In 2006, a wave of optimism followed the US Food and Drug Administration (FDA) approval of rituximab for the treatment of diffuse large B-cell lymphomas in combination with chemotherapy. After all, it was the first time in more than 25 years that a new therapeutic agent had improved survival in this aggressive subtype of lymphoid malignancy. In the new era of immunochemotherapy that was ushered in by rituximab, clinicians eagerly awaited the addition of more new agents to the armamentarium available for use against lymphoid malignancies.

Expectations were replaced by frustration as a relative drought of new approvals ensued, leaving those who treat these malignancies hoping for more. The last 5 years, however, have brought an abundance of new agents to the market, restoring hope for a significant change in outcomes for patients with lymphoid malignancies.

Between 2010 and 2014, the FDA issued roughly 25 new indication-specific drug approvals for agents designed to treat hematologic malignancies. These account for about 28% of all cancer drug approvals for this period-a statistic that is all the more remarkable when one considers the fact that lymphomas and leukemias accounted for less than 8% of all new cancers diagnosed in the United States in 2014.[1]

In this issue of ONCOLOGY, Dr. Siddiqi and Dr. Rosen elegantly summarize the data on the monoclonal antibodies approved by the FDA for the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia over the last 5 years.[2] These new agents bring to the table an array of new treatment strategies. Some have refined ways of attacking old targets. Others have innovated by finding clever ways to deliver cytotoxins intracellularly. A third group engages the host’s adaptive immune system in the fight against the malignant clone.

Antibody-directed cellular cytotoxicity (ADCC) and phagocytosis constitute the core mechanisms by which anti-CD20 therapy induces cell death in lymphoid malignancies. In contrast with chimeric rituximab, ofatumumab and obinutuzumab are novel humanized anti-CD20 monoclonal antibodies. Decreasing murine content to a minimum critical amount allows these next-generation monoclonal antibodies to curb immunogenicity to mouse sequences. Preclinical studies indicated that these new agents carry enhanced cell-killing properties compared with rituximab.[3,4]

The clinical studies of ofatumumab and obinutuzumab have been nicely summarized by our colleagues in their review. Improving on the foundation laid by rituximab is proving to be as much of an opportunity as it is a challenge. Several ongoing trials combining next-generation anti-CD20 monoclonal antibodies with standard and novel therapies are actively accruing.

While some researchers concentrated on improving the effectiveness of anti-CD20 targeting, others chose to enhance ADCC by focusing on a different surface marker. The early clinical data on epratuzumab, a humanized anti-CD22 monoclonal antibody, were encouraging, especially in combination with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone).[5] However, while the agent was initially promising, the concurrent emergence of other agents with greater efficacy led to a loss of enthusiasm for further development of treatment strategies incorporating epratuzumab.

Antibody-drug conjugates: Have we found our magic bullets?

Delivering potent cytotoxins to the interior of malignant cells while sparing normal tissues the untoward adverse effects of these cytotoxics is truly the “magic bullet” of cancer treatment. This epitome of targeted therapy, a concept that can allegedly be traced back more than a century to German physician Paul Ehrlich, has never felt so real. Monoclonal antibodies have proven to be the ideal vehicle for such specific delivery. It was not until recently, however, that technological advances in their design and production made it possible to use monoclonal antibodies to target cancer cells in innovative ways.

Inotuzumab ozogamicin and brentuximab vedotin are representatives of this new class of agents, known as antibody-drug conjugates. While the first targets CD20 and the latter binds to CD30, both effectively deliver toxins to malignant cells intracellularly. Their clinical activity has been clearly demonstrated in proof-of-concept studies. A number of clinical trials are actively investigating the role of antibody-drug conjugates in the treatment in many different hematologic malignancies.

Evading a host’s immune system to allow malignant clones to perpetuate unopposed may be one of cancer’s most critical evolutionary steps. Agents such as ipilimumab, pembrolizumab, nivolumab, and blinatumomab-not to mention completely revolutionary strategies such as chimeric antigen receptor therapy-make it easy to understand why cancer immunotherapy rightfully deserved 

 magazine’s designation as Breakthrough of the Year in 2013.[6]

The clever design of blinatumomab, an antibody with dual specificity for CD19 and CD3, allows cytotoxic T cells to effectively kill B-cell clones. The seminal work led by Bargou[7] and Topp[8,9] demonstrated the clinical efficacy of this novel treatment strategy in the management of relapsed/refractory non-Hodgkin lymphoma and B-cell acute lymphoblastic leukemia patients, respectively.

While the focus of immunotherapy has been on T-cell signaling, it is important not to lose sight of other factors present in the tumor microenvironment. The approval of siltuximab, a chimeric monoclonal antibody targeting interleukin-6, reminds us of the importance of cell signaling in determining the outcomes of tumor-host interactions.

