Advertisement

Management of early-stage non-small cell lung cancer using stereotactic ablative radiotherapy: Controversies, insights, and changing horizons

Published:December 10, 2014DOI:https://doi.org/10.1016/j.radonc.2014.11.036

      Abstract

      The use of stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer is growing rapidly, particularly since it has become the recommended therapy for unfit patients in current European and North American guidelines. As three randomized trials comparing surgery and SABR closed prematurely because of poor accrual, clinicians are faced with a dilemma in individual patient decision-making. Radiation oncologists, in particular, should be aware of the data from comparative effectiveness studies that suggest similar survival outcomes irrespective of local treatment modality. The necessity of obtaining a pathological diagnosis, particularly in frail patients prior to treatment remains a challenge, and this topic was addressed in recent European recommendations. Awareness of the high incidence of a second primary lung cancer in survivors, as well as other competing causes of mortality, is needed. The challenges in distinguishing focal scarring from recurrence after SABR also need to be appreciated by multidisciplinary tumor boards. With a shift in focus toward patient-centered decision-making, clinicians will need to be aware of these new developments and communicate effectively with patients, to ensure that treatment decisions are reflective of patient preferences. Priorities for additional research in the area are proposed.

      Keywords

      Lung cancer is a leading cause of cancer-related death worldwide [
      • Siegel R.
      • Ma J.
      • Zou Z.
      • Jemal A.
      Cancer statistics, 2014.
      ,
      • Malvezzi M.
      • Bertuccio P.
      • Levi F.
      • La Vecchia C.
      • Negri E.
      European cancer mortality predictions for the year 2014.
      ], and incident cases are expected to rise in the near future owing to an aging population [
      • Smith B.D.
      • Smith G.L.
      • Hurria A.
      • Hortobagyi G.N.
      • Buchholz T.A.
      Future of cancer incidence in the United States: burdens upon an aging, changing nation.
      ]. Although the majority of patients present with locally advanced or metastatic disease, the incidence of early-stage non-small cell lung cancer (ES-NSCLC) is expected to increase, due to a wider use of thoracic CT scans in general medical practice [
      • Fazel R.
      • Krumholz H.M.
      • Wang Y.
      • Ross J.S.
      • Chen J.
      • Ting H.H.
      • et al.
      Exposure to low-dose ionizing radiation from medical imaging procedures.
      ,
      • Berdahl C.T.
      • Vermeulen M.J.
      • Larson D.B.
      • Schull M.J.
      Emergency department computed tomography utilization in the United States and Canada.
      ], along with the implementation of formal CT screening, which has been shown to lead to earlier detection of early-stage cancers [
      • Aberle D.R.
      • DeMello S.
      • Berg C.D.
      • Black W.C.
      • Brewer B.
      • Church T.R.
      • et al.
      Results of the two incidence screenings in the National Lung Screening Trial.
      ,
      • Aberle D.R.
      • Adams A.M.
      • Berg C.D.
      • Black W.C.
      • Clapp J.D.
      • et al.
      National Lung Screening Trial Research T
      Reduced lung-cancer mortality with low-dose computed tomographic screening.
      ]. Although surgery is currently considered the standard of care for ES-NSCLC, elderly patients (i.e., ⩾65 years) commonly present with multiple comorbidities [
      • Janssen-Heijnen M.L.
      • Maas H.A.
      • Houterman S.
      • Lemmens V.E.
      • Rutten H.J.
      • Coebergh J.W.
      Comorbidity in older surgical cancer patients: influence on patient care and outcome.
      ]. The willingness to operate on such patients is variable [
      • Rogers Jr, S.O.
      • Gray S.W.
      • Landrum M.B.
      • Klabunde C.N.
      • Kahn K.L.
      • Fletcher R.H.
      • et al.
      Variations in surgeon treatment recommendations for lobectomy in early-stage non-small-cell lung cancer by patient age and comorbidity.
      ], largely due to higher risks of morbidity and mortality [
      • Senthi S.
      • Senan S.
      Surgery for early-stage lung cancer: post-operative 30-day versus 90-day mortality and patient-centred care.
      ,
      • Haasbeek C.J.
      • Palma D.
      • Visser O.
      • Lagerwaard F.J.
      • Slotman B.
      • Senan S.
      Early-stage lung cancer in elderly patients: a population-based study of changes in treatment patterns and survival in The Netherlands.
      ]. Elderly patients with ES-NSCLC pose a particular epidemiologic and public health challenge as they are both less likely to receive guideline recommended treatments [
      • Wang S.
      • Wong M.L.
      • Hamilton N.
      • Davoren J.B.
      • Jahan T.M.
      • Walter L.C.
      Impact of age and comorbidity on non-small-cell lung cancer treatment in older veterans.
      ], and less likely to participate in, or to be eligible for, clinical trials [
      • Hutchins L.F.
      • Unger J.M.
      • Crowley J.J.
      • Coltman Jr, C.A.
      • Albain K.S.
      Underrepresentation of patients 65 years of age or older in cancer-treatment trials.
      ].
      Historically, elderly patients were often not treated (Fig. 1). There are several reasons for this, including the fact that conventionally fractionated radiotherapy delivered using techniques available prior to 2000, was considered to offer marginal gains with the inconvenience of daily treatment over several weeks [
      • Rowell N.P.
      • Williams C.J.
      Radical radiotherapy for stage I/II non-small cell lung cancer in patients not sufficiently fit for or declining surgery (medically inoperable): a systematic review.
      ]. Conversely, stereotactic ablative radiotherapy (SABR), which is defined as the accurate and precise delivery of high doses of radiation over a few treatment fractions, is less cumbersome for patients and is associated with excellent local control [
      • Palma D.A.
      • Senan S.
      Improving outcomes for high-risk patients with early-stage non-small-cell lung cancer: insights from population-based data and the role of stereotactic ablative radiotherapy.
      ]. Radiation doses that are biologically equivalent to 100 Gy10 or more are required in lung SABR to achieve high local control rates [
      • Onishi H.
      • Shirato H.
      • Nagata Y.
      • Hiraoka M.
      • Fujino M.
      • Gomi K.
      • et al.
      Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi-institutional study.
      ,
      • Olsen J.R.
      • Robinson C.G.
      • El Naqa I.
      • Creach K.M.
      • Drzymala R.E.
      • Bloch C.
      • et al.
      Dose-response for stereotactic body radiotherapy in early-stage non-small-cell lung cancer.
      ]. These doses are in excess of what is practical using conventionally fractionated treatment schemes with standard techniques. Currently, the optimal SABR dose is unknown, although a meta-analysis suggests that highest (>146 Gy10) BED fractionations may have lower OS than medium–high (106–146 Gy10) fractionations [
      • Zhang J.
      • Yang F.
      • Li B.
      • Li H.
      • Liu J.
      • Huang W.
      • et al.
      Which is the optimal biologically effective dose of stereotactic body radiotherapy for stage I non-small-cell lung cancer? A meta-analysis.
      ]. In population studies, the increasing use of SABR for ES-NSCLC is associated with an overall survival benefit when compared to no treatment or conventional radiotherapy [
      • Haasbeek C.J.
      • Palma D.
      • Visser O.
      • Lagerwaard F.J.
      • Slotman B.
      • Senan S.
      Early-stage lung cancer in elderly patients: a population-based study of changes in treatment patterns and survival in The Netherlands.
      ,
      • Palma D.
      • Visser O.
      • Lagerwaard F.J.
      • Belderbos J.
      • Slotman B.J.
      • Senan S.
      Impact of introducing stereotactic lung radiotherapy for elderly patients with stage I non-small-cell lung cancer: a population-based time-trend analysis.
      ]. The growing use of SABR for thoracic malignancies worldwide is reflected by patterns of care studies from Europe [
      • Guckenberger M.
      • Allgauer M.
      • Appold S.
      • Dieckmann K.
      • Ernst I.
      • Ganswindt U.
      • et al.
      Safety and efficacy of stereotactic body radiotherapy for stage I non-small-cell lung cancer in routine clinical practice: a patterns-of-care and outcome analysis.
      ,
      • Ricardi U.
      • Frezza G.
      • Filippi A.R.
      • Badellino S.
      • Levis M.
      • Navarria P.
      • et al.
      Stereotactic ablative radiotherapy for stage I histologically proven non-small cell lung cancer: an Italian multicenter observational study.
      ], North America [
      • Lund C.R.
      • Cao J.Q.
      • Liu M.
      • Olson R.
      • Halperin R.
      • Schellenberg D.
      The distribution and patterns of practice of stereotactic ablative body radiotherapy in Canada.
      ,
      • Pan H.
      • Rose B.S.
      • Simpson D.R.
      • Mell L.K.
      • Mundt A.J.
      • Lawson J.D.
      Clinical practice patterns of lung stereotactic body radiation therapy in the United States: a secondary analysis.
      ,
      • Pan H.
      • Simpson D.R.
      • Mell L.K.
      • Mundt A.J.
      • Lawson J.D.
      A survey of stereotactic body radiotherapy use in the United States.
      ], and Asia [
      • Nagata Y.
      • Hiraoka M.
      • Mizowaki T.
      • Narita Y.
      • Matsuo Y.
      • Norihisa Y.
      • et al.
      Survey of stereotactic body radiation therapy in Japan by the Japan 3-D Conformal External Beam Radiotherapy Group.
      ].
      Figure thumbnail gr1
      Fig. 1Depiction of population trends of decreased surgical utilization, and increased proportion of untreated patients, with increasing age. The median overall survival of untreated patients in these studies ranged from 6.6 to approximately 12 months [
      • Haasbeek C.J.
      • Palma D.
      • Visser O.
      • Lagerwaard F.J.
      • Slotman B.
      • Senan S.
      Early-stage lung cancer in elderly patients: a population-based study of changes in treatment patterns and survival in The Netherlands.
      ,
      • Raz D.J.
      • Zell J.A.
      • Ou S.H.
      • Gandara D.R.
      • Anton-Culver H.
      • Jablons D.M.
      Natural history of stage I non-small cell lung cancer: implications for early detection.
      ,
      • Shirvani S.M.
      • Jiang J.
      • Chang J.Y.
      • Welsh J.W.
      • Gomez D.R.
      • Swisher S.
      • et al.
      Comparative effectiveness of 5 treatment strategies for early-stage non-small cell lung cancer in the elderly.
      ,
      • Varlotto J.
      • Fakiris A.
      • Flickinger J.
      • Medford-Davis L.
      • Liss A.
      • Shelkey J.
      • et al.
      Matched-pair and propensity score comparisons of outcomes of patients with clinical stage I non-small cell lung cancer treated with resection or stereotactic radiosurgery.
      ].
      In this review, we will discuss evolving trends in patient selection/outcomes, challenges faced in diagnostic management, the importance of quality assurance, and the challenges facing survivors following this treatment modality.

      Optimizing patient selection and outcomes

      Comparative effectiveness research (CER)

      CER refers to the generation of evidence that compares the benefits and harms of interventions designed to address the prevention, diagnosis, treatment or follow-up of a clinical condition [
      • Sox H.C.
      • Greenfield S.
      Comparative effectiveness research: a report from the Institute of Medicine.
      ]. CER assists all healthcare stakeholders in healthcare in making informed decisions to improve outcomes at the individual and population levels. The contrasting merits between randomized control trials (RCTs), the gold standard in CER, and observational studies have recently been highlighted as they pertain to specific challenges in oncology such as rising costs and rapidly evolving technology [
      • Booth C.M.
      • Tannock I.F.
      Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence.
      ,
      • Concato J.
      Is it time for medicine-based evidence?.
      ]. The challenges of performing RCTs, even when there is a good clinical question, have been clearly illustrated in lung SABR. Three phase III RCTs (ROSEL, STARS, RTOG 1021) comparing SABR with either lobectomy or sublobar resection were launched between 2008 and 2011, but all 3 failed to accrue [
      • Moghanaki D.
      • Karas T.
      Surgery versus SABR for NSCLC.
      ]. Nonetheless, development of their protocols provided the radiation oncology community with valuable standards in quality-assurance and credentialing for the broader implementation of lung SABR [
      • Guckenberger M.
      Stereotactic body radiotherapy for stage I NSCLC: the challenge of evidence-based medicine.
      ].
      In the absence of RCT data, other forms of CER are crucial in guiding decision making [
      • Louie A.V.
      • Senthi S.
      • Palma D.A.
      Surgery versus SABR for NSCLC.
      ]. Table 1 summarizes relevant CER studies using propensity-score matching, match-pair analysis, Markov modeling, cost-effectiveness and meta-analytic methodologies. In general, the main conclusion from the CER studies is that there is clinical equipoise when comparing SABR and surgery, especially in the face of competing risks of death associated with advanced age and increased comorbidities. It is important to note that studies employing matching technique designs are, by definition, unable to entirely eliminate measured confounders, and potential imbalances can exist due to unmeasured factors [
      • Bosco J.L.
      • Silliman R.A.
      • Thwin S.S.
      • Geiger A.M.
      • Buist D.S.
      • Prout M.N.
      • et al.
      A most stubborn bias: no adjustment method fully resolves confounding by indication in observational studies.
      ].
      Table 1CER studies comparing surgery versus SABR in stage I NSCLC.
      StudyStudy designNumber of patientsSurgical procedureOverall survivalConclusions/comments
      SurgerySABR
      Crabtree
      • Crabtree T.D.
      • Puri V.
      • Robinson C.
      • Bradley J.
      • Broderick S.
      • Patterson G.A.
      • et al.
      Analysis of first recurrence and survival in patients with stage I non-small cell lung cancer treated with surgical resection or stereotactic radiation therapy.
      Propensity-score matchingUnmatched: surgery = 458, SABR = 151

