April 1, 2020
- Summarizes how the ELCAP, NLST, and NELSON studies underscored the value of chest CT for lung cancer screening
- Identifies the current acceptable oncologic principles of resection for early-stage lung cancer
- Identifies available approaches to lobectomy for lung cancer, including MIS
- Outlines the potential use of immunotherapy as an adjunct to surgery in the treatment of NSCLC
Editor’s note: This article was initiated as part of a series of feature stories developed and written by members of the American College of Surgeons Clinical Research Program to inform Bulletin readers about research and issues that affect cancer surgeons and patients.
Recent data from the American Cancer Society demonstrate that overall cancer mortality in the U.S. dropped by 2.2 percent in 2016−2017—the sharpest annual fall ever recorded. Experts attributed this decline largely to advancements in lung cancer treatment.1 The last few decades witnessed significant positive changes in the management of non-small cell lung cancer (NSCLC) that led to improved survival for this disease. With the adoption of lung cancer screening in the U.S., the incidence of early-stage lung cancer detection has been on the rise.2 Management of screened lung nodules has become a science unto itself.
We also have witnessed advancements in the principles of oncologic resection for early-stage cancers. Lobectomy remains the treatment of choice for solid tumors with high-risk characteristics. However, we are seeing an increased trend toward sublobar resection (segmentectomy and wedge resection) for small subsolid nodules. The introduction of minimally invasive approaches to lung resection has made surgical treatment more appealing to patients. Postoperative outcomes of minimally invasive lung resection have been consistently comparable to the gold standard open approach and, therefore, have become more widely accepted. Finally, immunotherapy and targeted therapy also are gaining popularity. Neoadjuvant immunotherapy is now considered an acceptable approach when given within a clinical trial. The aim of this article is to describe the advancements in early detection and surgical treatment of lung cancer that led to improved lung cancer survival from a thoracic surgeon’s perspective.
The concept that computed tomography (CT) chest screening for lung cancer improves survival is credited to Henschke and colleagues and the Early Lung Cancer Action Program (ELCAP).3 In their landmark study published in the New England Journal of Medicine, ELCAP screened 31,567 high-risk patients between 1993 and 2005 with an annual low-dose chest CT (LDCT). They identified 412 patients with stage I lung cancer, and 302 participants were managed surgically. The 10-year survival rate was 88 percent and 92 percent, respectively. Those results shed light on the value of chest CT to screen for lung cancer.
Following the results of the ELCAP trial, two randomized, controlled trials changed the way we diagnose lung cancer today and are shifting the stage at diagnosis from late to early. The National Lung Screening Trial (NLST) was a landmark study in the U.S. that enrolled and randomized 53,454 participants between 2002 and 2004 to receive an annual LDCT or chest X ray for three years.4 Patients were followed through 2009 to determine five-year survival. The study demonstrated an associated 20 percent reduction in lung cancer mortality when annual LDCT was used to screen patients ages 55 to 74 years old and who were either smokers or had quit smoking within 15 years.
In our opinion, the key to determining the best management option requires an aggressive pulmonologist and a conservative thoracic surgeon.
The Dutch-Belgian Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON) trial, on the other hand, enrolled 15,789 patients (13,195 men and 2,594 women) ages 50−74 with a history of 15 pack-years of smoking (15 years of smoking one pack per day) or who had quit within the past 10 years. The patients were randomized to screening CT at years 1, 3, and 5.5 or no screening. The results of this trial were presented most recently at the International Association for the Study of Lung Cancer 19th World Conference on Lung Cancer in 2018 and published in the New England Journal of Medicine this year.5,6 The trial demonstrated that CT scanning decreased lung cancer-specific mortality by 26 percent in men and up to 61 percent in women over a 10-year period. Based on all these data, current recommendations are to offer screening for smokers older than 55 with a history of 30 pack-years, or for those who have quit within the past 15 years. We also screen patients with a 20 pack-years history who have other risk factors (exposure to radon, asbestos, arsenic or other carcinogens, World Trade Center smoke, secondhand smoke, or first-degree relative with lung cancer).
