant to offer surgery to older patients, presumably because of increased perioperative morbidity and mortality independently associated with advanced age.[35] Studies demonstrating improvements in preoperative selection, intraoperative management, surgical techniques, and postoperative care pathways show that advanced age alone should not disqualify a patient from being a candidate for surgical resection.[36-38] Instead, patient comorbidities and physiologic status are better determinants of outcome after lung resection; carefully selected older patients with good performance status and minimal comorbidities can recover well after major thoracic surgery.[38,39]

A preferred surgical approach to early-stage lung cancer in the very elderly patient has not been recommended, nor has an upper age limit been established beyond which lung resection would be contraindicated. Different single-institution studies suggest that minimally invasive lung cancer resection in the very elderly can be conducted with acceptable perioperative morbidity and mortality.[40-42] Mun and Kohno reviewed their early experience with 55 Japanese patients older than 80 years with clinical stage I lung cancer who underwent VATS resection and reported two postoperative deaths (3.6%) and a median length of stay of 8 days. Actuarial survival in this group was 76.4% and 65.9% at 3 years and 5 years, respectively.[41] Port et al reviewed their institutional experience and discovered that the VATS approach was associated with fewer complications compared with open thoracotomy in patients 80 years of age or older who underwent lobectomy for NSCLC. Acknowledging the selection biases and significant limitations inherent in a small single-center retrospective review, the authors noted that elderly patients who underwent VATS lobectomy were less likely to require ICU admission or post-discharge rehabilitation and had decreased lengths of stay.[42] Furthermore, although lobectomy is the current standard of care for early-stage lung cancer, a less invasive approach combined with limited lung resection for curative intent may also be considered in elderly patients with lung cancer who are too debilitated to undergo lobectomy but might otherwise tolerate surgery. A less extensive lung resection using VATS that achieves negative tumor margins is currently still preferred over nonsurgical options for treating early-stage NSCLC when a patient is unable to tolerate the physiologic impact of a lobectomy-although outcomes of stereotactic radiation are promising and may provide a reasonable alternative to surgery in some patients. On the other hand, a practical but still unanswered question is whether healthy individuals with very advanced age should undergo sublobar resection, trading the oncologic superiority of a lobectomy-open or VATS-for the perceived lesser perioperative morbidity of a resection of lesser extent. The effect of limited resection on overall long-term functional status and quality of life balanced with overall actuarial survival in this cohort has not been well studied.

CT Lung Cancer Screening and the Role of Less Invasive, Limited Resection of Very Small/Indolent Lung Lesions

The results of the recent NLST, which examined the use of LDCT imaging, has recharged interest in whether the routine use of sublobar resection for very-early-stage lung cancer lesions is oncologically appropriate. Additionally, CT imaging technology now allows better characterization and detection of subcentimeter lung lesions, which has generated interest among thoracic surgeons in evaluating whether lobectomy is uniformly superior to more limited resections. Specifically, the evidence compelling thoracic surgeons to undertake lobectomy in patients who are determined to have peripheral T1a tumors (≤ 2.0 cm) classified as adenocarcinoma in situ (AIS) or minimally invasive adenocarcinoma (MIA) is uncertain. Guidelines, understandably, are reluctant to recommend sublobar resection routinely over lobectomy-even in patients with T1aN0 lung cancer lesions-in the absence of randomized data confirming oncologic equivalence. The previously referenced LCSG landmark trial, which found that locoregional recurrence occurred more frequently with sublobar resection, did not distinguish between wedge resection and anatomic segmentectomy in its comparison with lobectomy.[1]

Two large retrospective studies using the SEER National Cancer Registry also each found statistically significant worse 5-year survival in patients with stage IA NSCLC who underwent sublobar resection compared with lobectomy; Chang et al found that 5-year survival was 44% for sublobar resection compared with 61% for anatomic resection (P < .0001), and Whitson et al found decreased overall (P < .0001) and cancer-specific survival (P = .0053) in the sublobar group compared with the lobectomy group.[35,43] In contrast, other investigators have not found inferior outcomes following sublobar resections-particularly anatomical segmentectomy-compared with lobectomy in early-stage lung cancer patients,[44-52] and this is likely to be especially true for less invasive or more indolent cancers detected during lung cancer screening. Although both types of sublobar resection preserve greater lung volume than lobectomy, wedge resections are performed without regard to anatomical bronchial segmental anatomy and do not allow intrapulmonary lymph node sampling, which may result in higher rates of cancer recurrence. Performing segmentectomy does allow for lymph node sampling but is technically more challenging, particularly if performed with VATS, as it requires detailed dissection of the bronchial segment and pulmonary arterial supply.