      matched: 112/group
      (Bi) lobectomy, 78% sublobar, 19%

      pneumonectomy, 4%
      78%, 3 yrs47%, 3 yrsAlthough surgical resection seems to result in better OS versus SABR, matching these patients remains challenging
      68%, 3 yrs52%, 3 yrs
      Matsuo
      • Matsuo Y.
      • Chen F.
      • Hamaji M.
      • Kawaguchi A.
      • Ueki N.
      • Nagata Y.
      • et al.
      Comparison of long-term survival outcomes between stereotactic body radiotherapy and sublobar resection for stage I non-small-cell lung cancer in patients at high risk for lobectomy: a propensity score matching analysis.
      Propensity-score matchingUnmatched: surgery = 65, SABR = 115

      matched: 53/group
      Sublobar resection56%, 5 yrs40%, 5 yrsSABR is an alternative to sublobar resection in high-risk patients who cannot tolerate lobectomy due to comorbidities
      Shirvani
      • Shirvani S.M.
      • Jiang J.
      • Chang J.Y.
      • Welsh J.
      • Likhacheva A.
      • Buchholz T.A.
      • et al.
      Lobectomy, sublobar resection, and stereotactic ablative radiotherapy for early-stage non-small cell lung cancers in the elderly.
      SEER population, propensity-score matchingUnmatched: surgery = 8711, SABR = 382

      matched: 251/group
      Lobectomy, 83%

      sublobar, 17%
      Lobectomy vs. SABR, HR 1.01 (SA: 1.16–1.28)Lobectomy is preferred for older adults fit for surgery. SABR is promising as it offers a lower risk of periprocedural death
      Solda
      • Solda F.
      • Lodge M.
      • Ashley S.
      • Whitington A.
      • Goldstraw P.
      • Brada M.
      Stereotactic radiotherapy (SABR) for the treatment of primary non-small cell lung cancer; Systematic review and comparison with a surgical cohort.
      Systematic reviewWeighted average of surgical patients from IASLC database vs. reviewed SABR studies68%, 2 yrs70%, 2 yrsResults favor direct comparison of surgery and SABR for operable localized NSCLC
      Varlotto
      • Varlotto J.
      • Fakiris A.
      • Flickinger J.
      • Medford-Davis L.
      • Liss A.
      • Shelkey J.
      • et al.
      Matched-pair and propensity score comparisons of outcomes of patients with clinical stage I non-small cell lung cancer treated with resection or stereotactic radiosurgery.
      Match-pair and propensity scoringUnmatched: surgery = 180, SABR = 137

      matched: 89/group
      Lobectomy, 73%

      wedge, 27%
      69%, 3 yrs

      86%, 3 yrs
      41%, 3 yrs

      42%, 3 yrs
      On manual matching, wedge and lobectomy had significantly improved OS over SABR, differences disappeared when adjusting for propensity score
      Verstegen
      • Verstegen N.E.
      • Oosterhuis J.W.
      • Palma D.A.
      • Rodrigues G.
      • Lagerwaard F.J.
      • van der Elst A.
      • et al.
      Stage I-II non-small-cell lung cancer treated using either stereotactic ablative radiotherapy (SABR) or lobectomy by video-assisted thoracoscopic surgery (VATS): outcomes of a propensity score-matched analysis.
      Propensity-score matchingUnmatched: 86 surgery, 527 SABR

      matched: 64/group
      VATS lobectomy77%, 3 yrs80%, 3 yrsNo significant difference in OS supports the need to compare the two treatments in a randomized control trial
      Grills
      • Grills I.S.
      • Mangona V.S.
      • Welsh R.
      • Chmielewski G.
      • McInerney E.
      • Martin S.
      • et al.
      Outcomes after stereotactic lung radiotherapy or wedge resection for stage I non-small-cell lung cancer.
      RetrospectiveSurgery = 69

      SABR = 55
      Wedge resection87%, 30 m72%, 30 mOS was improved after surgery. SABR patients tended to be older with more comorbidities
      Louie
      • Louie A.V.
      • Rodrigues G.
      • Hannouf M.
      • Zaric G.S.
      • Palma D.A.
      • Cao J.Q.
      • et al.
      Stereotactic body radiotherapy versus surgery for medically operable stage I non-small-cell lung cancer: a Markov model-based decision analysis.
      Markov modelLobectomy and SABR outcomes modeled from various sourcesAt 5 yrs, surgery 2–3% benefit in OSLarge patient numbers would be required to detect small differences in OS
      Shah
      • Shah A.
      • Hahn S.M.
      • Stetson R.L.
      • Friedberg J.S.
      • Pechet T.T.
      • Sher D.J.
      Cost-effectiveness of stereotactic body radiation therapy versus surgical resection for stage I non-small cell lung cancer.
      Markov modelLobectomy, wedge resection and SABR outcomes modeled from various sourcesNot reported, model validated based on recurrence patternsSABR is the dominant strategy compared to wedge resection. In patients eligible for lobectomy, surgery is most cost-effective
      Zheng
      • Zheng X.
      • Schipper M.
      • Kidwell K.
      • Lin J.
      • Reddy R.
      • Ren Y.
      • et al.
      Survival outcome after stereotactic body radiation therapy and surgery for stage I non-small cell lung cancer: a meta-analysis.
      Meta-analysisForty SABR studies (n = 4850) and 23 surgery studies (n = 7071)∼80%, 3 yrs57%, 3 yrsWhen adjusting for potential operability in SABR patients, no difference found in OS
      yrs = year, m = months, OS = overall survival, SA = sensitivity analyses.
      Despite the challenges faced by RCTs comparing SABR and other modalities for ES-NSCLC, randomized comparisons have been possible in some cases. For example, the stereotactic precision and conventional radiotherapy evaluation (SPACE) trial randomized 102 ES-NSCLC patients to either SABR (66 Gy in 3 fractions at the isocenter and 45 Gy at the periphery, over 1 week) versus conventional radiotherapy (relatively homogeneous 70 Gy in 35 fractions over 7 weeks) [
      • Nyman J.
      • Hallqvist A.
      • Lund J.A.
      • Brustugun O.T.
      • Bergström P.
      • Friesland S.
      • et al.
      SPACE – a randomized study of SBRT vs conventional fractionated radiotherapy in medically inoperable stage I NSCLC.
      ]. The use of larger margins around the target (20 mm versus 5–10 mm) was required in the conventional arm. The results have been presented only in abstract form with limited follow-up, however, local control did not differ between the two modalities. The conventional treatment was associated with a higher risk of grade 1–2 toxicity (increased rates of esophagitis and pneumonitis). SPACE suggests that although high rates of local control may be achieved with long courses of conventional RT, the therapeutic ratio is better with SABR when compared with conventional radiotherapy using large margins. Accrual to a similarly designed RCT (CHISEL, Clinicaltrials.gov, NCT01014130) is ongoing; however, unlike SPACE, CHISEL employs smaller margins and cone beam CT setup in the conventional RT arm.
      In view of the rising healthcare costs, economic evaluations of SABR in lung cancer deserve mention [
      • Rosenblatt E.
      • Izewska J.
      • Anacak Y.
      • Pynda Y.
      • Scalliet P.
      • Boniol M.
      • et al.
      Radiotherapy capacity in European countries: an analysis of the Directory of Radiotherapy Centres (DIRAC) database.
      ,
      • van Loon J.
      • Grutters J.
      • Macbeth F.
      Evaluation of novel radiotherapy technologies: what evidence is needed to assess their clinical and cost effectiveness, and how should we get it?.
      ,
      • Lievens Y.
      • Grau C.
      Health economics in radiation oncology: introducing the ESTRO HERO project.
      ]. Cost-effectiveness analyses (CEA) have consistently demonstrated that while lobectomy appears to be preferred over SABR for operable ES-NSCLC, SABR is cost-effective when compared to sublobar resection [
      • Shah A.
      • Hahn S.M.
      • Stetson R.L.
      • Friedberg J.S.
      • Pechet T.T.
      • Sher D.J.
      Cost-effectiveness of stereotactic body radiation therapy versus surgical resection for stage I non-small cell lung cancer.
      ,
      • Puri V.
      • Crabtree T.D.
      • Kymes S.
      • Gregory M.
      • Bell J.
      • Bradley J.D.
      • et al.
      A comparison of surgical intervention and stereotactic body radiation therapy for stage I lung cancer in high-risk patients: a decision analysis.
      ,
      • Louie A.V.
      • Rodrigues G.B.
      • Palma D.A.
      • Senan S.
      Measuring the population impact of introducing stereotactic ablative radiotherapy for stage I non-small cell lung cancer in Canada.
      ]. For medically inoperable patients, SABR dominates (less costly, improved survival) conventional radiotherapy, a finding that is generalizable to different healthcare payer models [
      • Louie A.V.
      • Rodrigues G.B.
      • Palma D.A.
      • Senan S.
      Measuring the population impact of introducing stereotactic ablative radiotherapy for stage I non-small cell lung cancer in Canada.
      ,
      • Mitera G.
      • Swaminath A.
      • Rudoler D.
      • Seereeram C.
      • Giuliani M.
      • Leighl N.
      • et al.
      Cost-effectiveness analysis comparing conventional versus stereotactic body radiotherapy for surgically ineligible stage I non-small-cell lung cancer.
      ,
      • Sher D.J.
      • Wee J.O.
      • Punglia R.S.
      Cost-effectiveness analysis of stereotactic body radiotherapy and radiofrequency ablation for medically inoperable, early-stage non-small cell lung cancer.
      ,
      • Lanni Jr, T.B.
      • Grills I.S.
      • Kestin L.L.
      • Robertson J.M.
      Stereotactic radiotherapy reduces treatment cost while improving overall survival and local control over standard fractionated radiation therapy for medically inoperable non-small-cell lung cancer.
      ].