With increased screening, the management of identified lung nodules is becoming a science unto itself. It is requiring specialized expertise to determine the best algorithm to manage the findings on an individual basis. Some data demonstrate that of the multiple nodules detected on screening CTs, only a few will eventually turn out to be of significance.7 The real challenge would be to determine the right time and right place to act upon such nodules. For example, the NELSON trial had a lower false positive rate than the NLST trial. This variance was attributed to the volumetric measurements defined by the NELSON trial in following lung nodules in contrast to the two-dimensional monitoring in the NLST. However, it is more likely the result of our increased understanding of the basic characteristics of suspicious nodules and changes in size and characteristics over time (doubling time). Therefore, vigilant comparisons and continued follow-up are crucial to timely and effective determination of the lesions that may require intervention. A multidisciplinary team approach involving a thoracic surgeon is widely accepted and preferred.
In our opinion, the key to determining the best management option requires an aggressive pulmonologist and a conservative thoracic surgeon. To minimize the chances of stage progression, the pulmonologist or screening physician should have a low threshold to refer the patient to a thoracic surgeon for a possible intervention. On the other hand, the thoracic surgeon should look thoroughly into the nodule characteristics and its progression over time before recommending an intervention in order to minimize unnecessary consequential complications. Shared decision making within a multidisciplinary team approach is an integral part of our practice in the management of incidental pulmonary nodules identified on CT screening.
Surgical resection is considered the treatment of choice for early-stage lung cancer to offer the highest chance of cure.8 The basic oncologic principles in the surgical management of early-stage NSCLC are to use an intraoperative approach to mediastinal lymph nodes and to determine the extent of parenchymal resection (lobectomy versus sublobar: segmentectomy/wedge).
Thorough preoperative staging should be performed by a board-certified thoracic surgeon participating in multidisciplinary clinics and tumor boards specialized in lung cancer. In addition, preoperative staging with advanced imaging, including positron emission tomography (PET)/CT, and histologic mediastinal node assessment with endobronchial ultrasound or mediastinoscopy is considered an integral part of the preoperative workup.9 This systematic approach to staging NSCLC has had an impact on intraoperative mediastinal node evaluation.
From a technical perspective, the intraoperative evaluation of N2 disease (the presence of ipsilateral mediastinal nodal metastases) has been a subject of debate, which was relatively settled at the beginning of the last decade. The American College of Surgeons Oncology Group (ACOSOG) Z0030 trial published in 2011 was one of the largest studies that compared full mediastinal nodal dissection (complete retrieval of mediastinal nodes from all nodal stations) with systematic sampling (stations 2R, 4R, 7, and 10R for right tumors; stations 5, 6, 7, and 10L for left tumors).10 A total of 525 patients underwent systematic sampling followed by dissection. The results showed that only 21 patients (4 percent) with N2 disease were missed by systematic sampling. Those results indicated that either approach to mediastinal lymph nodes is acceptable.