With new hope come new challenges. As we watch the arrival of this new group of agents, each new answer unfolds into several questions. How can we best determine the comparative efficacy of these new agents? How can these new agents and new treatment strategies be best incorporated into approaches that include the currently available options? How will the cost of these new therapies influence their use in the rapidly changing healthcare delivery system? How do we protect ourselves from the risks of accelerated approvals and limited safety data when our patients plead for new and better options?

The next few years hold great promise, as new agents emerge and others consolidate their place on our shelves. We will be forced to rethink strategies and redefine management as a new era of immuno-oncology dawns. Indeed, there are many challenges-but they are among the best kind.

Dr. Ansell receives research funding from Seattle Genetics, Bristol-Myers Squibb, and Celldex, Inc. Dr. Villasboas has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article. 

 Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9-29.

 Siddiqi T, Rosen ST. Novel biologic agents for non-Hodgkin lymphoma and chronic lymphocytic leukemia. Part 1: monoclonal antibodies. Oncology (Williston Park). 2015;29:198-203.

 Teeling JL, French RR, Cragg MS, et al. Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood. 2004;104:1793-800.

 Herter S, Herting F, Mundigl O, et al. Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models. Mol Cancer Ther. 2013;12:2031-42.

 Micallef IN, Maurer MJ, Wiseman GA, et al. Epratuzumab with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated diffuse large B-cell lymphoma. Blood. 2011;118:4053-61.

 Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science. 2013;342:1432-3.

 Bargou R, Leo E, Zugmaier G, et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science. 2008;321:974-7.

 Topp MS, GÃ¶kbuget N, Zugmaier G, et al. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 2014;32:4134-40.

 Topp MS, GÃ¶kbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2014 Dec 16. [Epub ahead of print]

Articles

The next few years hold great promise, as new agents emerge and others consolidate their place on our shelves. We will be forced to rethink strategies and redefine management as a new era of immuno-oncology dawns.

The Era of Immuno-Oncology: Are We There Yet? 

Minimally invasive thoracic resection has been reported to reduce the cost and morbidity of lung cancer surgery. The evidence supporting this position is outlined in a review article in this issue of ONCOLOGY.[1] The importance of this information has recently escalated, as the Centers for Medicare and Medicaid Services (CMS) finally agreed to provide reimbursement for low-dose CT screening in high risk cohorts.[2] This new strategy for the early detection of lung cancer will more frequently find early-stage cancers than in the past, and this may represent the most favorable setting for employing minimally invasive surgical techniques.

The final CMS coverage decision requires shared decision making, including “the use of one or more decision aids.”[2] This stipulation arises out of a desire to ensure that the appropriate discussion of relevant information regarding potential benefits and harms of screening routinely occurs. This requirement is intuitively appealing, and sharing procedural information is considered to be an inherent part of the relationship between healthcare providers and their patients. However, with regard to the lung cancer screening process, no evidence exists that any benefit is derived from the requirement to use a decision aid tool.

What will perhaps prove far more helpful to such discussions in the long run will be the routine capture of data about all aspects of the management of patients who undergo screening. The surgical management of patients in the National Lung Screening Trial (NLST) was not specified in the study protocol, and so the favorable results of that trial emerged from a patchwork of community standards from the various sites involved in the NLST. Going forward, the opportunity exists to create prospective registries designed to more completely capture relevant prognostic information that will be able to inform future discussions about the optimal surgical intervention.[3,4]

As noted in the review, a state of equipoise now exists for various surgical options in the treatment of early lung cancer,[1] underscoring the need for shared decision making. Because varying risks are associated with nearly each aspect of the surgical decision, including type of surgery, extent of surgery, and even extent of staging, the need to solicit patient preference is great. This will presumably lead, in turn, to even more variation in the procedures being performed. Capturing this information-as well as other information not previously captured (especially details regarding the imaging findings)-in prospective registries should result in highly useful data regarding relative benefits and harms under different conditions.

As suggested by the Lung Cancer Alliance Framework Process, a new approach is needed in which care providers are dynamically committed to a range of best-practice and related quality provisions that are documented and followed for outcomes, thus allowing for protocols to be continuously updated based on knowledge derived from these registries.[5] Other imaging issues related to quality control features are inherent to the new American College of Radiology CT accreditation program, which requires use of Lung–RADS or a similar structured reporting and management system.[6] With this new advocacy-driven, continuously evolving quality approach, responsible implementation of lung cancer screening is on much firmer footing.

Dr. Yankelevitz is a named inventor on a number of patents and patent applications relating to the evaluation of diseases of the chest, including measurement of nodules. Some of these are owned by Cornell Research Foundation (CRF). As an inventor named on these patents, Dr. Yankelevitz is entitled to a share of any compensation which CRF may receive from its commercialization of the patented products. Dr. Mulshine has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

 Cheng AM, Wood DE. Current status of minimally invasive reserction of ealy lung cancers. Oncology. 2015;29:160-6.