      Developments in surgery

      In recent years, much attention has been paid toward reducing the toxicity of surgery in ES-NSCLC, and recent prospective RCTs such as the ACOSOG Z0030 [
      • Darling G.E.
      • Allen M.S.
      • Decker P.A.
      • Ballman K.
      • Malthaner R.A.
      • Inculet R.I.
      • et al.
      Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma: results of the American College of Surgery Oncology Group Z0030 Trial.
      ] and Z0032 [
      • Fernando H.C.
      • Landreneau R.J.
      • Mandrekar S.J.
      • Nichols F.C.
      • Hillman S.L.
      • Heron D.E.
      • et al.
      Impact of brachytherapy on local recurrence rates after sublobar resection: results from ACOSOG Z4032 (alliance), a phase III randomized trial for high-risk operable non-small-cell lung cancer.
      ] report low mortality rates. However, the vast majority of patients are treated outside of trials, where survival is likely to be poorer, and results from specialized surgical databases may not be generalizable to broad clinical practice [
      • Palma D.A.
      • Senan S.
      Improving outcomes for high-risk patients with early-stage non-small-cell lung cancer: insights from population-based data and the role of stereotactic ablative radiotherapy.
      ,
      • LaPar D.J.
      • Bhamidipati C.M.
      • Lau C.L.
      • Jones D.R.
      • Kozower B.D.
      The Society of Thoracic Surgeons General Thoracic Surgery Database: establishing generalizability to national lung cancer resection outcomes.
      ]. For example, a recent SEER-Medicare analysis revealed a national rate of in-hospital postoperative complications exceeding 50% among patients older than 65 years, with a 30-day mortality of 4.2% [
      • Rueth N.M.
      • Parsons H.M.
      • Habermann E.B.
      • Groth S.S.
      • Virnig B.A.
      • Tuttle T.M.
      • et al.
      Surgical treatment of lung cancer: predicting postoperative morbidity in the elderly population.
      ]. Both the 30-day and 90-day mortality were lower at teaching hospitals, with 90-day mortality being 5.4% (teaching) versus 7.8% (non-teaching) (p = 0.001).
      Lobectomy is considered the current treatment of choice in patients with adequate lung function [
      • Vansteenkiste J.
      • De Ruysscher D.
      • Eberhardt W.E.
      • Lim E.
      • Senan S.
      • Felip E.
      • et al.
      Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ]. More limited resections, such as a segmentectomy (i.e., macroscopic removal of the tumor with the division of vessels and bronchi within an anatomical segment) and wedge resection, may be associated with increased local recurrences for tumors measuring more than 2 cm. The optimal surgical techniques for lesions measuring 2 cm or smaller, are the subject of ongoing RCTs. The use of video-assisted thoracoscopic surgery (VATS) is increasing, but the available RCTs have not been sufficiently powered to detect important differences between the thoracoscopic and open techniques in either overall or disease-free survival [
      • Vansteenkiste J.
      • De Ruysscher D.
      • Eberhardt W.E.
      • Lim E.
      • Senan S.
      • Felip E.
      • et al.
      Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ]. This is despite the fact that fewer hilar and mediastinal lymph nodes are generally sampled during a VATS procedure, than with open thoracotomy [
      • Boffa D.J.
      • Kosinski A.S.
      • Paul S.
      • Mitchell J.D.
      • Onaitis M.
      Lymph node evaluation by open or video-assisted approaches in 11,500 anatomic lung cancer resections.
      ,
      • Licht P.B.
      • Jorgensen O.D.
      • Ladegaard L.
      • Jakobsen E.
      A national study of nodal upstaging after thoracoscopic versus open lobectomy for clinical stage I lung cancer.
      ].
      Proponents of surgery, even for patients with ES-NSCLC who are at high risk for surgery, have strongly argued that the improved diagnosis of occult nodal disease, and subsequent administration of chemotherapy to such patients, will lead to survival benefits [
      • Osarogiagbon R.U.
      • Yu X.
      Nonexamination of lymph nodes and survival after resection of non-small cell lung cancer.
      ]. However, even in patients who fulfilled the criteria of being at high risk and who were treated in the ACOSOG Z0032 trial, 31% underwent no nodal evaluation [
      • Kent M.
      • Landreneau R.
      • Mandrekar S.
      • Hillman S.
      • Nichols F.
      • Jones D.
      • et al.
      Segmentectomy versus wedge resection for non-small cell lung cancer in high-risk operable patients.
      ]. In tumors detected by a CT-screening program, all of which were treated by general thoracic surgeons at specialized centers, a mediastinal nodal resection was performed in only 55% of patients who underwent a sublobar resection [
      • Altorki N.K.
      • Yip R.
      • Hanaoka T.
      • Bauer T.
      • Aye R.
      • Kohman L.
      • et al.
      Sublobar resection is equivalent to lobectomy for clinical stage 1A lung cancer in solid nodules.
      ]. The fact that differences in nodal harvesting do not influence survival in this study, as well as population studies [
      • Licht P.B.
      • Jorgensen O.D.
      • Ladegaard L.
      • Jakobsen E.
      A national study of nodal upstaging after thoracoscopic versus open lobectomy for clinical stage I lung cancer.
      ], suggests that the purported benefits of a surgical procedure should be scrutinized carefully, particularly in view of the competing non-cancer causes of mortality in those who underwent a sublobar resection in the I-ELCAP study. Similarly, more than half of all high-risk patients with ES-NSCLC who were treated in ACOSOG Z0032 had intercurrent deaths due to non-cancer causes [
      • Fernando H.C.
      • Landreneau R.J.
      • Mandrekar S.J.
      • Nichols F.C.
      • Hillman S.L.
      • Heron D.E.
      • et al.
      Impact of brachytherapy on local recurrence rates after sublobar resection: results from ACOSOG Z4032 (alliance), a phase III randomized trial for high-risk operable non-small-cell lung cancer.
      ].
      The majority of RCTs, including the largest (ACOSOG Z0030) that addressed this issue, have failed to demonstrate a survival benefit of a mediastinal lymph node dissection (MLND) as opposed to nodal sampling [
      • Darling G.E.
      • Allen M.S.
      • Decker P.A.
      • Ballman K.
      • Malthaner R.A.
      • Inculet R.I.
      • et al.
      Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma: results of the American College of Surgery Oncology Group Z0030 Trial.
      ]. Fig. 2 provides a schematic on the relative merits of the number needed to treat (NNT) and number needed to harm (NNH) when considering the potential advantage of surgery to provide information that can be used to guide decision-making on adjuvant systemic therapy. This calculation exercise is based on the assumption that approximately 15% of clinical ES-NSCLC patients are upstaged with nodal disease at the time of surgery, despite negative pre-operative mediastinal staging [
      • Boffa D.J.
      • Kosinski A.S.
      • Paul S.
      • Mitchell J.D.
      • Onaitis M.
      Lymph node evaluation by open or video-assisted approaches in 11,500 anatomic lung cancer resections.
      ,
      • Licht P.B.
      • Jorgensen O.D.
      • Ladegaard L.
      • Jakobsen E.
      A national study of nodal upstaging after thoracoscopic versus open lobectomy for clinical stage I lung cancer.
      ], an estimate that may need to be reconsidered when more data are forthcoming from the use of minimally invasive modalities to stage the mediastinum such as endobronchial and endoscopic ultrasound needle aspirations (EBUS and EUS, respectively) in SABR patients [
      • Su S.
      • Scott W.J.
      • Allen M.S.
      • Darling G.E.
      • Decker P.A.
      • McKenna R.J.
      • et al.
      Patterns of survival and recurrence after surgical treatment of early stage non-small cell lung carcinoma in the ACOSOG Z0030 (ALLIANCE) trial.
      ]. As the ultimate survival impact of improved staging for NSCLC patients eligible for SABR is unknown, clinical trials evaluating the use of pre-treatment EBUS and EUS are underway (Clinicaltrials.gov, NCT01786590).
      Figure thumbnail gr2
      Fig. 2Schematic demonstrating the number needed to treat (NNT) when considering surgery to guide adjuvant chemotherapy decision-making for stage I NSCLC at 5 years [
      • Boffa D.J.
      • Kosinski A.S.
      • Paul S.
      • Mitchell J.D.
      • Onaitis M.
      Lymph node evaluation by open or video-assisted approaches in 11,500 anatomic lung cancer resections.
      ,
      • Licht P.B.
      • Jorgensen O.D.
      • Ladegaard L.
      • Jakobsen E.
      A national study of nodal upstaging after thoracoscopic versus open lobectomy for clinical stage I lung cancer.
      ,
      • Felip E.
      • Rosell R.
      • Maestre J.A.
      • Rodriguez-Paniagua J.M.
      • Moran T.
      • Astudillo J.
      • et al.
      Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-small-cell lung cancer.
      ,
      • Pignon J.P.
      • Tribodet H.
      • Scagliotti G.V.
      • Douillard J.Y.
      • Shepherd F.A.
      • Stephens R.J.
      • et al.
      Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group.
      ]. Conversely, number needed to harm (NNH) when considering a post-operative mortality rate of at least 1%, is 100 or less
      [
      • Senthi S.
      • Senan S.
      Surgery for early-stage lung cancer: post-operative 30-day versus 90-day mortality and patient-centred care.
      ]
      .

      Who benefits from adjuvant systemic therapy?

      The rates and patterns of failure following SABR for ES-NSCLC have been reported to be broadly similar to those after surgery, with the predominant pattern being distant metastases in approximately 20% of cases [
      • Robinson C.G.
      • DeWees T.A.
      • El Naqa I.M.
      • Creach K.M.
      • Olsen J.R.
      • Crabtree T.D.
      • et al.
      Patterns of failure after stereotactic body radiation therapy or lobar resection for clinical stage I non-small-cell lung cancer.
      ,
      • Senthi S.
      • Lagerwaard F.J.
      • Haasbeek C.J.
      • Slotman B.J.
      • Senan S.
      Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: a retrospective analysis.
      ]. To help guide the identification of patients who may benefit from systemic therapy after SABR, models have been developed to predict for systemic disease, with a higher pretreatment FDG-PET maximum standardized uptake value (SUVmax) and larger tumor size (T2) often cited [
      • Nair V.J.
      • MacRae R.
      • Sirisegaram A.
      • Pantarotto J.R.
      Pretreatment [18F]-fluoro-2-deoxy-glucose positron emission tomography maximum standardized uptake value as predictor of distant metastasis in early-stage non-small cell lung cancer treated with definitive radiation therapy: rethinking the role of positron emission tomography in personalizing treatment based on risk status.
      ,
      • Takeda A.
      • Sanuki N.
      • Fujii H.
      • Yokosuka N.
      • Nishimura S.
      • Aoki Y.
      • et al.
      Maximum standardized uptake value on FDG-PET is a strong predictor of overall and disease-free survival for non-small-cell lung cancer patients after stereotactic body radiotherapy.
      ,
      • Allibhai Z.
      • Taremi M.
      • Bezjak A.
      • Brade A.
      • Hope A.J.
      • Sun A.
      • et al.
      The impact of tumor size on outcomes after stereotactic body radiation therapy for medically inoperable early-stage non-small cell lung cancer.
      ]. In one such model, image-based biomarkers were studied in 117 patients with ES-NSCLC, and it was postulated that tumor size, contact with the mediastinal pleura, and SUVmax could be used to construct a prognostic index for patients at highest risk for developing metastases [
      • Shultz D.B.
      • Trakul N.
      • Abelson J.A.
      • Murphy J.D.
      • Maxim P.G.
      • Le Q.T.
      • et al.
      Imaging features associated with disease progression after stereotactic ablative radiotherapy for stage I non-small-cell lung cancer.
      ]. For patients with distant failure, biomarker targets such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangement have paved the way for tyrosine kinase inhibitors (e.g., gefitinib/erlotinib, and crizotinib, respectively) as first line treatments in the metastatic setting [
      • Eakin E.G.
      • Resnikoff P.M.
      • Prewitt L.M.
      • Ries A.L.
      • Kaplan R.M.
      Validation of a new dyspnea measure: the UCSD Shortness of breath questionnaire. University of California, San Diego.
      ]. Currently, the role of targeted agents following SABR for ES-NSCLC is unclear. It has been reported that caution should be employed when SABR and VEGF-modulating drugs are used in the same patient, even when separated by 2–3 months or more, since this has been reported to be associated with an increase in esophageal fistulae [
      • Stephans K.L.
      • Djemil T.
      • Diaconu C.
      • Reddy C.A.
      • Xia P.
      • Woody N.M.
      • et al.
      Esophageal dose tolerance to hypofractionated stereotactic body radiation therapy: risk factors for late toxicity.
      ] and grade 3–5 bowel ulceration or perforation (in the abdominal SABR setting) [
      • Barney B.M.
      • Markovic S.N.
      • Laack N.N.
      • Miller R.C.
      • Sarkaria J.N.
      • Macdonald O.K.
      • et al.
      Increased bowel toxicity in patients treated with a vascular endothelial growth factor inhibitor (VEGFI) after stereotactic body radiation therapy (SBRT).
      ]. Interstitial lung disease and fatal pneumonitis have been reported when an epidermal growth factor receptor inhibitor was used with lung SABR, despite acceptable dosimetry [
      • Hsieh C.H.
      • Chang H.T.
      • Lin S.C.
      • Chen Y.J.
      • Wang L.Y.
      • Hsieh Y.P.
      • et al.
      Toxic risk of stereotactic body radiotherapy and concurrent helical tomotherapy followed by erlotinib for non-small-cell lung cancer treatment – case report.
      ]. More safety data are required in order to establish safety of combined use of targeted systemic agents and SABR.

      Central tumors

      In centrally located ES-NSCLC, more extensive surgical resections such as pneumonectomy or broncho-angioplastic procedures may be required in order to achieve a radical excision. Irrespective of the type of surgery performed, rates of perioperative mortality and surgical complications are approximately 5% and 25%, respectively [
      • Senthi S.
      • Haasbeek C.J.
      • Slotman B.J.
      • Senan S.
      Outcomes of stereotactic ablative radiotherapy for central lung tumours: a systematic review.
      ]. SABR has been used as an alternative in this context, with mixed results in early years. The Radiation Therapy Oncology Group (RTOG) 0236 trial excluded tumor within a 2 cm radius of the trachea and bronchial tree (the so-called “no fly zone”), as results from a phase 2 trial demonstrated that such patients had a 2-year freedom from grade 3 to 5 toxicity rate of only 54% [
      • Timmerman R.
      • Paulus R.
      • Galvin J.
      • Michalski J.
      • Straube W.
      • Bradley J.
      • et al.
      Stereotactic body radiation therapy for inoperable early stage lung cancer.
      ,
      • Timmerman R.
      • McGarry R.
      • Yiannoutsos C.
      • Papiez L.
      • Tudor K.
      • DeLuca J.
      • et al.
      Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer.
      ]. Since then, non-randomized data have shown that other, more protracted hypofractionated schemes are well tolerated, as such protracted schedules reduce the risk of late toxicity by using a lower dose per fraction. A recent systematic review of treatment of central tumors, based on mostly retrospective data, found an overall treatment-related mortality rate of 2.7%, with grade ⩾3 toxicity occurring in less than 9% of cases [
      • Senthi S.
      • Haasbeek C.J.
      • Slotman B.J.
      • Senan S.
      Outcomes of stereotactic ablative radiotherapy for central lung tumours: a systematic review.
      ]. Life-threatening toxicities included severe bronchial stenosis, hemoptysis, and fistulae [
      • Corradetti M.N.
      • Haas A.R.
      • Rengan R.
      Central-airway necrosis after stereotactic body-radiation therapy.
      ]. However, with a BED less that 210 Gy3, which corresponds to a dose of approximately 60 Gy in 8 fractions, the treatment mortality rate was 1%. The review concluded that post SABR survival in ES-NSCLC is not affected by tumor location (provided that adequate doses can be delivered to the target), that prescription doses in excess of 100 Gy10 are required to achieve local control rates greater than 85%, and that treatment related mortality can be reduced by 75% when biological normal tissue doses are 210 Gy3 or less.
      In patients for whom dose constraints for standard SABR fractionation schedules are unable to be met, such as those with large tumor size, or significant overlap of the PTV with the esophagus or large airways, alternative hypofractionated schemes have been described. For example, one report described use of a strategy of 70 Gy in 10 fractions when constraints for a 50 Gy in 4 fraction central tumor protocol were exceeded [
      • Li Q.
      • Swanick C.W.
      • Allen P.K.
      • Gomez D.R.
      • Welsh J.W.
      • Liao Z.
      • et al.
      Stereotactic ablative radiotherapy (SABR) using 70Gy in 10 fractions for non-small cell lung cancer: exploration of clinical indications.
      ]. Ultimately, these and other studies may help guide clinical management as results from the RTOG 0813 phase 1/2 dose escalation study for SABR in central lesions are awaited.