A third approach that some thoracic surgeons advocate is lobe-specific mediastinal node dissection. This approach involves the dissection (complete removal of nodes) of only the mediastinal stations that drain the specific lobe of interest in a predictable pattern. With this approach, lower lobe tumors would receive lower mediastinal station dissection only, and upper lobe tumors would receive upper mediastinal lymph node dissection. Retrospective reviews have shown similar rates of recurrence after lobe-specific dissection or total mediastinal node dissection.11
The ongoing Japan Clinical Oncology Group trial (JCOG 1413) is randomizing patients to either mediastinal node dissection or lobe-specific dissection.12 Results of this trial may provide more information regarding this approach to mediastinal nodes. In general, either technique for mediastinal nodal assessment is acceptable when performed appropriately. When systematic sampling is preferred, one should avoid skipping stations and follow the recommended nodal levels described by the ACOSOG Z0030 trial. When lobe-specific dissection is chosen, the surgeon should perform a thorough dissection to minimize the chances of missing N2 disease. Even though the evidence supporting operative mediastinal node staging is weak, most investigators advocate a systematic approach, sampling at least one N1 station and three or more N2 stations. Therefore, for right-sided resections, stations R9, R8, 7, R10, R4, and R2 nodes should be sampled, and for left-sided resections, the L9, L8, 7, 6, and 5 (and L4 nodes and the L2 when accessible) stations are sampled. Attention to the recurrent laryngeal nerve location and its preservation should take priority over a complete dissection of the level 5 lymph nodes.9,13
The extent of parenchymal resection for early-stage NSCLC remains a hot topic of debate among thoracic surgical oncologists. In fact, the surgical treatment of lung cancer evolved from an extremely aggressive approach via pneumonectomy as the gold standard in the 19th century before lobectomy was popularized in the mid-20th century. This aggressive approach to lung cancer treatment was mostly following the footsteps of William S. Halsted, MD, FACS, who introduced radical mastectomy as the treatment of choice for breast cancer in 1894.14 As our understanding of lung cancer evolved, lobectomy became the gold standard surgical treatment option for NSCLC in the 1950s.8,15-17 In the mid-1980s, Errett and colleagues proposed sublobar resection as an acceptable treatment for early-stage lung cancer.18
The concept of sublobar resection gained popularity among experts treating NSCLC, mostly because of its role in preserving lung parenchyma and subsequently preserving pulmonary function, as well as its associated lower postoperative morbidity. As the use of sublobar resection increased, the National Cancer Institute (NCI) and its Lung Cancer Study Group designed a randomized controlled trial that compared sublobar resection with lobectomy in tumors smaller than 3 centimeters.19 The study demonstrated no difference in overall survival, but it showed a significant increase in the rate of local recurrence after wedge and segmentectomy resections compared to lobectomy (threefold and twofold, respectively).
Despite its randomized nature, this study was heavily criticized. The sample size included in the comparison was relatively small (247 patients). Moreover, there was no compliance with the 2 centimeter prestudy set surgical margins for the sublobar arm, and the investigators did not provide an objective method to define local recurrence between the groups based on the size of the resected tumor.20 However, this study was just one that demonstrated increased local recurrence after sublobar resection. A retrospective review by Landrenau and colleagues demonstrated similar findings when comparing wedge resection with lobectomy outcomes.21
Therefore, segmentectomy in the 20th century was considered a suboptimal resection for lung cancer. In the new millennium, the previously mentioned pioneering efforts to introduce lung cancer screening, led by Henchke and colleagues and later reaffirmed by the NLST trial, led to the diagnosis of more peripheral and smaller lesions. This increase in earlier diagnosis and the overall weaknesses of the studies against sublobar resection drove the continued interest of thoracic surgeons to find a potential role for sublobar resection for early-stage lung cancer.3,4
Data on sublobar resection focused on pinpointing the subgroups that would benefit most from this less invasive operation. Many authors demonstrated acceptable long-term survival and local recurrence rates after sublobar resections for small (< 2 cm) and peripheral node negative lung cancer. Studies also focused on determining the optimal resection margin. Most authors agree that the ideal recommended margin is greater than the diameter of the lesion being removed.22-27
Without question, the introduction of MIS techniques, including robot-assisted lobectomy and VATS, for lung resection may have contributed to making lung cancer surgery a more appealing treatment option to patients and referring physicians.