 Centers for Medicare and Medicaid Services. Decision memo for screening for lung cancer with low dose computed tomography (LDCT) (CAG-00439N). Available from: 

http://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=274

 Aberle D, Adams A, Berg C, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395-409.

 Mulshine JL, D’Amico TA. Issues with implementing a high-quality lung cancer screening program. CA Cancer J Clin. 2014;64:352-63.

 Lung Cancer Alliance. National framework for excellence in lung cancer screening and continuum of care. Available from: 

http://www.lungcanceralliance.org/assets/docs/am-i-at-risk/NationalFramework.pdf

 Kazerooni EA, Armstrong MR, Amorosa JK, et al. ACR CT accreditation program and the lung cancer screening program designation. J Am Coll Radiol.2015;12:38-42.

A state of equipoise now exists for various surgical options in the treatment of early lung cancer, underscoring the need for shared decision making.

Shared Decision Making and Screening: An Ongoing Dialogue Informed by Data

Lung cancer is the leading cause of cancer death in both men and women worldwide. The Centers for Medicare & Medicaid Services (CMS) recently approved Medicare coverage for low-dose spiral CT screening in at-risk individuals, leading to more cancers being detected at an earlier stage. As a result, more patients will likely seek out potentially curative surgery. Drs. Cheng and Wood provide a well-written summary of the current state of minimally invasive surgery to resect early-stage lung cancers.[1]

Surgery with complete resection and lymph node removal remains the gold standard for the treatment of early lung cancers. Lobectomy is recommended by the American College of Chest Physicians (ACCP) in patients with stage I or II non–small-cell lung cancer (NSCLC) who will tolerate it (a grade 1B recommendation).[2] For patients who cannot tolerate a lobectomy the ACCP recommends sublobar resection with adequate margins (preferably segmentectomy) over other treatment modalities.[2]

However, the US population is growing older, and the increasing number of elderly patients with early-stage tumors with significant comorbidities will require physicians to consider alternative approaches to these often more frail patients. Stereotactic body radiation therapy (SBRT) is one option that has gained momentum as an alternative to surgical resection in nonoperative patients and those at high risk for postoperative comorbidities. A Surveillance, Epidemiology and End Results (SEER) database analysis of patients 75 years or older with early-stage NSCLC treated between 2003 and 2009 reported a 4.2% rate of SBRT use in the United States.[3] In some parts of Europe, this rate is substantially higher. Palma and colleagues queried the Amsterdam Cancer Registry for patients 75 years or older with early-stage lung cancer treated between 1999 and 2007.[4] They reported a 16% increase in the use of primary radiotherapy during the study period, with 23% of patients being treated with SBRT between 2005 and 2007.[4]

Advantages of SBRT include the ability to achieve negative margins on central lesions, reduced short-term morbidity, the lack of an anesthesia requirement for treatment, and the minimal collateral injury to surrounding tissue. However, patients who undergo SBRT are usually staged radiographically (rather than via systematic sampling of lymph nodes and pathology), introducing the risk of understaging and the potential for denial of adjuvant chemotherapy that might be beneficial. In addition, local recurrence is more difficult to assess following SBRT than it is following surgical resection, on account of the post-surgical inflammation and scar tissue often left after therapy. Thus, for now, surgery remains the preferred treatment modality.

Video-assisted thoracic surgery (VATS) is an approach that may fill the need for a surgical method more likely to be tolerated by frail elderly patients. VATS techniques for lobectomy were introduced more than 20 years ago and have been shown to result in shorter recovery times and equivalent long-term survival compared with open thoracotomy. Despite this evidence, the adoption of VATS for lung cancer surgery has lagged significantly when compared with other minimally invasive procedures, such as laparoscopic cholecystectomy. The reasons for this are many, but are rooted in the fact that less than 50% of lung resections are performed by dedicated general thoracic surgeons. In addition, the complexity of the procedure necessitates a rather long and steep learning curve and requires experience in performing these operations with some regularity.

However, with the approval of lung cancer screening for high-risk individuals by CMS, an increasing number of patients will be diagnosed with early-stage NSCLC. Many of these patients will be frail, and perhaps among those most likely to benefit from a VATS approach. Fortunately, as more patients with lung nodules are identified, the number of surgeons performing VATS pulmonary resections is also expected to rise, for a number of reasons. Residents and fellows graduating from modern training programs have extensive exposure to minimally invasive techniques and are expected to perform VATS lobectomies prior to graduation. In addition, technologic advances in minimally invasive equipment, including robotics, will make it easier for the “open” surgeon to routinely perform VATS surgery. Market pressure, patient demand, and the mounting evidence supporting VATS lobectomy will be catalysts for many surgeons to adopt minimally invasive techniques. Finally, as the Society of Thoracic Surgeons general thoracic database matures and public reporting of outcomes becomes a reality, patients will be able to view ratings and consolidate their care at the highest performing programs. These are likely to be institutions with general thoracic surgeons who are adept at minimally invasive pulmonary surgery.