      Diagnostic management

      Need for pre-treatment pathology prior to SABR

      A pathological confirmation of malignancy is generally preferred prior to the initiation of any curative-intent therapy for ES-NSCLC [
      • Vansteenkiste J.
      • De Ruysscher D.
      • Eberhardt W.E.
      • Lim E.
      • Senan S.
      • Felip E.
      • et al.
      Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ]. In practice, the reported rates of histological confirmation of malignancy prior to SABR for ES-NSCLC are variable, ranging from 35% to 100% (Table 2). A population study found that patient age and co-morbidity predicted for the likelihood of not having a pathological diagnosis in lung cancer [
      • Khakwani A.
      • Rich A.L.
      • Tata L.J.
      • Powell H.A.
      • Stanley R.A.
      • Baldwin D.R.
      • et al.
      The pathological confirmation rate of lung cancer in England using the NLCA database.
      ]. Many candidates for SABR have co-morbidities including compromised pulmonary and cardiac function, that may heighten the risks associated with transthoracic biopsy, or repeated biopsy if the initial attempt is inconclusive [
      • Inoue T.
      • Shimizu S.
      • Onimaru R.
      • Takeda A.
      • Onishi H.
      • Nagata Y.
      • et al.
      Clinical outcomes of stereotactic body radiotherapy for small lung lesions clinically diagnosed as primary lung cancer on radiologic examination.
      ,
      • Chowdhry V.K.
      • Chowdhry A.K.
      • Goldman N.
      • Scalzetti E.M.
      • Grage R.A.
      • Bogart J.A.
      Complications from computed tomography-guided core needle biopsy for patients receiving stereotactic body radiation therapy for early-stage lesions of the lung.
      ].
      Table 2Studies demonstrating the variable rates of pathologic confirmation worldwide prior to SABR in ES-NSCLC.
      ReferenceStudy typeNumber of patientsRegion% BiopsyOverall survival
      Haasbeek
      • Haasbeek C.J.
      • Palma D.
      • Visser O.
      • Lagerwaard F.J.
      • Slotman B.
      • Senan S.
      Early-stage lung cancer in elderly patients: a population-based study of changes in treatment patterns and survival in The Netherlands.
      Population registry1570Netherlands7250% (2 yrs)
      Ricardi
      • Ricardi U.
      • Frezza G.
      • Filippi A.R.
      • Badellino S.
      • Levis M.
      • Navarria P.
      • et al.
      Stereotactic ablative radiotherapy for stage I histologically proven non-small cell lung cancer: an Italian multicenter observational study.
      Retrospective196Italy10068% (3 yrs)
      Guckenberger
      • Guckenberger M.
      • Allgauer M.
      • Appold S.
      • Dieckmann K.
      • Ernst I.
      • Ganswindt U.
      • et al.
      Safety and efficacy of stereotactic body radiotherapy for stage I non-small-cell lung cancer in routine clinical practice: a patterns-of-care and outcome analysis.
      Retrospective591Central Europe8547% (3 yrs)
      Grills
      • Grills I.S.
      • Hope A.J.
      • Guckenberger M.
      • Kestin L.L.
      • Werner-Wasik M.
      • Yan D.
      • et al.
      A collaborative analysis of stereotactic lung radiotherapy outcomes for early-stage non-small-cell lung cancer using daily online cone-beam computed tomography image-guided radiotherapy.
      Retrospective505United States

      Canada

      Netherlands

      Germany
      87–95

      72

      41

      70
      48% (3 yrs)
      Onishi
      • Onishi H.
      • Yoshiyuki S.
      • Yasuo M.
      • Kenji T.
      • Yukinori M.
      • Akifumi M.
      Japanese multi-institutional study of stereotactic body radiation therapy for more than 2000 patients with stage I non-small cell lung cancer.
      Retrospective2278Japan7391% (2 yrs)
      Senthi
      • Senthi S.
      • Lagerwaard F.J.
      • Haasbeek C.J.
      • Slotman B.J.
      • Senan S.
      Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: a retrospective analysis.
      Retrospective676Amsterdam3541 mo (md)
      Baumann
      • Baumann P.
      • Nyman J.
      • Hoyer M.
      • Wennberg B.
      • Gagliardi G.
      • Lax I.
      • et al.
      Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy.
      Prospective57Sweden

      Denmark

      Norway
      6760% (3 yrs)
      Timmerman
      • Timmerman R.
      • Paulus R.
      • Galvin J.
      • Michalski J.
      • Straube W.
      • Bradley J.
      • et al.
      Stereotactic body radiation therapy for inoperable early stage lung cancer.
      Prospective55North America10056% (3 yrs)
      yrs = years, mo = months, md = median.
      Models to predict the probability of malignancy using clinical, CT [
      • Gould M.K.
      • Donington J.
      • Lynch W.R.
      • Mazzone P.J.
      • Midthun D.E.
      • Naidich D.P.
      • et al.
      Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed.: American College of Chest Physicians evidence-based clinical practice guidelines.
      ], and FDG-PET features [
      • Grogan E.L.
      • Deppen S.A.
      • Ballman K.V.
      • Andrade G.M.
      • Verdial F.C.
      • Aldrich M.C.
      • et al.
      Accuracy of fluorodeoxyglucose-positron emission tomography within the clinical practice of the American College of Surgeons Oncology Group Z4031 trial to diagnose clinical stage I non-small cell lung cancer.
      ] of a solitary pulmonary nodule (SPN) have been developed. The term SPN has been defined as a single, well-circumscribed, radiographic opacity that measures up to 3 cm in diameter, and is surrounded completely by aerated lung [
      • Gould M.K.
      • Donington J.
      • Lynch W.R.
      • Mazzone P.J.
      • Midthun D.E.
      • Naidich D.P.
      • et al.
      Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed.: American College of Chest Physicians evidence-based clinical practice guidelines.
      ]. Caution should be employed, however, if such models have not been validated for specific geographic regions of practice [
      • Deppen S.A.
      • Phillips S.
      • McPheeters M.
      • Aldrich M.C.
      • Blume J.
      • Penson D.F.
      • et al.
      Benign disease prevalence after surgical lung resection varies geographically in the US Medicare population, implications for lung cancer screening [abstract].
      ]. Use of FDG-PET may perform poorly when used for a clinical diagnosis of stage I NSCLC, in areas where granulomatous disease and other infectious etiologies are endemic [
      • Grogan E.L.
      • Deppen S.A.
      • Ballman K.V.
      • Andrade G.M.
      • Verdial F.C.
      • Aldrich M.C.
      • et al.
      Accuracy of fluorodeoxyglucose-positron emission tomography within the clinical practice of the American College of Surgeons Oncology Group Z4031 trial to diagnose clinical stage I non-small cell lung cancer.
      ]. In an American population-based analysis, the rate of benign diagnosis after surgery for suspected lung cancer ranged from 1.3% to 25.0% [
      • Deppen S.A.
      • Phillips S.
      • McPheeters M.
      • Aldrich M.C.
      • Blume J.
      • Penson D.F.
      • et al.
      Benign disease prevalence after surgical lung resection varies geographically in the US Medicare population, implications for lung cancer screening [abstract].
      ]. Increasing rates in the pathologic diagnosis of benign disease is correlated with the growing use of video-assisted thoracoscopic surgery (VATS) [
      • Vansteenkiste J.
      • De Ruysscher D.
      • Eberhardt W.E.
      • Lim E.
      • Senan S.
      • Felip E.
      • et al.
      Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ], and is not without toxicity. In a review of surgical patients in the Dutch–Belgian randomized lung cancer screening trial (NELSON), the rate of major and minor post-operative complications in cases that ultimately proved to be benign were 17% and 21%, respectively [
      • Van’t Westeinde S.C.
      • Horeweg N.
      • De Leyn P.
      • Groen H.J.
      • Lammers J.W.
      • Weenink C.
      • et al.
      Complications following lung surgery in the Dutch–Belgian randomized lung cancer screening trial.
      ]. These results demonstrate a need for regular audit of surgery and pathology results both at the institutional and regional/national geographic levels.
      A likelihood of malignancy threshold of 85% has been suggested prior to treatment of a SPN without pathologic confirmation of malignancy (Table 3) [
      • Senan S.
      • Paul M.A.
      • Lagerwaard F.J.
      Treatment of early-stage lung cancer detected by screening: surgery or stereotactic ablative radiotherapy?.
      ]. A similar estimate was derived using a decision analytic model, where strategies of surveillance, performing SABR in a PET-avid SPN in the absence of pathology, and performing a biopsy in a PET-avid SPN prior to SABR, were evaluated using existing data on performance of diagnostic tests, toxicity/complication rates, and recurrence/survival outcomes [
      • Louie A.V.
      • Senan S.
      • Patel P.
      • Ferket B.S.
      • Lagerwaard F.J.
      • Rodrigues G.B.
      • et al.
      When is a biopsy-proven diagnosis necessary before stereotactic ablative radiotherapy for lung cancer? A decision analysis.
      ]. This study determined that a PET-directed SABR strategy (without prior biopsy) could be warranted above a point estimate of malignancy of 85%, a finding that was highly sensitive to the diagnostic performance of biopsy, as well as the ability of subsequent CT follow-up surveillance to appropriately detect false negative SPNs to allow for treatment thereafter. One caveat to the use of PET-directed management strategies is that there is a need for standardization of FDG-PET methodology, as variability in imaging protocols will result in heterogeneity of reported SUVs [
      • Boellaard R.
      Need for standardization of 18F-FDG PET/CT for treatment response assessments.
      ].
      Table 3Studies addressing likelihood of malignancy threshold recommendations to inform the appropriate use of SABR for ES-NSCLC in the absence of pathologic confirmation.
      ReferenceStudy typeRecommended threshold (%)Comments
      American College of Chest Physicians
      • Gould M.K.
      • Donington J.
      • Lynch W.R.
      • Mazzone P.J.
      • Midthun D.E.
      • Naidich D.P.
      • et al.
      Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed.: American College of Chest Physicians evidence-based clinical practice guidelines.
      Consensus-based guideline65No distinction between surgery and non-surgical treatment modalities
      International Association for the Study of Lung Cancer
      • Field J.K.
      • Smith R.A.
      • Aberle D.R.
      • Oudkerk M.
      • Baldwin D.R.
      • Yankelevitz D.
      • et al.
      International Association for the study of Lung Cancer Computed Tomography Screening Workshop 2011 report.
      Consensus-based guideline85Indirectly addressed, as the number of resections for benign disease should be less than 15% in a CT-screened population
      Senan
      • Senan S.
      • Paul M.A.
      • Lagerwaard F.J.
      Treatment of early-stage lung cancer detected by screening: surgery or stereotactic ablative radiotherapy?.
      Expert opinion85Suggests combining volume-doubling time with a predictive model to establish risk of malignancy
      Louie
      • Louie A.V.
      • Senan S.
      • Patel P.
      • Ferket B.S.
      • Lagerwaard F.J.
      • Rodrigues G.B.
      • et al.
      When is a biopsy-proven diagnosis necessary before stereotactic ablative radiotherapy for lung cancer? A decision analysis.
      Decision analysis85Threshold sensitive to the uncertainty in diagnostic performance of biopsy and the ability to reliably detect false negatives on surveillance

      Quality assurance and generalizability

      Technologic advances and rigorous quality assurance programs have improved the ability of radiation oncologists to confidently deliver large hypofractionated doses in SABR with accuracy and precision [
      • Kirkpatrick J.P.
      • Kelsey C.R.
      • Palta M.
      • Cabrera A.R.
      • Salama J.K.
      • Patel P.
      • et al.
      Stereotactic body radiotherapy: a critical review for nonradiation oncologists.
      ]. Incremental advances include: the use of 4D-CT (time-based correlation of respiratory motion with CT images) to account for tumor motion during the breathing cycle, verification of tumor position prior to treatment with image guidance (e.g., cone beam CTs or fiducial-based strategies), and more accurate dosimetry when employing algorithms that account for different tissue inhomogeneities.
      Proper radiation planning, prescription and delivery are key to achieving optimal outcomes. The use of less accurate radiotherapy planning algorithms was found to be associated with more local failures [
      • Latifi K.
      • Oliver J.
      • Baker R.
      • Dilling T.J.
      • Stevens C.W.
      • Kim J.
      • et al.
      Study of 201 non-small cell lung cancer patients given stereotactic ablative radiation therapy shows local control dependence on dose calculation algorithm.
      ], a finding recapitulated in the preliminary results of two prospective multicentre studies in potentially operable patients from Japan that reported local failure rates of 14% at 3 years [
      • Nagata Y.
      • Hiraoka M.
      • Shibata T.
      • Kokubo M.
      • Karasawa K.
      • Shioyama Y.
      • et al.
      A phase ii trial of stereotactic body radiation therapy for operable T1N0M0 non-small cell lung cancer: Japan Clinical Oncology Group (JCOG0403).
      ]. Furthermore, optimal prescriptions require coverage of the entire tumor volume with a high dose, and failure to achieve high enough doses at the periphery of the tumor is associated with higher recurrence risks [
      • Vansteenkiste J.
      • De Ruysscher D.
      • Eberhardt W.E.
      • Lim E.
      • Senan S.
      • Felip E.
      • et al.
      Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • Senan S.
      • Palma D.A.
      • Lagerwaard F.J.
      Stereotactic ablative radiotherapy for stage I NSCLC: recent advances and controversies.
      ].
      Several commercial platforms are available to deliver SABR. While differences in treatment capabilities exist in the various lung SABR delivery platforms, a systematic review found no differences in overall survival for ES-NSCLC when using different technologies [
      • Solda F.
      • Lodge M.
      • Ashley S.
      • Whitington A.
      • Goldstraw P.
      • Brada M.
      Stereotactic radiotherapy (SABR) for the treatment of primary non-small cell lung cancer; Systematic review and comparison with a surgical cohort.
      ]. Published guidelines in both North America [
      • Potters L.
      • Kavanagh B.
      • Galvin J.M.
      • Hevezi J.M.
      • Janjan N.A.
      • Larson D.A.
      • et al.
      American Society for Therapeutic Radiology and Oncology (ASTRO) and American College of Radiology (ACR) practice guideline for the performance of stereotactic body radiation therapy.
      ,
      • Sahgal A.
      • Roberge D.
      • Schellenberg D.
      • Purdie T.G.
      • Swaminath A.
      • Pantarotto J.
      • et al.
      The Canadian Association of Radiation Oncology scope of practice guidelines for lung, liver and spine stereotactic body radiotherapy.
      ,
      • Benedict S.H.
      • Yenice K.M.
      • Followill D.
      • Galvin J.M.
      • Hinson W.
      • Kavanagh B.
      • et al.
      Stereotactic body radiation therapy: the report of AAPM Task Group 101.
      ] and the European Union [
      • Vansteenkiste J.
      • De Ruysscher D.
      • Eberhardt W.E.
      • Lim E.
      • Senan S.
      • Felip E.
      • et al.
      Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ,
      • Guckenberger M.
      • Andratschke N.
      • Alheit H.
      • Holy R.
      • Moustakis C.
      • Nestle U.
      • et al.
      Definition of stereotactic body radiotherapy: principles and practice for the treatment of stage I non-small cell lung cancer.
      ] have supported institutional credentialing procedures, standardization of normal tissue tolerances, and increased discourse on the use of SABR in a multidisciplinary setting.