A number of Japanese studies have shown promising outcomes with VATS segmentectomy.[50,53-55] The Japanese thoracic surgeons reported that VATS segmentectomy compared favorably with VATS lobectomy and had similar perioperative outcomes, without evidence of increased locoregional recurrence. Similarly, Altorki et al found adjusted 10-year survival outcomes comparable to those seen with lobectomy when sublobar resection was used to treat early solid nodule lung cancers (clinical stage 1A tumors) identified by a lung cancer CT screening protocol.[52] At this time, larger prospective clinical studies are needed to more decisively qualify the role of VATS segmentectomy in early-stage lung cancer; consequently, the thoracic oncology community awaits the completion of two randomized studies investigating the extent of lung resection necessary-lobectomy or sublobar resection-for optimal surgical outcomes in early-stage NSCLC.[56,57]

Another practical clinical question that needs to be addressed in more detail is the specific role of VATS wedge resection in the treatment of early-stage NSCLC lesions. Based on conclusions drawn from several studies that found oncologic outcomes with segmentectomy to be superior to wedge resection, both NCCN and ACCP guidelines currently recommend that sublobar anatomical resection (segmentectomy) be preferred over wedge resection whenever sublobar resection is required.[28,29] However, modern radiographic imaging can identify small indeterminate lesions, and the use of various thoracoscopic localization techniques will allow thoracic surgeons to better visualize and identify difficult nodules that otherwise would not be palpable or identified by VATS.[58] The optimal extent of resection when removing precancerous lesions or adenocarcinomas with minimal invasion is unclear. Early lung lesions are likely to be increasingly detected by CT as lung cancer screening programs become more widespread across the United States. Given the likelihood that patients with early lung lesions are at increased risk for having synchronous lung lesions or for developing metachronous lesions, minimally invasive parenchymal lung-sparing techniques will have a prominent role in treatment. It is still unclear whether a VATS segmentectomy or a nonanatomic minimally invasive wedge resection with adequate negative margins is needed in this setting. Data emerging from Japan, where CT lung cancer screening already has been widely implemented, suggest that a VATS wedge resection may be an effective approach for small (≤ 2 cm) pure ground glass opacities and those indolent lesions that are histologically determined to be AIS or MIA.[59-62] As clinical prognosis is better correlated with our understanding of lung tumor biology and the various subtle radiographic characteristics associated with precancerous and very early lung cancer lesions, thoracic surgeons will need to draw on this new knowledge to guide the extent of lung resection required for optimal long-term outcomes.

Conclusion

The popularity of minimally invasive thoracic surgery has expanded the surgical options that thoracic surgeons can offer to patients with early-stage lung cancer. Although lobectomy remains the standard operation for stage I NSCLC, current guidelines recommend that VATS can be performed in appropriately selected patients by board-certified thoracic surgeons as an acceptable alternative to thoracotomy. Independent of the surgical approach, systematic lymph node evaluation remains critical for accurate cancer staging and guides subsequent decision making regarding additional therapy. The growth of the elderly population and the support for national CT screening of individuals at high risk for lung cancer portends a growing demand for minimally invasive approaches as surgically curable lung cancer is identified at earlier stages. As our ability to detect and predict lung cancer progression improves, the extent of lung resection required for curative intent will evolve. Currently, sublobar lung resection is reserved for early-stage lung cancer patients who cannot tolerate surgical lobectomy. However, as subgroups of very-early-stage lung cancer patients are identified with node-negative, indolent lesions, minimally invasive limited resections are expected to become more routine.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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