As we move forward into the promising future of early detection for lung cancer and the prospect of making strides in survival and cure, thoracic surgeons will continue to be called upon to innovate and to determine, for each patient, the surgical approach that will be most effective and have the fewest comorbidities. Smaller early-stage tumors may lend themselves to less radical lung parenchymal sparing resections or no surgery at all. The authors of this review do a fine job of framing the present and future challenges that all of us face when treating lung cancer. I am hopeful we can capitalize on the promise of early detection of this deadly disease.

Dr. Liptay is a consultant and course director for Covidien

 Cheng AM, Wood DE. Minimally invasive resection of early lung cancer. Oncology (Williston Park). 2015;29:160-6.

 Howington JA, Blum MG, Chang AC, et al. Treatment of stage I and II non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2013;143(5suppl):e278S-e313S.

 Shirvani SM, Jiang J, Chang JY, Welsh J, Likhacheva A, Buchholz TA, et al. Lobectomy, sublobar resection, and stereotactic ablative radiotherapy for early-stage non-small cell lung cancers in the elderly. JAMA Surg 2014;149:1244-53.

 Palma D, Visser O, Lagerwaard FJ, et al. Impact of introducing stereotactic lung radiotherapy for elderly patients with stage I non-small cell lung cancer: a population-based time-trend analysis. J Clin Oncol. 2010;28:5153-9.

Smaller early-stage tumors may lend themselves to less radical lung parenchymal sparing resections or no surgery at all.

Smaller Incisions for Smaller 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.

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 (

 = .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 (

 = .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 (

 = .016), and improved 4-year postresection survival (

 = .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; 

 = .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; 

 = .001) and N2 stations (1.9 stations vs 2.4 stations; 

 < .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%; 

 < .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; 

 = .0327; median number of nodes examined: 10 vs 9, 

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 (

 < .0001), and Whitson et al found decreased overall (

 = .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.

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.

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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 Yan TD, Black D, Bannon PG, McCaughan BC. Systematic review and meta-analysis of randomized and nonrandomized trials on safety and efficacy of video-assisted thoracic surgery lobectomy for early-stage non-small-cell lung cancer. J Clin Oncol. 2009;27:2553-62.

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 Farjah F, Wood DE, Mulligan MS, et al. Safety and efficacy of video-assisted versus conventional lung resection for lung cancer. J Thorac Cardiovasc Surg. 2009;137:1415-21.

 Mathisen DJ. Is video-assisted thoracoscopic lobectomy inferior to open lobectomy oncologically? Ann Thorac Surg. 2013;96:755-6.

 Denlinger CE, Fernandez F, Meyers BF, et al. Lymph node evaluation in video-assisted thoracoscopic lobectomy versus lobectomy by thoracotomy. Ann Thorac Surg. 2010;89:1730-5; discussion 36.

 Merritt RE, Hoang CD, Shrager JB. Lymph node evaluation achieved by open lobectomy compared with thoracoscopic lobectomy for N0 lung cancer. Ann Thorac Surg. 2013;96:1171-7.

 Lee PC, Nasar A, Port JL, et al. Long-term survival after lobectomy for non-small cell lung cancer by video-assisted thoracic surgery versus thoracotomy. Ann Thorac Surg. 2013;96:951-60; discussion 60-1.

 Licht PB, Jorgensen OD, Ladegaard L, Jakobsen E. A national study of nodal upstaging after thoracoscopic versus open lobectomy for clinical stage I lung cancer. Ann Thorac Surg. 2013;96:943-9; discussion 49-50.

 Boffa DJ, Kosinski AS, Paul S, et al. Lymph node evaluation by open or video-assisted approaches in 11,500 anatomic lung cancer resections. Ann Thorac Surg. 2012;94:347-53; discussion 53.

 Boffa DJ, Allen MS, Grab JD, et al. Data from The Society of Thoracic Surgeons General Thoracic Surgery database: the surgical management of primary lung tumors. J Thorac Cardiovasc Surg. 2008;135:247-54.

 Howington JA, Blum MG, Chang AC, et al. Treatment of stage I and II non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed. American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143:e278S-e313S.

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professionals/physician_glos/PDF/nscl.pdf. Accessed February 11, 2015.

 Farjah F, Flum DR, Varghese TK, Jr, et al. Surgeon specialty and long-term survival after pulmonary resection for lung cancer. Ann Thorac Surg. 2009;87:995-1004; discussion 05-6.