      Survivorship

      The utility of surveillance following curative lung cancer resection has previously been questioned, as historically, only 1–4% of recurrences undergo salvage resection [
      • Furman M.J.
      • Lambert L.A.
      • Sullivan M.E.
      • Whalen G.F.
      Rational follow-up after curative cancer resection.
      ]. Survivorship in lung cancer, however, extends beyond the detection of salvageable recurrences. Investigators from Memorial Sloan Kettering Cancer Center (MSKCC) have proposed a thoracic survivorship model that considers risk of second primary lung cancer (SPLC), quality of life (QoL), preventative care (such as routine screening for other malignancies), and the management of comorbid conditions that require active management [
      • Huang J.
      • Logue A.E.
      • Ostroff J.S.
      • Park B.J.
      • McCabe M.
      • Jones D.R.
      • et al.
      Comprehensive long-term care of patients with lung cancer: development of a Novel Thoracic Survivorship Program.
      ]. As the MKSCC model was mostly comprised of surgical patients, we highlight survivorship challenges following lung SABR here.

      QoL

      A systematic review of QoL following surgery for lung cancer found that dyspnea, fatigue and decreases in physical functioning can persist for at least 2 years following treatment [
      • Poghosyan H.
      • Sheldon L.K.
      • Leveille S.G.
      • Cooley M.E.
      Health-related quality of life after surgical treatment in patients with non-small cell lung cancer: a systematic review.
      ]. Changes in pulmonary function (PF) after SABR appear to be correlated with pretreatment PF: those with the worst pretreatment PF tend to improve, while those with the best pretreatment PF have modest losses [
      • Guckenberger M.
      • Kestin L.L.
      • Hope A.J.
      • Belderbos J.
      • Werner-Wasik M.
      • Yan D.
      • et al.
      Is there a lower limit of pretreatment pulmonary function for safe and effective stereotactic body radiotherapy for early-stage non-small cell lung cancer?.
      ,
      • Stanic S.
      • Paulus R.
      • Timmerman R.D.
      • Michalski J.M.
      • Barriger R.B.
      • Bezjak A.
      • et al.
      No clinically significant changes in pulmonary function following stereotactic body radiation therapy for early- stage peripheral non-small cell lung cancer: an analysis of RTOG 0236.
      ]. The few reports describing QoL following SABR for lung cancer have limited follow-up and are largely comprised of patients who are less fit at baseline. In general, these reports describe minimal clinically meaningful changes [
      • Lagerwaard F.J.
      • Aaronson N.K.
      • Gundy C.M.
      • Haasbeek C.J.
      • Slotman B.J.
      • Senan S.
      Patient-reported quality of life after stereotactic ablative radiotherapy for early-stage lung cancer.
      ]. Although hypothesis generating, modeling studies have postulated that potential survival benefits of lobectomy, when compared to SABR for medically operable ES-NSCLC patients, may be mitigated by QoL considerations [
      • Louie A.V.
      • Rodrigues G.
      • Hannouf M.
      • Zaric G.S.
      • Palma D.A.
      • Cao J.Q.
      • et al.
      Stereotactic body radiotherapy versus surgery for medically operable stage I non-small-cell lung cancer: a Markov model-based decision analysis.
      ].

      Second primary lung cancer (SPLC)

      Survivors of lung cancer are at risk of developing a second primary lung cancer (SPLC) at a rate of approximately 3% per year [
      • Jaklitsch M.T.
      • Jacobson F.L.
      • Austin J.H.
      • Field J.K.
      • Jett J.R.
      • Keshavjee S.
      • et al.
      The American Association for Thoracic Surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups.
      ], a risk that is highest in the first year and persists even after a decade [
      • Surapaneni R.
      • Singh P.
      • Rajagopalan K.
      • Hageboutros A.
      Stage I lung cancer survivorship: risk of second malignancies and need for individualized care plan.
      ]. In both the MKSCC model and in a RCT comparing chest X-ray and minimal dose CT surveillance, a high proportion of SPLC cases were detected in asymptomatic individuals [
      • Hanna W.C.
      • Paul N.S.
      • Darling G.E.
      • Moshonov H.
      • Allison F.
      • Waddell T.K.
      • et al.
      Minimal-dose computed tomography is superior to chest X-ray for the follow-up and treatment of patients with resected lung cancer.
      ]. SPLCs are also prevalent in survivors of other smoking-related primary malignancies such as head and neck and esophageal cancers; in the former, they account for over 50% of non-head and neck cancer-related deaths [
      • Baxi S.S.
      • Pinheiro L.C.
      • Patil S.M.
      • Pfister D.G.
      • Oeffinger K.C.
      • Elkin E.B.
      Causes of death in long-term survivors of head and neck cancer.
      ]. On the basis of current evidence, SABR also appears to be a valid first-line alternative to surgery in medically operable patients with SPLC, particularly as QoL considerations become more important during the survivorship period.
      In patients previously treated with pneumonectomy for lung cancer, and who developed a subsequent malignancy in their remaining lung, the operative mortality and complication rates are as high as 8% and 40%, respectively [
      • Donington J.S.
      • Miller D.L.
      • Rowland C.C.
      • Deschamps C.
      • Allen M.S.
      • Trastek V.F.
      • et al.
      Subsequent pulmonary resection for bronchogenic carcinoma after pneumonectomy.
      ]. The limited experience using SABR for such patients is encouraging with no reports of treatment-related mortality in the available literature [
      • Thompson R.
      • Giuliani M.
      • Yap M.L.
      • Atallah S.
      • Le L.W.
      • Sun A.
      • et al.
      Stereotactic body radiotherapy in patients with previous pneumonectomy: safety and efficacy.
      ,
      • Senthi S.
      • Haasbeek C.J.
      • Lagerwaard F.J.
      • Verbakel W.F.
      • de Haan P.F.
      • Slotman B.J.
      • et al.
      Radiotherapy for a second primary lung cancer arising post-pneumonectomy: planning considerations and clinical outcomes.
      ]. Finally, when comparing outcomes of SPLC using SABR with first primary lung cancer, there do not appear to be any differences in efficacy in overall survival or recurrence [
      • Griffioen G.H.
      • Lagerwaard F.J.
      • Haasbeek C.J.
      • Slotman B.J.
      • Senan S.
      A brief report on outcomes of stereotactic ablative radiotherapy for a second primary lung cancer: evidence in support of routine CT surveillance.
      ].

      Ground glass opacities (GGOs)

      Early invasive lung adenocarcinomas can present with in-situ, multi-focal lesions that appear as regions of GGOs [
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • Nicholson A.G.
      • Geisinger K.R.
      • Yatabe Y.
      • et al.
      International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma.
      ]. Management of GGOs is currently evolving, as some data suggest that a sublobar resection may be adequate [
      • Tsutani Y.
      • Miyata Y.
      • Nakayama H.
      • Okumura S.
      • Adachi S.
      • Yoshimura M.
      • et al.
      Appropriate sublobar resection choice for ground glass opacity-dominant clinical stage IA lung adenocarcinoma: wedge resection or segmentectomy.
      ], while others suggest that the indolent nature of pure GGO lesions may justify an active surveillance approach until a solid component develops [
      • Naidich D.P.
      • Bankier A.A.
      • MacMahon H.
      • Schaefer-Prokop C.M.
      • Pistolesi M.
      • Goo J.M.
      • et al.
      Recommendations for the management of subsolid pulmonary nodules detected at CT: a statement from the Fleischner Society.
      ]. Compared to other NSCLC subtypes treated with SABR, adenocarcinoma in situ (formerly termed bronchoalveolar carcinoma) appears to have similar patterns of failure [
      • Badiyan S.N.
      • Bierhals A.J.
      • Olsen J.R.
      • Creach K.M.
      • Garsa A.A.
      • Dewees T.
      • et al.
      Stereotactic body radiation therapy for the treatment of early-stage minimally invasive adenocarcinoma or adenocarcnioma in situ (formerly bronchioloalveolar carcinoma): a patterns of failure analysis.
      ]. However, one caveat in the use of SABR for GGO-predominant lesions is the risk for underdosing the target volume due to a loss of electronic disequilibrium. In one study, the delivered dose to a subcentimeter peripherally-located GGO surrounded by low-density emphysematous lung was estimated to be more than 20% less than the calculated dose using a less advanced treatment planning algorithm [
      • Louie A.V.
      • Senan S.
      • Dahele M.
      • Slotman B.
      • Verbakel W.F.
      Stereotactic ablative radiotherapy for sub-centimeter lung tumors: clinical, dosimetric and image guidance considerations.
      ].

      Distinguishing fibrosis versus recurrence

      Radiation-induced lung injury following lung SABR can manifest as CT-density changes in up to 90% of cases at 2 years after treatment [
      • Palma D.A.
      • van Sornsen de Koste J.
      • Verbakel W.F.
      • Vincent A.
      • Senan S.
      Lung density changes after stereotactic radiotherapy: a quantitative analysis in 50 patients.
      ]. As these changes can occasionally mimic recurrence, traditional metrics to assess tumor response following definitive RT such as the Response Evaluation Criteria in Solid Tumors (RECIST) criteria may result in misdiagnosis of fibrosis as a recurrence, which may lead to unnecessary diagnostic and therapeutic procedures [
      • Dunlap N.E.
      • Yang W.
      • McIntosh A.
      • Sheng K.
      • Benedict S.H.
      • Read P.W.
      • et al.
      Computed tomography-based anatomic assessment overestimates local tumor recurrence in patients with mass-like consolidation after stereotactic body radiotherapy for early-stage non-small cell lung cancer.
      ]. Further confounding the ability to properly diagnose a local recurrence, benign lung injury may result in FDG-avidity following SABR [
      • Pastis Jr, N.J.
      • Greer T.J.
      • Tanner N.T.
      • Wahlquist A.E.
      • Gordon L.L.
      • Sharma A.K.
      • et al.
      Assessing the utility of FDG PET-CT after stereotactic body radiotherapy for early stage non-small cell lung cancer.
      ] and these changes can persist for up to a year. Although SUVmax values as high as 7 have been reported in the setting of benign lung injury following SABR [
      • Singhvi M.
      • Lee P.
      Illustrative cases of false positive biopsies after stereotactic body radiation therapy for lung cancer based on abnormal FDG-PET-CT imaging.
      ], a systematic review suggests that an SUVmax value above 5 is highly suggestive of recurrence [
      • Bollineni V.R.
      • Widder J.
      • Pruim J.
      • Langendijk J.A.
      • Wiegman E.M.
      Residual (1)(8)F-FDG-PET uptake 12 weeks after stereotactic ablative radiotherapy for stage I non-small-cell lung cancer predicts local control.
      ]. High-risk features (HRFs) on serial CT scan suggestive of recurrence include: enlarging opacity, sequential enlargement, enlargement after 12 months, bulging margin, linear margin disappearance, loss air bronchogram, and cranio-caudal growth. Employing a minimum cut-off of ⩾3 of these HRFs has been demonstrated to have high sensitivity and specificity (greater than 90%) of recurrence, with a recommendation to proceed to biopsy or salvage treatment (Fig. 3) [
      • Huang K.
      • Senthi S.
      • Palma D.A.
      • Spoelstra F.O.
      • Warner A.
      • Slotman B.J.
      • et al.
      High-risk CT features for detection of local recurrence after stereotactic ablative radiotherapy for lung cancer.
      ]. With the increasing using of lung SABR, distinguishing fibrosis from recurrence is a research priority for survivorship, as salvage treatment by surgery [
      • Neri S.
      • Takahashi Y.
      • Terashi T.
      • Hamakawa H.
      • Tomii K.
      • Katakami N.
      • et al.
      Surgical treatment of local recurrence after stereotactic body radiotherapy for primary and metastatic lung cancers.
      ,
      • Chen F.
      • Matsuo Y.
      • Yoshizawa A.
      • Sato T.
      • Sakai H.
      • Bando T.
      • et al.
      Salvage lung resection for non-small cell lung cancer after stereotactic body radiotherapy in initially operable patients.
      ,
      • Allibhai Z.
      • Cho B.C.
      • Taremi M.
      • Atallah S.
      • Hope A.
      • Hwang D.
      • et al.
      Surgical salvage following stereotactic body radiotherapy for early-stage NSCLC.
      ] or repeat SABR [
      • Trakul N.
      • Harris J.P.
      • Le Q.T.
      • Hara W.Y.
      • Maxim P.G.
      • Loo Jr, B.W.
      • et al.
      Stereotactic ablative radiotherapy for reirradiation of locally recurrent lung tumors.
      ] while feasible, are not without toxicity.
      Figure thumbnail gr3
      Fig. 3Use of high-risk features (HRFs) on CT to diagnose recurrence. In patient 1, a 5 month follow-up CT shows an enlarging opacity, with additional scans showing fibrosis with no additional HRFs. No evidence of local recurrence. In patient 2, diffuse consolidation is demonstrated at 6 months. Additional HRFs are demonstrated after 12 months. The patient was diagnosed with a local recurrence at 21 months and underwent salvage lobectomy shortly after.
      The European Society of Medical Oncology consensus conference on lung cancer recommended 6 monthly CT scans for 3 years for patients who are suitable for salvage treatment, followed by annual CT scans thereafter [
      • Vansteenkiste J.
      • Crino L.
      • Dooms C.
      • Douillard J.Y.
      • Faivre-Finn C.
      • Lim E.
      • et al.
      2nd ESMO consensus conference on lung cancer: early-stage non-small-cell lung cancer consensus on diagnosis treatment and followup.
      ]. Frequency of follow-up may be decreased and tailored for individuals who are not candidates for salvage treatment. The role of surveillance using FDG-PET has not been clearly defined, though its selective use is recommended when recurrence after SABR is suspected based on serial CT imaging. As FDG-PET is associated with a high incidence of false positive findings in this setting, biopsy should be sought whenever possible.