We are eagerly awaiting the results of two randomized controlled trials that compare sublobar resection to lobectomy in early-stage disease. The first is a multi-institutional phase III trial designed by the Japan Clinical Oncology Group and the West Japan Oncology Group. The trial began enrolling a target of 1,100 patients with early-stage lung cancer (< 2 cm) in 2009 over a period of three years. The cohort was randomized for lobectomy or segmentectomy and the primary outcome is overall survival. The second trial also is a phase III multi-institutional study designed in North America to randomize a target of 701 patients with early-stage (< 2 cm) lung cancer to sublobar (wedge/segmentectomy) versus lobectomy. This study started accruing patients in 2007 and is expected to be completed in March 2021.23,27
Those studies will possibly change the way we treat lung cancer and may further contribute to decreased mortality by offering a lesser parenchymal resection to healthier patients. In the meantime, the consensus for the surgical management of early-stage lung cancer favors lobectomy with lymph node staging via sampling at least three mediastinal levels. Segmentectomy is an acceptable option when node-negative tumors are smaller than 2 centimeters in diameter and radiologic surveillance confirms long doubling time (≥ 400 days), the nodule is at least 50 percent composed of ground glass appearance on CT, or the patient has pure adenocarcinoma in situ histology.9
Without question, the introduction of minimally invasive surgery (MIS) techniques, including robot-assisted lobectomy and video-assisted thoracoscopic surgery (VATS), for lung resection may have contributed to making lung cancer surgery a more appealing treatment option to patients and referring physicians. Their appeal lies in smaller incisions, less postoperative pain, and shorter length of stay. Thus, MIS probably increased the number of moderately higher-risk patients choosing surgery over radiation and receiving the most appropriate oncologic treatment for their stage. Subsequently, the acceptance of MIS for NSCLC treatment may have contributed to the overall improvement in lung cancer survival and to the sharpest ever annual drop in the overall cancer mortality mentioned at the beginning of this article.
Data comparing short-term outcomes of MIS with open lobectomy demonstrate lower morbidity associated with MIS. One could argue that the push from industry or from proponents of MIS to publish data on robotic or VATS lobectomy has resulted in publication bias. However, early postoperative morbidity and mortality after MIS lobectomy has consistently shown that this approach is acceptable and safe. Moreover, robotic lobectomy has been shown in some studies to be associated with shorter length of stay and lower complication rates than VATS and open procedures.28,29
Multiple studies comparing robotic or VATS with open operations demonstrated similar oncologic survival outcomes. A retrospective review from the Society of Thoracic Surgeons database by Kneuertz and colleagues compared cancer recurrence and five-year overall survival after robotic, VATS, and open lobectomy for NSCLC.30 The cohort included 514 patients who were propensity matched for tumor characteristics and patient risk factors and comorbidities (robotic = 245, VARS = 118, and open = 151). All patients underwent oncologic lobectomy at a single institution between 2012 and 2017. The authors did not find a statistically significant difference in stage for comparisons of disease-free survival or overall five-year survival between groups. Another propensity matched comparison by Yang and colleagues demonstrated similar overall survival in patients who underwent lobectomy between 2002 and 2012 for clinical stage I NSCLC.31 This study also was based on a single institution experience and included a total of 516 patients who underwent lobectomy for NSCLC (172 patients in each group). The overall five-year survival rates were 77.6 percent, 73.5 percent, and 77.9 percent, and disease-free survival rates were 72.7 percent, 65.5 percent, and 69.0 percent in robotic, VATS, and open groups, respectively.
Even though the available data are too limited to promote MIS as the gold standard yet, it would appear that MIS is capable of producing excellent and superior outcomes when used in the right context on select patient populations. We believe that if an MIS operation does not compromise the oncological principles and is performed by a safe, experienced, and sensible thoracic surgeon, outcomes would be outstanding. We like to label these oncologic and safety principles as the universal tenets of a high-quality MIS resection. From this perspective, it is important for the thoracic surgeon to be comfortable and experienced in handling both approaches—MIS and open. Some patients may benefit from one approach over another depending on multiple factors, including the patient’s overall health or the tumor size and location. The surgeon’s understanding of when to offer MIS versus open, how soon to convert, and when to avoid an attempt at MIS is crucial. The temptation to finish an operation with smaller incisions should not compromise patient safety, long-term oncologic outcomes, or unreasonably prolong the time under general anesthesia.
Most specialized lung cancer treatment centers in the U.S. and elsewhere offer MIS technology for the treatment of early-stage lung cancer. With the technological advancements and the increased familiarity in navigating the minimally invasive platforms, surgeons using robotic surgery rarely need to convert to an open thoracotomy. In fact, when the universal tenets of a high-quality MIS resection are applied, outcomes should be optimal. Prior to adopting the robotic approach, surgeons should attain proper training and credentialing.32,33 A suggested robotic thoracoscopic lobectomy technique would use a totally thoracoscopic four-arm approach and follow the principles of conventional lobectomy. It should include thoracoscopic exploration of the chest cavity followed by circumferential pleural release; mediastinal lymph node assessment, with deference to the surgeon’s preference for dissection or systematic sampling; definition of any aberrant anatomy; and individual ligation of pulmonary venous, arterial, and bronchial branches. A chest drain is usually placed for 24 hours, with the goal of patient discharge on postoperative day two.