 Goodney PP, Lucas FL, Stukel TA, Birkmeyer JD. Surgeon specialty and operative mortality with lung resection. Ann Surg. 2005;241:179-84.

 Schipper PH, Diggs BS, Ungerleider RM, Welke KF. The influence of surgeon specialty on outcomes in general thoracic surgery: a national sample 1996 to 2005. Ann Thorac Surg. 2009;88:1566-72; discussion 72-3.

 Silvestri GA, Handy J, Lackland D, et al. Specialists achieve better outcomes than generalists for lung cancer surgery. Chest. 1998;114:675-80.

 Wood DE. What is most important in improving outcomes after pulmonary lobectomy: the surgeon or the approach? Eur J Cardiothorac Surg. 2013;43:817-9.

 American Cancer Society. What are the key statistics about lung cancer? Available from: 

http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-key-statistics

 Smith BD, Smith GL, Hurria A, et al. Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol. 2009;27:2758-65.

 Chang MY, Mentzer SJ, Colson YL, et al. Factors predicting poor survival after resection of stage IA non-small cell lung cancer. J Thorac Cardiovasc Surg. 2007;134:850-6.

 Okami J, Ito Y, Higashiyama M, et al. Sublobar resection provides an equivalent survival after lobectomy in elderly patients with early lung cancer. Ann Thorac Surg. 2010;90:1651-6.

 Mery CM, Pappas AN, Bueno R, et al. Similar long-term survival of elderly patients with non-small cell lung cancer treated with lobectomy or wedge resection within the surveillance, epidemiology, and end results database. Chest. 2005;128:237-45.

 Brokx HA, Visser O, Postmus PE, Paul MA. Surgical treatment for octogenarians with lung cancer: results from a population-based series of 124 patients. J Thorac Oncol. 2007;2:1013-7.

 Sawada S, Komori E, Nogami N, et al. Advanced age is not correlated with either short-term or long-term postoperative results in lung cancer patients in good clinical condition. Chest. 2005;128:1557-63.

 Cattaneo SM, Park BJ, Wilton AS, et al. Use of video-assisted thoracic surgery for lobectomy in the elderly results in fewer complications. Ann Thorac Surg. 2008;85:231-5; discussion 35-6.

 Mun M Kohno T. Video-assisted thoracic surgery for clinical stage I lung cancer in octogenarians. Ann Thorac Surg. 2008;85:406-11.

 Port JL, Mirza FM, Lee PC, et al. Lobectomy in octogenarians with non-small cell lung cancer: ramifications of increasing life expectancy and the benefits of minimally invasive surgery. Ann Thorac Surg. 2011;92:1951-7.

 Whitson BA, Groth SS, Andrade RS, et al. Survival after lobectomy versus segmentectomy for stage I non-small cell lung cancer: a population-based analysis. Ann Thorac Surg. 2011;92:1943-50.

 Koike T, Yamato Y, Yoshiya K, et al. Intentional limited pulmonary resection for peripheral T1 N0 M0 small-sized lung cancer. J Thorac Cardiovasc Surg. 2003;125:924-8.

 Martin-Ucar AE, Nakas A, Pilling JE, et al. A case-matched study of anatomical segmentectomy versus lobectomy for stage I lung cancer in high-risk patients. Eur J Cardiothorac Surg. 2005;27:675-9.

 Okada M, Koike T, Higashiyama M, et al. Radical sublobar resection for small-sized non-small cell lung cancer: a multicenter study. J Thorac Cardiovasc Surg. 2006;132:769-75.

 Shapiro M, Weiser TS, Wisnivesky JP, et al. Thoracoscopic segmentectomy compares favorably with thoracoscopic lobectomy for patients with small stage I lung cancer. J Thorac Cardiovasc Surg. 2009;137:1388-93.

 Kates M, Swanson S, Wisnivesky JP. Survival following lobectomy and limited resection for the treatment of stage I non-small cell lung cancer<=1 cm in size: a review of SEER data. Chest. 2011;139:491-6.

 Nakamura H, Taniguchi Y, Miwa K, et al. Comparison of the surgical outcomes of thoracoscopic lobectomy, segmentectomy, and wedge resection for clinical stage I non-small cell lung cancer. Thorac Cardiovasc Surg. 2011;59:137-41.

 Yamashita S, Chujo M, Kawano Y, et al. Clinical impact of segmentectomy compared with lobectomy under complete video-assisted thoracic surgery in the treatment of stage I non-small cell lung cancer. J Surg Res. 2011;166:46-51.

 Okada M, Nishio W, Sakamoto T, et al. Effect of tumor size on prognosis in patients with non-small cell lung cancer: the role of segmentectomy as a type of lesser resection. J Thorac Cardiovasc Surg. 2005;129:87-93.