      Shared decision making

      In situations where there is clinical equipoise between treatment modalities, shared decision-making (SDM) has been encouraged to try and align medical management with a patient’s preference and values [
      • Oshima Lee E.
      • Emanuel E.J.
      Shared decision making to improve care and reduce costs.
      ]. SDM is a process in which patients and physicians discuss the current evidence on different treatment options and mutually arrive at a clinical management plan [
      • Stacey D.
      • Samant R.
      • Bennett C.
      Decision making in oncology: a review of patient decision aids to support patient participation.
      ]. Achieving this often requires the input of a multidisciplinary team, and currently these initiatives vary in practice from ad hoc to routine. In healthcare systems where implementing such a policy for all patients is not feasible, focusing efforts on high-risk surgical patients would afford the highest value [
      • Glance L.G.
      • Osler T.M.
      • Neuman M.D.
      Redesigning surgical decision making for high-risk patients.
      ]. For instance, risks such as poorer QoL and higher 30- and 90-day post-treatment mortality after surgery in ES-NSCLC [
      • Senthi S.
      • Senan S.
      Surgery for early-stage lung cancer: post-operative 30-day versus 90-day mortality and patient-centred care.
      ] may be particularly relevant for older patients who are more likely to have significant co-morbidities [
      • Vest M.T.
      • Herrin J.
      • Soulos P.R.
      • Decker R.H.
      • Tanoue L.
      • Michaud G.
      • et al.
      Use of new treatment modalities for non-small cell lung cancer care in the medicare population.
      ]. Conversely, while SABR may be considered attractive as an outpatient procedure with rare treatment-related mortality, for those desiring certainty, the development of benign CT changes during follow-up that mimic recurrence may be a source of anxiety.

      Conclusions

      SABR is now established as the preferred treatment option for medically inoperable patients with peripherally located ES-NSCLC. Although RCTs in medically operable/borderline operable patients, designed to compare surgery and SABR have been unable to accrue, non-randomized comparative effectiveness analysis argues for clinical equipoise between these treatments. Comparative effectiveness research will be instrumental in guiding decision-making for other emerging indications and addressing unanswered questions related to the use of SABR in ES-NSCLC (Table 4).
      Table 4Priority areas for research on the use of SABR for ES-NSCLC.
      Patient selection
      • If a RCT is not feasible in medically operable ES-NSCLC patients, investigate the role of SABR through CER using detailed prospective registration of comorbidity and toxicity data
      • Establish the risks and benefits of SABR in CT-screened ES-NSCLC lung cancer patients
      • Develop robust prediction models for distant metastasis risk in order to guide adjuvant treatment
      • Establish the safety and appropriate administration of adjuvant systemic therapy
      • Identify patients in whom SABR should not be offered, due to high risk of early mortality from competing causes
      Quality assurance
      • Monitor outcomes of SABR in community practice, as well as salvage surgery due to misclassification of benign fibrosis
      • Establish optimal SABR doses for central tumors
      • Determine safe dose-toxicity criteria for critical normal organs
      Diagnostic management
      • Establish the role of biopsy in the FDG-PET era in different global populations
      • Determine the role of EBUS/EUS for staging subgroups of FDG-PET staged patients
      Survivorship
      • Explore the safety and role of surgical or re-SABR salvage
      CER = comparative effectiveness research, SDM = shared decision making, EBUS = endobronchial ultrasound, EUS = endoscopic ultrasound.

      Conflict of interest

      Drs. Senan and Dahele have received honoraria and travel support from Varian Medical Systems. Dr. Dahele has received honoraria and travel support from BrainLAB AG. Drs. Senan and Palma hold a non-commercial patent for the use of advance imaging feature analysis to assess for response after radiotherapy. The VU University Medical Center has a research agreement with Varian Medical Systems.

      Acknowledgments

      This work was supported by the Western University Resident Research Career Development Program Award, and a 2014 Detweiler Travelling Fellowship, Royal College of Physicians and Surgeons of Canada, to Dr. Louie.