The more important challenge facing thoracic surgeons is to identify the predictors of poor outcomes associated with each approach. Such predictors would help establish an objective methodology to evaluate which procedures to avoid based on each patient’s condition.
On the other hand, when using any minimally invasive approach, familiarity and comfort in manipulating the platform is strongly advised. This savviness is usually achieved through a surgeon’s sensibility, training and practice, continuous self-assessment, and expert observation. Sensibility is an important thoracic surgery feature that not only contributes to choosing the suitable approach, but also helps determine when to convert to a different one. Complications are bound to occur with any approach. Therefore, when choosing a specific approach for our patients, we should resist the race for referrals, push from the industry, or other external factors from motivating our choice.34 Patient safety is the number one factor to be considered, a complete oncologic resection is the second priority, and using a minimally invasive approach comes third.
All available approaches to lobectomy for lung cancer have their advantages and disadvantages. The debate over whether MIS is superior, inferior, or equivalent to the open approach for lung cancer treatment may never be settled and probably is futile. The more important challenge facing thoracic surgeons is to identify the predictors of poor outcomes associated with each approach. Such predictors would help establish an objective methodology to evaluate which procedures to avoid based on each patient’s condition.
Despite all the advances in surgical techniques and therapy for early-stage disease, postoperative recurrence continues to be of significant concern.35 Consequently, the use of immunotherapy as an adjunct to surgery in the treatment of NSCLC is under investigation. Immune checkpoint inhibitors, such as nivolumab (Opdivo), pembrolizumab, durvalumab (Imfinzi), and atezolizumab (Tecentriq), are monoclonal antibodies that inhibit PD-1 or PD-L1 receptors involved in inhibiting the body’s natural immune response. The idea behind checkpoint blockade is to help halt the tumor’s suppression of T-cells against the foreign cancer and subsequently boost the body’s immune response. Theoretically, the neoadjuvant approach is thought to be more effective than adjuvant treatment because the presence of tumor cell receptors could potentially activate more T-cells and further enhances the immunity.36
The field of neoadjuvant immunotherapy is still in its infancy. Clinical trials are ongoing and the coming few years will determine if this approach to NSCLC will fade away or become mainstream.
Early data from case series, phase I, and phase II clinical trials demonstrated promising results. However, the potential increase in complication rates associated with immunotherapy is still of concern, and the dosage and timing of treatment will need to be tweaked. No treatment comes free of adverse reactions. Based on the very limited published data on postoperative complications after neoadjuvant immunotherapy, there has been an increased incidence of low-grade adverse events that may raise concerns among thoracic surgeons. These complications include pseudo progression (that is, temporary tumor edema that could lead to a more difficult dissection), bronchopleural fistulas, pneumonitis with its subsequent worsening pulmonary function that could affect the extent of surgical resection, prolonged air leak, and an increased rate of conversion to open thoracotomy.37-39 However, these preliminary data are very limited and based on case reports and small case series. The field of neoadjuvant immunotherapy is still in its infancy. Clinical trials are ongoing and the coming few years will determine if this approach to NSCLC will fade away or become mainstream.
The treatment of early-stage lung cancer from a surgeon’s perspective has evolved considerably over the last few decades. The introduction of lung cancer screening programs helped identify and treat patients at an earlier stage, which reduced the risk of death from lung cancer. Moreover, abandoning pneumonectomy for lobectomy and introducing sublobar resections as an acceptable treatment option for select smaller tumors has increased the number of patients eligible for surgical treatment, offering them a better chance for survival. Finally, the introduction of advanced technology and MIS further increased the pool of surgically treatable patients. All the advancements outlined in this article have positively affected overall survival of lung cancer patients and led to the overall drop in cancer-related deaths in the U.S. We are eagerly awaiting the results of ongoing clinical trials to further advance lung cancer treatment and survival.