 Altorki NK, Yip R, Hanaoka T, et al. Sublobar resection is equivalent to lobectomy for clinical stage 1A lung cancer in solid nodules. J Thorac Cardiovasc Surg. 2014;147:754-62; Discussion 62-4.

 Shiraishi T, Shirakusa T, Iwasaki A, et al. Video-assisted thoracoscopic surgery (VATS) segmentectomy for small peripheral lung cancer tumors: intermediate results. Surg Endosc. 2004;18:1657-62.

 Watanabe A, Ohori S, Nakashima S, et al. Feasibility of video-assisted thoracoscopic surgery segmentectomy for selected peripheral lung carcinomas. Eur J Cardiothorac Surg. 2009;35:775-80; discussion 80.

 Moroga T, Yamashita S, Tokuishi K, et al. Thoracoscopic segmentectomy with intraoperative evaluation of sentinel nodes for stage I non-small cell lung cancer. Ann Thorac Cardiovasc Surg. 2012;18:89-94.

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https://clinicaltrials.gov/ct2/show/NCT00499330

 Nakamura K, Saji H, Nakajima R, et al. A phase III randomized trial of lobectomy versus limited resection for small-sized peripheral non-small cell lung cancer (JCOG0802/WJOG4607L). Jpn J Clin Oncol. 2010;40:271-4.

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 Nakata M, Sawada S, Saeki H, et al. Prospective study of thoracoscopic limited resection for ground-glass opacity selected by computed tomography. Ann Thorac Surg. 2003;75:1601-5; discussion 05-6.

 Watanabe S, Watanabe T, Arai K, et al. Results of wedge resection for focal bronchioloalveolar carcinoma showing pure ground-glass attenuation on computed tomography. Ann Thorac Surg. 2002;73:1071-5.

 Yamada S, Kohno T. Video-assisted thoracic surgery for pure ground-glass opacities 2 cm or less in diameter. Ann Thorac Surg. 2004;77:1911-5.

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.

Minimally Invasive Resection of Early Lung Cancers 

In recent years, progress in the treatment of patients with cancer, especially those with advanced disease, has resulted in high treatment costs, with only marginal improvements in benefit. From a societal perspective, this cost is not sustainable.[1] Therefore, using economic data in treatment decision making is a growing field, with the promise of controlling costs without impacting quality of care. In countries with a national healthcare system, such as the United Kingdom, the cost-effectiveness of an intervention has to be within a given threshold for a drug to gain approval. This approach has not been adopted in the United States.

Another mechanism for containing cost is to limit the population of patients who are eligible for a given intervention, including drugs. The use of pharmacogenomic data to identify an eligible population is appealing, as this makes it possible to reduce the heterogeneity of patients and thus improve the effectiveness and/or reduce the side effects of a treatment.[2] However, many pharmacogenomic tests have substantial cost, and thus the question is whether the results of a test justify its cost.

In this issue of ONCOLOGY, Goldstein and colleagues review cost-effectiveness data for genomic testing in the management of colorectal cancer.[3] They review the role of assessment of host-related genes involved in drug metabolism, as well as the use of tumor signatures as potential markers for drug choice. Their review, although it is unique and timely, lacks information about the perspective from which these costs and effects are assessed. In other words, it is unclear whether the costs and effects are assessed from a payer, patient, or societal perspective. Identifying these perspectives is of the utmost importance, however, since depending on the perspective, interpretation of the results will be different. For example, if pharmacokinetic testing for fluorouracil (5-FU) is adopted in clinical practice, patients will need sampling at 3 and 7 hours after initiation of the 5-FU infusion; the cost of keeping patients for this period of time is significant to both the provider and the patient. This cost is not included in the modeling, and thus the final conclusion and the recommendation to adopt this approach in practice needs to be addressed.

Testing for uridine 5'-diphospho-glucuronosyltransferase 1A1 (

) and its clinical implications in the care of patients with colorectal cancer is controversial, and so are the cost-effectiveness analyses that have been performed for this test. We agree with the authors that testing for 

 should only be done when the results will affect clinical care and that cost-effectiveness data should not change the utilization of the test.

 is linked to treatment decision making, and testing for 

 (codons 12 and 13) has been shown to improve the cost-effectiveness of treatment with anti–epidermal growth factor receptor (EGFR) antibodies.[4,5] Therefore, widespread adoption of 

testing, with its ability to better select the population of patients who will benefit from treatment with anti-EGFR antibodies, as well as to avoid the detrimental effects of these agents in the 

-mutated population, will improve the value of treatment with anti-EGFR antibodies-from payer, patient, and societal perspectives.