      References

        • Siegel R.
        • Ma J.
        • Zou Z.
        • Jemal A.
        Cancer statistics, 2014.
        CA Cancer J Clin. 2014; 64: 9-29
        • Malvezzi M.
        • Bertuccio P.
        • Levi F.
        • La Vecchia C.
        • Negri E.
        European cancer mortality predictions for the year 2014.
        Ann Oncol. 2014;
        • Smith B.D.
        • Smith G.L.
        • Hurria A.
        • Hortobagyi G.N.
        • Buchholz T.A.
        Future of cancer incidence in the United States: burdens upon an aging, changing nation.
        J Clin Oncol. 2009; 27: 2758-2765
        • Fazel R.
        • Krumholz H.M.
        • Wang Y.
        • Ross J.S.
        • Chen J.
        • Ting H.H.
        • et al.
        Exposure to low-dose ionizing radiation from medical imaging procedures.
        N Engl J Med. 2009; 361: 849-857
        • Berdahl C.T.
        • Vermeulen M.J.
        • Larson D.B.
        • Schull M.J.
        Emergency department computed tomography utilization in the United States and Canada.
        Ann Emerg Med. 2013; 62: e3
        • Aberle D.R.
        • DeMello S.
        • Berg C.D.
        • Black W.C.
        • Brewer B.
        • Church T.R.
        • et al.
        Results of the two incidence screenings in the National Lung Screening Trial.
        N Engl J Med. 2013; 369: 920-931
        • Aberle D.R.
        • Adams A.M.
        • Berg C.D.
        • Black W.C.
        • Clapp J.D.
        • et al.
        • National Lung Screening Trial Research T
        Reduced lung-cancer mortality with low-dose computed tomographic screening.
        N Engl J Med. 2011; 365: 395-409
        • Janssen-Heijnen M.L.
        • Maas H.A.
        • Houterman S.
        • Lemmens V.E.
        • Rutten H.J.
        • Coebergh J.W.
        Comorbidity in older surgical cancer patients: influence on patient care and outcome.
        Eur J Cancer. 2007; 43: 2179-2193
        • Rogers Jr, S.O.
        • Gray S.W.
        • Landrum M.B.
        • Klabunde C.N.
        • Kahn K.L.
        • Fletcher R.H.
        • et al.
        Variations in surgeon treatment recommendations for lobectomy in early-stage non-small-cell lung cancer by patient age and comorbidity.
        Ann Surg Oncol. 2010; 17: 1581-1588
        • Senthi S.
        • Senan S.
        Surgery for early-stage lung cancer: post-operative 30-day versus 90-day mortality and patient-centred care.
        Eur J Cancer. 2014; 50: 675-677
        • Haasbeek C.J.
        • Palma D.
        • Visser O.
        • Lagerwaard F.J.
        • Slotman B.
        • Senan S.
        Early-stage lung cancer in elderly patients: a population-based study of changes in treatment patterns and survival in The Netherlands.
        Ann Oncol. 2012; 23: 2743-2747
        • Wang S.
        • Wong M.L.
        • Hamilton N.
        • Davoren J.B.
        • Jahan T.M.
        • Walter L.C.
        Impact of age and comorbidity on non-small-cell lung cancer treatment in older veterans.
        J Clin Oncol. 2012; 30: 1447-1455
        • Hutchins L.F.
        • Unger J.M.
        • Crowley J.J.
        • Coltman Jr, C.A.
        • Albain K.S.
        Underrepresentation of patients 65 years of age or older in cancer-treatment trials.
        N Engl J Med. 1999; 341: 2061-2067
        • Rowell N.P.
        • Williams C.J.
        Radical radiotherapy for stage I/II non-small cell lung cancer in patients not sufficiently fit for or declining surgery (medically inoperable): a systematic review.
        Thorax. 2001; 56: 628-638
        • Palma D.A.
        • Senan S.
        Improving outcomes for high-risk patients with early-stage non-small-cell lung cancer: insights from population-based data and the role of stereotactic ablative radiotherapy.
        Clin Lung Cancer. 2013; 14: 1-5
        • Onishi H.
        • Shirato H.
        • Nagata Y.
        • Hiraoka M.
        • Fujino M.
        • Gomi K.
        • et al.
        Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi-institutional study.
        J Thorac Oncol. 2007; 2: S94-S100
        • Olsen J.R.
        • Robinson C.G.
        • El Naqa I.
        • Creach K.M.
        • Drzymala R.E.
        • Bloch C.
        • et al.
        Dose-response for stereotactic body radiotherapy in early-stage non-small-cell lung cancer.
        Int J Radiat Oncol Biol Phys. 2011; 81: e299-e303
        • Zhang J.
        • Yang F.
        • Li B.
        • Li H.
        • Liu J.
        • Huang W.
        • et al.
        Which is the optimal biologically effective dose of stereotactic body radiotherapy for stage I non-small-cell lung cancer? A meta-analysis.
        Int J Radiat Oncol Biol Phys. 2011; 81: e305-e316
        • Palma D.
        • Visser O.
        • Lagerwaard F.J.
        • Belderbos J.
        • Slotman B.J.
        • Senan S.
        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: 5153-5159
        • Guckenberger M.
        • Allgauer M.
        • Appold S.
        • Dieckmann K.
        • Ernst I.
        • Ganswindt U.
        • et al.
        Safety and efficacy of stereotactic body radiotherapy for stage I non-small-cell lung cancer in routine clinical practice: a patterns-of-care and outcome analysis.
        J Thorac Oncol. 2013; 8: 1050-1058
        • Ricardi U.
        • Frezza G.
        • Filippi A.R.
        • Badellino S.
        • Levis M.
        • Navarria P.
        • et al.
        Stereotactic ablative radiotherapy for stage I histologically proven non-small cell lung cancer: an Italian multicenter observational study.
        Lung Cancer. 2014;
        • Lund C.R.
        • Cao J.Q.
        • Liu M.
        • Olson R.
        • Halperin R.
        • Schellenberg D.
        The distribution and patterns of practice of stereotactic ablative body radiotherapy in Canada.
        J Med Imaging Radiat Sci. 2013; ([In press])
        • Pan H.
        • Rose B.S.
        • Simpson D.R.
        • Mell L.K.
        • Mundt A.J.
        • Lawson J.D.
        Clinical practice patterns of lung stereotactic body radiation therapy in the United States: a secondary analysis.
        Am J Clin Oncol. 2013; 36: 269-272
        • Pan H.
        • Simpson D.R.
        • Mell L.K.
        • Mundt A.J.
        • Lawson J.D.
        A survey of stereotactic body radiotherapy use in the United States.
        Cancer. 2011; 117: 4566-4572
        • Nagata Y.
        • Hiraoka M.
        • Mizowaki T.
        • Narita Y.
        • Matsuo Y.
        • Norihisa Y.
        • et al.
        Survey of stereotactic body radiation therapy in Japan by the Japan 3-D Conformal External Beam Radiotherapy Group.
        Int J Radiat Oncol Biol Phys. 2009; 75: 343-347
        • Sox H.C.
        • Greenfield S.
        Comparative effectiveness research: a report from the Institute of Medicine.
        Ann Intern Med. 2009; 151: 203-205
        • Booth C.M.
        • Tannock I.F.
        Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence.
        Br J Cancer. 2014; 110: 551-555
        • Concato J.
        Is it time for medicine-based evidence?.
        JAMA. 2012; 307: 1641-1643
        • Moghanaki D.
        • Karas T.
        Surgery versus SABR for NSCLC.
        Lancet Oncol. 2013; 14: e490-e491
        • Guckenberger M.
        Stereotactic body radiotherapy for stage I NSCLC: the challenge of evidence-based medicine.
        J Thorac Oncol. 2014; 9: e17-e18
        • Louie A.V.
        • Senthi S.
        • Palma D.A.
        Surgery versus SABR for NSCLC.
        Lancet Oncol. 2013; 14: e491
        • Bosco J.L.
        • Silliman R.A.
        • Thwin S.S.
        • Geiger A.M.
        • Buist D.S.
        • Prout M.N.
        • et al.
        A most stubborn bias: no adjustment method fully resolves confounding by indication in observational studies.
        J Clin Epidemiol. 2010; 63: 64-74
        • Nyman J.
        • Hallqvist A.
        • Lund J.A.
        • Brustugun O.T.
        • Bergström P.
        • Friesland S.
        • et al.
        SPACE – a randomized study of SBRT vs conventional fractionated radiotherapy in medically inoperable stage I NSCLC.
        Radiother Oncol. 2014; 111: 232(S)
        • Rosenblatt E.
        • Izewska J.
        • Anacak Y.
        • Pynda Y.
        • Scalliet P.
        • Boniol M.
        • et al.
        Radiotherapy capacity in European countries: an analysis of the Directory of Radiotherapy Centres (DIRAC) database.
        Lancet Oncol. 2013; 14: e79-e86
        • van Loon J.
        • Grutters J.
        • Macbeth F.
        Evaluation of novel radiotherapy technologies: what evidence is needed to assess their clinical and cost effectiveness, and how should we get it?.
        Lancet Oncol. 2012; 13: e169-e177
        • Lievens Y.
        • Grau C.
        Health economics in radiation oncology: introducing the ESTRO HERO project.
        Radiother Oncol. 2012; 103: 109-112
        • Shah A.
        • Hahn S.M.
        • Stetson R.L.
        • Friedberg J.S.
        • Pechet T.T.
        • Sher D.J.
        Cost-effectiveness of stereotactic body radiation therapy versus surgical resection for stage I non-small cell lung cancer.
        Cancer. 2013; 119: 3123-3132
        • Puri V.
        • Crabtree T.D.
        • Kymes S.
        • Gregory M.
        • Bell J.
        • Bradley J.D.
        • et al.
        A comparison of surgical intervention and stereotactic body radiation therapy for stage I lung cancer in high-risk patients: a decision analysis.
        J Thorac Cardiovasc Surg. 2012; 143: 428-436
        • Louie A.V.
        • Rodrigues G.B.
        • Palma D.A.
        • Senan S.
        Measuring the population impact of introducing stereotactic ablative radiotherapy for stage I non-small cell lung cancer in Canada.
        Oncologist. 2014;
        • Mitera G.
        • Swaminath A.
        • Rudoler D.
        • Seereeram C.
        • Giuliani M.
        • Leighl N.
        • et al.
        Cost-effectiveness analysis comparing conventional versus stereotactic body radiotherapy for surgically ineligible stage I non-small-cell lung cancer.
        J Oncol Pract. 2014;
        • Sher D.J.
        • Wee J.O.
        • Punglia R.S.
        Cost-effectiveness analysis of stereotactic body radiotherapy and radiofrequency ablation for medically inoperable, early-stage non-small cell lung cancer.
        Int J Radiat Oncol Biol Phys. 2011; 81: e767-e774
        • Lanni Jr, T.B.
        • Grills I.S.
        • Kestin L.L.
        • Robertson J.M.
        Stereotactic radiotherapy reduces treatment cost while improving overall survival and local control over standard fractionated radiation therapy for medically inoperable non-small-cell lung cancer.
        Am J Clin Oncol. 2011; 34: 494-498
        • Darling G.E.
        • Allen M.S.
        • Decker P.A.
        • Ballman K.
        • Malthaner R.A.
        • Inculet R.I.
        • et al.
        Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma: results of the American College of Surgery Oncology Group Z0030 Trial.
        J Thorac Cardiovasc Surg. 2011; 141: 662-670
        • Fernando H.C.
        • Landreneau R.J.
        • Mandrekar S.J.
        • Nichols F.C.
        • Hillman S.L.
        • Heron D.E.
        • et al.
        Impact of brachytherapy on local recurrence rates after sublobar resection: results from ACOSOG Z4032 (alliance), a phase III randomized trial for high-risk operable non-small-cell lung cancer.
        J Clin Oncol. 2014;
        • LaPar D.J.
        • Bhamidipati C.M.
        • Lau C.L.
        • Jones D.R.
        • Kozower B.D.
        The Society of Thoracic Surgeons General Thoracic Surgery Database: establishing generalizability to national lung cancer resection outcomes.
        Ann Thorac Surg. 2012; 94 ([Discussion 21]): 216-221
        • Rueth N.M.
        • Parsons H.M.
        • Habermann E.B.
        • Groth S.S.
        • Virnig B.A.
        • Tuttle T.M.
        • et al.
        Surgical treatment of lung cancer: predicting postoperative morbidity in the elderly population.
        J Thorac Cardiovasc Surg. 2012; 143: 1314-1323
        • Vansteenkiste J.
        • De Ruysscher D.
        • Eberhardt W.E.
        • Lim E.
        • Senan S.
        • Felip E.
        • et al.
        Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2013; 24: vi89-vi98
        • Boffa D.J.
        • Kosinski A.S.
        • Paul S.
        • Mitchell J.D.
        • Onaitis M.
        Lymph node evaluation by open or video-assisted approaches in 11,500 anatomic lung cancer resections.
        Ann Thorac Surg. 2012; 94 ([Discussion 53]): 347-353
        • Licht P.B.
        • Jorgensen O.D.
        • 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 ([Discussion 9–50]): 943-949
        • Osarogiagbon R.U.
        • Yu X.
        Nonexamination of lymph nodes and survival after resection of non-small cell lung cancer.
        Ann Thorac Surg. 2013; 96: 1178-1189
        • Kent M.
        • Landreneau R.
        • Mandrekar S.
        • Hillman S.
        • Nichols F.
        • Jones D.
        • et al.
        Segmentectomy versus wedge resection for non-small cell lung cancer in high-risk operable patients.
        Ann Thorac Surg. 2013; 96 ([Discussion 54–5]): 1747-1754
        • Altorki N.K.
        • Yip R.
        • Hanaoka T.
        • Bauer T.
        • Aye R.
        • Kohman L.
        • et al.
        Sublobar resection is equivalent to lobectomy for clinical stage 1A lung cancer in solid nodules.
        J Thorac Cardiovasc Surg. 2014; 147 ([Discussion 62–4]): 754-762
        • Su S.
        • Scott W.J.
        • Allen M.S.
        • Darling G.E.
        • Decker P.A.
        • McKenna R.J.
        • et al.
        Patterns of survival and recurrence after surgical treatment of early stage non-small cell lung carcinoma in the ACOSOG Z0030 (ALLIANCE) trial.
        J Thorac Cardiovasc Surg. 2014; 147 ([Discussion 52–3]): 747-752
        • Robinson C.G.
        • DeWees T.A.
        • El Naqa I.M.
        • Creach K.M.
        • Olsen J.R.
        • Crabtree T.D.
        • et al.
        Patterns of failure after stereotactic body radiation therapy or lobar resection for clinical stage I non-small-cell lung cancer.
        J Thorac Oncol. 2013; 8: 192-201
        • Senthi S.
        • Lagerwaard F.J.
        • Haasbeek C.J.
        • Slotman B.J.
        • Senan S.
        Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: a retrospective analysis.
        Lancet Oncol. 2012; 13: 802-809
        • Nair V.J.
        • MacRae R.
        • Sirisegaram A.
        • Pantarotto J.R.
        Pretreatment [18F]-fluoro-2-deoxy-glucose positron emission tomography maximum standardized uptake value as predictor of distant metastasis in early-stage non-small cell lung cancer treated with definitive radiation therapy: rethinking the role of positron emission tomography in personalizing treatment based on risk status.
        Int J Radiat Oncol Biol Phys. 2014; 88: 312-318
        • Takeda A.
        • Sanuki N.
        • Fujii H.
        • Yokosuka N.
        • Nishimura S.
        • Aoki Y.
        • et al.
        Maximum standardized uptake value on FDG-PET is a strong predictor of overall and disease-free survival for non-small-cell lung cancer patients after stereotactic body radiotherapy.
        J Thorac Oncol. 2014; 9: 65-73
        • Allibhai Z.
        • Taremi M.
        • Bezjak A.
        • Brade A.
        • Hope A.J.
        • Sun A.
        • et al.
        The impact of tumor size on outcomes after stereotactic body radiation therapy for medically inoperable early-stage non-small cell lung cancer.
        Int J Radiat Oncol Biol Phys. 2013; 87: 1064-1070
        • Shultz D.B.
        • Trakul N.
        • Abelson J.A.
        • Murphy J.D.
        • Maxim P.G.
        • Le Q.T.
        • et al.
        Imaging features associated with disease progression after stereotactic ablative radiotherapy for stage I non-small-cell lung cancer.
        Clin Lung Cancer. 2014; 15: e3
        • Eakin E.G.
        • Resnikoff P.M.
        • Prewitt L.M.
        • Ries A.L.
        • Kaplan R.M.
        Validation of a new dyspnea measure: the UCSD Shortness of breath questionnaire. University of California, San Diego.
        Chest. 1998; 113: 619-624
        • Stephans K.L.
        • Djemil T.
        • Diaconu C.
        • Reddy C.A.
        • Xia P.
        • Woody N.M.
        • et al.
        Esophageal dose tolerance to hypofractionated stereotactic body radiation therapy: risk factors for late toxicity.
        Int J Radiat Oncol Biol Phys. 2014;
        • Barney B.M.
        • Markovic S.N.
        • Laack N.N.
        • Miller R.C.
        • Sarkaria J.N.
        • Macdonald O.K.
        • et al.
        Increased bowel toxicity in patients treated with a vascular endothelial growth factor inhibitor (VEGFI) after stereotactic body radiation therapy (SBRT).
        Int J Radiat Oncol Biol Phys. 2013; 87: 73-80
        • Hsieh C.H.
        • Chang H.T.
        • Lin S.C.
        • Chen Y.J.
        • Wang L.Y.
        • Hsieh Y.P.
        • et al.
        Toxic risk of stereotactic body radiotherapy and concurrent helical tomotherapy followed by erlotinib for non-small-cell lung cancer treatment – case report.
        BMC Cancer. 2010; 10: 696
        • Senthi S.
        • Haasbeek C.J.
        • Slotman B.J.
        • Senan S.
        Outcomes of stereotactic ablative radiotherapy for central lung tumours: a systematic review.
        Radiother Oncol. 2013; 106: 276-282
        • Timmerman R.