Knowledge of microsatellite instability (MSI) status can not only guide treatment decisions in patients with stage II disease; it can also assist with providing recommendations for screening of first-degree relatives of patients with Lynch syndrome. Questions regarding the method by which MSI is tested and the population of patients who are eligible for testing are beyond the scope of this commentary. We agree with the authors that MSI testing for all patients who meet the Bethesda criteria is relevant and cost-effective.[6] Also, MSI testing for those with stage II disease who are candidates for chemotherapy is clinically relevant, although no published cost-effectiveness analysis exists in support of this recommendation.

Gene expression profiling for patients with stage II disease is a relatively new addition to the armamentarium of genomic tests for colorectal cancer. The Oncotype DX assay has been validated as a prognostic marker; however, its results are not predictive of benefit from adjuvant chemotherapy.[7-9] Therefore, use of the results of this nonpredictive test to guide treatment decisions can only be viewed as a mechanism to relieve the anxiety of the treating oncologist who recommends against chemotherapy, and cannot be the subject of a valid cost-effectiveness analysis from any perspective!

Use of next-generation sequencing (NGS) data in the clinic is growing, although issues such as the timing of testing, interpretation of the results, and access to treatment options when the results are available are currently unresolved and remain under investigation. Although we fully agree with Dr. Goldstein and colleagues that NGS in today’s environment is not cost-effective, from a societal perspective, we have to look at NGS as an investment in the future. The challenge is indexing the findings along with other clinical information for future mining. In exchange for Medicare payment for their tests, we might ask Foundation Medicine, Caris Life Sciences, and others to develop a database for storing the results of the test linked with tumor registry data, such as those of the Surveillance, Epidemiology and End Results program, for exploration in the future.

In the end, although genomic testing can improve the cost-effectiveness of a treatment, assessing the cost-effectiveness of genomic testing outside the context of its impact on treatment is not practical. Given the emergence of more efficient methods of genomic and genetic testing and the decline in the cost of performing these tests, they will be part of everyday treatment decisions in the near future-yet data for their impact on the cost-effectiveness of available treatments will lag behind their availability and use. For now, clinicians are tasked to use these tests wisely.

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article. 

 Smith TJ, Hillner BE. Bending the cost curve in cancer care. N Engl J Med. 2011;364:2060-5.

 Frank M, Mittendorf T. Influence of pharmacogenomic profiling prior to pharmaceutical treatment in metastatic colorectal cancer on cost effectiveness: a systematic review. Pharmacoeconomics. 2013;31:215-28.

 Goldstein DA, Shaib WL, Flowers CXR. Cost and effectiveness of genomic testing in the management of colorectal cancer. Oncology (Williston Park). 2015;29:175-83.

 Behl AS, Goddard KA, Flottemesch TJ, et al. Cost-effectiveness analysis of screening for KRAS and BRAF mutations in metastatic colorectal cancer. J Natl Cancer Inst. 2012;104:1785-95.

 Health Quality Ontario. KRAS testing for anti-EGFR therapy in advanced colorectal cancer: an evidence-based and economic analysis. Ont Health Technol Assess Ser. 2010;10:1-49.

 Barzi A, Sadeghi S, Kattan MW, Meropol NJ. Comparative effectiveness of screening strategies for Lynch syndrome. J Natl Cancer Inst. 2015. In press.

 Yothers G, O’Connell MJ, Lee M, et al. Validation of the 12-gene colon cancer recurrence score in NSABP C-07 as a predictor of recurrence in patients with stage II and III colon cancer treated with fluorouracil and leucovorin (FU/LV) and FU/LV plus oxaliplatin. J Clin Oncol. 2013;31:4512-9.

 Gray RG, Quirke P, Handley K, et al. Validation study of a quantitative multigene reverse transcriptase-polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer. J Clin Oncol. 2011;29:4611-9.

 Venook AP, Niedzwiecki D, Lopatin M, et al. Biologic determinants of tumor recurrence in stage II colon cancer: validation study of the 12-gene recurrence score in cancer and leukemia group B (CALGB) 9581. J Clin Oncol. 2013;31:1775-81.

Although genomic testing can improve the cost-effectiveness of a treatment, assessing the cost-effectiveness of genomic testing outside the context of its impact on treatment is not practical.

Cost-Effectiveness of Genomic Testing for Colorectal Cancer: Are We There Yet? 

Colorectal cancer has been extensively molecularly characterized in recent years. In addition to furthering the understanding of biologic hallmarks of the disease, the ultimate goal of these studies has been to provide tools that would allow us to identify subgroups of colorectal cancer with prognostic and predictive implications, either for the anticipation of toxicity or for selection of the best therapy, or both. As a result of these efforts, multiple genomic tests have become available for clinical use in early-stage and advanced colorectal cancer. Goldstein and colleagues have carefully reviewed the cost-effectiveness of these tests in this issue of ONCOLOGY[1]; their evaluation is timely, considering the widespread availability of high-throughput technologies for genomic profiling.

The authors recognize that the cost-effectiveness of a prognostic test can be easily measured only if it specifically guides treatment decisions. Given the lack of validated predictive biomarkers for benefit from adjuvant chemotherapy in early-stage colorectal cancer, clinicians are left with only prognostic tests that estimate risk of relapse to help them with treatment individualization. Because of the modest therapeutic benefit of fluorouracil (5-FU)-based treatment, prognostic biomarkers for its use have their greatest potential benefit in stage II disease, a setting in which they can facilitate the identification of subsets of patients with lower or higher risk of relapse and for whom adjuvant chemotherapy could be avoided or favored, respectively. Microsatellite instability (MSI), for example, has been consistently associated with low recurrence rates and a very good outcome without adjuvant treatment, supporting a no-adjuvant-treatment approach in patients with MSI tumors.

On the other hand, predictions of poor prognosis based on pathologic factors have not been consistently tied to benefit from adjuvant chemotherapy in stage II colorectal cancer,[2] raising concern about the real value of complex alternative tests such as prognostic gene expression signatures in this setting. These genomic signatures could have the greatest clinical utility as complements to analysis of T stage and MSI status, specifically for patients who have pT3 microsatellite stable (MSS) stage II disease. The Oncotype DX colon cancer gene expression array is the prognostic score that has been most widely validated, and despite a high score being an independent risk factor for recurrence in multivariable models, differences in outcomes for low-risk and high-risk patients are only modest from a clinical perspective. Cross-comparison of Oncotype DX scores with poor-risk clinical and pathologic factors, such as those recommended by the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), and European Society for Medical Oncology (ESMO) guidelines, has not been extensively conducted. Prospective empiric evidence is scarce, and the test does not influence the treatment decision in the majority of patients.[3] Furthermore, economic studies assessing the cost-effectiveness of these signatures for selecting patients with colorectal cancer at high risk for recurrence (and for basing adjuvant chemotherapy decision making on this criterion) are not yet available.

Focusing on advanced colorectal cancer, in which validated and clinically useful predictive markers are widely used to select anti–epidermal growth factor receptor (EGFR) therapy, the absence of specific sensitivity/resistance patterns for infrequent mutant alleles in 

 genes should not prevent clinicians from ordering extended 

 testing to help tailor therapy. There are a number of justifications for this approach. First, in some prospective randomized trials, a detrimental effect has been observed with the addition of anti-EGFR agents to chemotherapy in patients whose tumors harbor mutations in 

.[4-6] Second, following advances in next-generation sequencing, the development of targeted agents for use in treating colorectal cancer is moving from the “one test–one drug” paradigm to a genomically stratified model.[7] Early clinical trials have shown that targeted therapies matched against 

 mutations may offer promising treatment opportunities in colorectal cancer. Specifically for the 

 V600 population, studies have shown that treatment with selective BRAF inhibitors in combination with other targeted agents (EGFR, mitogen-activated protein/extracellular signal-regulated kinase [MEK], and/or phosphatidylinositol 4,5-bisphosphate 3-kinase [PI3K] inhibitors) can lead to unprecedented response rates in highly chemo-refractory patients.[8,9] In summary, given the potentially detrimental effects of anti-EGFR therapies and the benefit demonstrated in early clinical trials with novel agents, the cost-effectiveness of extended 

 mutation profiling needs to be reexamined.

The potential benefits of multiplexed genotyping platforms in individual patients with colorectal cancer have already been demonstrated, and the next logical step is to facilitate larger clinical trials with biomarker-driven therapies. However, there are many obstacles for implementation of next-generation sequencing in clinical practice:

o How to integrate and make biologic sense of the substantial amounts of genomic data?

• How to distinguish a driver from a passen- ger genetic aberration?

• How to deal with incidental findings?

• How to define which mutations engender sensitivity to specific targeted agents?

• How to select therapy in the case of multiple aberrations?

The identification and characterization of gene signatures, driver events, and pharmacogenomics in molecularly homogeneous subsets of patients is likely to advance effective drug development strategies in colorectal cancer.

Oncology Vol 29 No 3

The Era of Immuno-Oncology: Are We There Yet?

Shared Decision Making and Screening: An Ongoing Dialogue Informed by Data

Smaller Incisions for Smaller Cancers

Minimally Invasive Resection of Early Lung Cancers

Cost-Effectiveness of Genomic Testing for Colorectal Cancer: Are We There Yet?

Genomic Testing in Colorectal Cancer: How Much Is Enough?

Costs and Effectiveness of Genomic Testing in the Management of Colorectal Cancer

Novel Biologic Agents for Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia-Part 1: Monoclonal Antibodies

Renal Cancer Management in a Patient With Chronic Kidney Disease