        • Paulus R.
        • Galvin J.
        • Michalski J.
        • Straube W.
        • Bradley J.
        • et al.
        Stereotactic body radiation therapy for inoperable early stage lung cancer.
        JAMA. 2010; 303: 1070-1076
        • Timmerman R.
        • McGarry R.
        • Yiannoutsos C.
        • Papiez L.
        • Tudor K.
        • DeLuca J.
        • et al.
        Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer.
        J Clin Oncol. 2006; 24: 4833-4839
        • Corradetti M.N.
        • Haas A.R.
        • Rengan R.
        Central-airway necrosis after stereotactic body-radiation therapy.
        N Engl J Med. 2012; 366: 2327-2329
        • Li Q.
        • Swanick C.W.
        • Allen P.K.
        • Gomez D.R.
        • Welsh J.W.
        • Liao Z.
        • et al.
        Stereotactic ablative radiotherapy (SABR) using 70Gy in 10 fractions for non-small cell lung cancer: exploration of clinical indications.
        Radiother Oncol. 2014;
        • Khakwani A.
        • Rich A.L.
        • Tata L.J.
        • Powell H.A.
        • Stanley R.A.
        • Baldwin D.R.
        • et al.
        The pathological confirmation rate of lung cancer in England using the NLCA database.
        Lung Cancer. 2013; 79: 125-131
        • Inoue T.
        • Shimizu S.
        • Onimaru R.
        • Takeda A.
        • Onishi H.
        • Nagata Y.
        • et al.
        Clinical outcomes of stereotactic body radiotherapy for small lung lesions clinically diagnosed as primary lung cancer on radiologic examination.
        Int J Radiat Oncol Biol Phys. 2009; 75: 683-687
        • Chowdhry V.K.
        • Chowdhry A.K.
        • Goldman N.
        • Scalzetti E.M.
        • Grage R.A.
        • Bogart J.A.
        Complications from computed tomography-guided core needle biopsy for patients receiving stereotactic body radiation therapy for early-stage lesions of the lung.
        Clin Lung Cancer. 2014; 15: 302-306
        • Gould M.K.
        • Donington J.
        • Lynch W.R.
        • Mazzone P.J.
        • Midthun D.E.
        • Naidich D.P.
        • et al.
        Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed.: American College of Chest Physicians evidence-based clinical practice guidelines.
        Chest. 2013; 143: e93S-e120S
        • Grogan E.L.
        • Deppen S.A.
        • Ballman K.V.
        • Andrade G.M.
        • Verdial F.C.
        • Aldrich M.C.
        • et al.
        Accuracy of fluorodeoxyglucose-positron emission tomography within the clinical practice of the American College of Surgeons Oncology Group Z4031 trial to diagnose clinical stage I non-small cell lung cancer.
        Ann Thorac Surg. 2014; 97: 1142-1148
        • Deppen S.A.
        • Phillips S.
        • McPheeters M.
        • Aldrich M.C.
        • Blume J.
        • Penson D.F.
        • et al.
        Benign disease prevalence after surgical lung resection varies geographically in the US Medicare population, implications for lung cancer screening [abstract].
        in: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6–10; Washington, DC. AACR, Philadelphia (PA)2013 ([Abstract Nr. 3628. 2013])
        • Van’t Westeinde S.C.
        • Horeweg N.
        • De Leyn P.
        • Groen H.J.
        • Lammers J.W.
        • Weenink C.
        • et al.
        Complications following lung surgery in the Dutch–Belgian randomized lung cancer screening trial.
        Eur J Cardiothorac Surg. 2012; 42: 420-429
        • Senan S.
        • Paul M.A.
        • Lagerwaard F.J.
        Treatment of early-stage lung cancer detected by screening: surgery or stereotactic ablative radiotherapy?.
        Lancet Oncol. 2013; 14: e270-e274
        • Louie A.V.
        • Senan S.
        • Patel P.
        • Ferket B.S.
        • Lagerwaard F.J.
        • Rodrigues G.B.
        • et al.
        When is a biopsy-proven diagnosis necessary before stereotactic ablative radiotherapy for lung cancer? A decision analysis.
        Chest. 2014; 146: 1021-1028
        • Boellaard R.
        Need for standardization of 18F-FDG PET/CT for treatment response assessments.
        J Nucl Med. 2011; 52: 93S-100S
        • Kirkpatrick J.P.
        • Kelsey C.R.
        • Palta M.
        • Cabrera A.R.
        • Salama J.K.
        • Patel P.
        • et al.
        Stereotactic body radiotherapy: a critical review for nonradiation oncologists.
        Cancer. 2014; 120: 942-954
        • Latifi K.
        • Oliver J.
        • Baker R.
        • Dilling T.J.
        • Stevens C.W.
        • Kim J.
        • et al.
        Study of 201 non-small cell lung cancer patients given stereotactic ablative radiation therapy shows local control dependence on dose calculation algorithm.
        Int J Radiat Oncol Biol Phys. 2014; 88: 1108-1113
        • Nagata Y.
        • Hiraoka M.
        • Shibata T.
        • Kokubo M.
        • Karasawa K.
        • Shioyama Y.
        • et al.
        A phase ii trial of stereotactic body radiation therapy for operable T1N0M0 non-small cell lung cancer: Japan Clinical Oncology Group (JCOG0403).
        Int J Radiat Oncol Biol Phys. 2010; 78: s27-s28
        • Senan S.
        • Palma D.A.
        • Lagerwaard F.J.
        Stereotactic ablative radiotherapy for stage I NSCLC: recent advances and controversies.
        J Thorac Dis. 2011; 3: 189-196
        • Solda F.
        • Lodge M.
        • Ashley S.
        • Whitington A.
        • Goldstraw P.
        • Brada M.
        Stereotactic radiotherapy (SABR) for the treatment of primary non-small cell lung cancer; Systematic review and comparison with a surgical cohort.
        Radiother Oncol. 2013;
        • Potters L.
        • Kavanagh B.
        • Galvin J.M.
        • Hevezi J.M.
        • Janjan N.A.
        • Larson D.A.
        • et al.
        American Society for Therapeutic Radiology and Oncology (ASTRO) and American College of Radiology (ACR) practice guideline for the performance of stereotactic body radiation therapy.
        Int J Radiat Oncol Biol Phys. 2010; 76: 326-332
        • Sahgal A.
        • Roberge D.
        • Schellenberg D.
        • Purdie T.G.
        • Swaminath A.
        • Pantarotto J.
        • et al.
        The Canadian Association of Radiation Oncology scope of practice guidelines for lung, liver and spine stereotactic body radiotherapy.
        Clin Oncol (R Coll Radiol). 2012; 24: 629-639
        • Benedict S.H.
        • Yenice K.M.
        • Followill D.
        • Galvin J.M.
        • Hinson W.
        • Kavanagh B.
        • et al.
        Stereotactic body radiation therapy: the report of AAPM Task Group 101.
        Med Phys. 2010; 37: 4078-4101
        • Guckenberger M.
        • Andratschke N.
        • Alheit H.
        • Holy R.
        • Moustakis C.
        • Nestle U.
        • et al.
        Definition of stereotactic body radiotherapy: principles and practice for the treatment of stage I non-small cell lung cancer.
        Strahlenther Onkol. 2014; 190: 26-33
        • Furman M.J.
        • Lambert L.A.
        • Sullivan M.E.
        • Whalen G.F.
        Rational follow-up after curative cancer resection.
        J Clin Oncol. 2013; 31: 1130-1133
        • Huang J.
        • Logue A.E.
        • Ostroff J.S.
        • Park B.J.
        • McCabe M.
        • Jones D.R.
        • et al.
        Comprehensive long-term care of patients with lung cancer: development of a Novel Thoracic Survivorship Program.
        Ann Thorac Surg. 2014;
        • Poghosyan H.
        • Sheldon L.K.
        • Leveille S.G.
        • Cooley M.E.
        Health-related quality of life after surgical treatment in patients with non-small cell lung cancer: a systematic review.
        Lung Cancer. 2013; 81: 11-26
        • Guckenberger M.
        • Kestin L.L.
        • Hope A.J.
        • Belderbos J.
        • Werner-Wasik M.
        • Yan D.
        • et al.
        Is there a lower limit of pretreatment pulmonary function for safe and effective stereotactic body radiotherapy for early-stage non-small cell lung cancer?.
        J Thorac Oncol. 2012; 7: 542-551
        • Stanic S.
        • Paulus R.
        • Timmerman R.D.
        • Michalski J.M.
        • Barriger R.B.
        • Bezjak A.
        • et al.
        No clinically significant changes in pulmonary function following stereotactic body radiation therapy for early- stage peripheral non-small cell lung cancer: an analysis of RTOG 0236.
        Int J Radiat Oncol Biol Phys. 2014; 88: 1092-1099
        • Lagerwaard F.J.
        • Aaronson N.K.
        • Gundy C.M.
        • Haasbeek C.J.
        • Slotman B.J.
        • Senan S.
        Patient-reported quality of life after stereotactic ablative radiotherapy for early-stage lung cancer.
        J Thorac Oncol. 2012; 7: 1148-1154
        • Louie A.V.
        • Rodrigues G.
        • Hannouf M.
        • Zaric G.S.
        • Palma D.A.
        • Cao J.Q.
        • et al.
        Stereotactic body radiotherapy versus surgery for medically operable stage I non-small-cell lung cancer: a Markov model-based decision analysis.
        Int J Radiat Oncol Biol Phys. 2011; 81: 964-973
        • Jaklitsch M.T.
        • Jacobson F.L.
        • Austin J.H.
        • Field J.K.
        • Jett J.R.
        • Keshavjee S.
        • et al.
        The American Association for Thoracic Surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups.
        J Thorac Cardiovasc Surg. 2012; 144: 33-38
        • Surapaneni R.
        • Singh P.
        • Rajagopalan K.
        • Hageboutros A.
        Stage I lung cancer survivorship: risk of second malignancies and need for individualized care plan.
        J Thorac Oncol. 2012; 7: 1252-1256
        • Hanna W.C.
        • Paul N.S.
        • Darling G.E.
        • Moshonov H.
        • Allison F.
        • Waddell T.K.
        • et al.
        Minimal-dose computed tomography is superior to chest X-ray for the follow-up and treatment of patients with resected lung cancer.
        J Thorac Cardiovasc Surg. 2014; 147: 30-33
        • Baxi S.S.
        • Pinheiro L.C.
        • Patil S.M.
        • Pfister D.G.
        • Oeffinger K.C.
        • Elkin E.B.
        Causes of death in long-term survivors of head and neck cancer.
        Cancer. 2014; 120: 1507-1513
        • Donington J.S.
        • Miller D.L.
        • Rowland C.C.
        • Deschamps C.
        • Allen M.S.
        • Trastek V.F.
        • et al.
        Subsequent pulmonary resection for bronchogenic carcinoma after pneumonectomy.
        Ann Thorac Surg. 2002; 74 ([Discussion 8–9]): 154-158
        • Thompson R.
        • Giuliani M.
        • Yap M.L.
        • Atallah S.
        • Le L.W.
        • Sun A.
        • et al.
        Stereotactic body radiotherapy in patients with previous pneumonectomy: safety and efficacy.
        J Thorac Oncol. 2014; 9: 843-847
        • Senthi S.
        • Haasbeek C.J.
        • Lagerwaard F.J.
        • Verbakel W.F.
        • de Haan P.F.
        • Slotman B.J.
        • et al.
        Radiotherapy for a second primary lung cancer arising post-pneumonectomy: planning considerations and clinical outcomes.
        J Thorac Dis. 2013; 5: 116-122
        • Griffioen G.H.
        • Lagerwaard F.J.
        • Haasbeek C.J.
        • Slotman B.J.
        • Senan S.
        A brief report on outcomes of stereotactic ablative radiotherapy for a second primary lung cancer: evidence in support of routine CT surveillance.
        J Thorac Oncol. 2014; 9: 1222-1225
        • Travis W.D.
        • Brambilla E.
        • Noguchi M.
        • Nicholson A.G.
        • Geisinger K.R.
        • Yatabe Y.
        • et al.
        International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma.
        J Thorac Oncol. 2011; 6: 244-285
        • Tsutani Y.
        • Miyata Y.
        • Nakayama H.
        • Okumura S.
        • Adachi S.
        • Yoshimura M.
        • et al.
        Appropriate sublobar resection choice for ground glass opacity-dominant clinical stage IA lung adenocarcinoma: wedge resection or segmentectomy.
        Chest. 2014; 145: 66-71
        • Naidich D.P.
        • Bankier A.A.
        • MacMahon H.
        • Schaefer-Prokop C.M.
        • Pistolesi M.
        • Goo J.M.
        • et al.
        Recommendations for the management of subsolid pulmonary nodules detected at CT: a statement from the Fleischner Society.
        Radiology. 2013; 266: 304-317
        • Badiyan S.N.
        • Bierhals A.J.
        • Olsen J.R.
        • Creach K.M.
        • Garsa A.A.
        • Dewees T.
        • et al.
        Stereotactic body radiation therapy for the treatment of early-stage minimally invasive adenocarcinoma or adenocarcnioma in situ (formerly bronchioloalveolar carcinoma): a patterns of failure analysis.
        Radiat Oncol. 2013; 8: 4
        • Louie A.V.
        • Senan S.
        • Dahele M.
        • Slotman B.
        • Verbakel W.F.
        Stereotactic ablative radiotherapy for sub-centimeter lung tumors: clinical, dosimetric and image guidance considerations.
        Int J Radiat Oncol Biol Phys. 2014; 90: 843-849
        • Palma D.A.
        • van Sornsen de Koste J.
        • Verbakel W.F.
        • Vincent A.
        • Senan S.
        Lung density changes after stereotactic radiotherapy: a quantitative analysis in 50 patients.
        Int J Radiat Oncol Biol Phys. 2011; 81: 974-978
        • Dunlap N.E.
        • Yang W.
        • McIntosh A.
        • Sheng K.
        • Benedict S.H.
        • Read P.W.
        • et al.
        Computed tomography-based anatomic assessment overestimates local tumor recurrence in patients with mass-like consolidation after stereotactic body radiotherapy for early-stage non-small cell lung cancer.
        Int J Radiat Oncol Biol Phys. 2012; 84: 1071-1077
        • Pastis Jr, N.J.
        • Greer T.J.
        • Tanner N.T.
        • Wahlquist A.E.
        • Gordon L.L.
        • Sharma A.K.
        • et al.
        Assessing the utility of FDG PET-CT after stereotactic body radiotherapy for early stage non-small cell lung cancer.
        Chest. 2014;
        • Singhvi M.
        • Lee P.
        Illustrative cases of false positive biopsies after stereotactic body radiation therapy for lung cancer based on abnormal FDG-PET-CT imaging.
        BMJ Case Rep. 2013; 2013
        • Bollineni V.R.
        • Widder J.
        • Pruim J.
        • Langendijk J.A.
        • Wiegman E.M.
        Residual (1)(8)F-FDG-PET uptake 12 weeks after stereotactic ablative radiotherapy for stage I non-small-cell lung cancer predicts local control.
        Int J Radiat Oncol Biol Phys. 2012; 83: e551-e555
        • Huang K.
        • Senthi S.
        • Palma D.A.
        • Spoelstra F.O.
        • Warner A.
        • Slotman B.J.
        • et al.
        High-risk CT features for detection of local recurrence after stereotactic ablative radiotherapy for lung cancer.
        Radiother Oncol. 2013; 109: 51-57
        • Neri S.
        • Takahashi Y.
        • Terashi T.
        • Hamakawa H.
        • Tomii K.
        • Katakami N.
        • et al.
        Surgical treatment of local recurrence after stereotactic body radiotherapy for primary and metastatic lung cancers.
        J Thorac Oncol. 2010; 5: 2003-2007
        • Chen F.
        • Matsuo Y.
        • Yoshizawa A.
        • Sato T.
        • Sakai H.
        • Bando T.
        • et al.
        Salvage lung resection for non-small cell lung cancer after stereotactic body radiotherapy in initially operable patients.
        J Thorac Oncol. 2010; 5: 1999-2002
        • Allibhai Z.
        • Cho B.C.
        • Taremi M.
        • Atallah S.
        • Hope A.
        • Hwang D.
        • et al.
        Surgical salvage following stereotactic body radiotherapy for early-stage NSCLC.
        Eur Respir J. 2012; 39: 1039-1042
        • Trakul N.
        • Harris J.P.
        • Le Q.T.
        • Hara W.Y.
        • Maxim P.G.
        • Loo Jr, B.W.
        • et al.
        Stereotactic ablative radiotherapy for reirradiation of locally recurrent lung tumors.
        J Thorac Oncol. 2012; 7: 1462-1465
        • Vansteenkiste J.
        • Crino L.
        • Dooms C.
        • Douillard J.Y.
        • Faivre-Finn C.
        • Lim E.
        • et al.
        2nd ESMO consensus conference on lung cancer: early-stage non-small-cell lung cancer consensus on diagnosis treatment and followup.
        Ann Oncol. 2014; 25: 1462-1474
        • Oshima Lee E.
        • Emanuel E.J.
        Shared decision making to improve care and reduce costs.
        N Engl J Med. 2013; 368: 6-8
        • Stacey D.
        • Samant R.
        • Bennett C.
        Decision making in oncology: a review of patient decision aids to support patient participation.
        CA Cancer J Clin. 2008; 58: 293-304
        • Glance L.G.
        • Osler T.M.
        • Neuman M.D.
        Redesigning surgical decision making for high-risk patients.
        N Engl J Med. 2014; 370: 1379-1381
        • Vest M.T.
        • Herrin J.
        • Soulos P.R.
        • Decker R.H.
        • Tanoue L.
        • Michaud G.
        • et al.
        Use of new treatment modalities for non-small cell lung cancer care in the medicare population.
        Chest. 2013; 143: 429-435
        • Raz D.J.
        • Zell J.A.
        • Ou S.H.
        • Gandara D.R.
        • Anton-Culver H.
        • Jablons D.M.
        Natural history of stage I non-small cell lung cancer: implications for early detection.
        Chest. 2007; 132: 193-199
        • Shirvani S.M.
        • Jiang J.
        • Chang J.Y.
        • Welsh J.W.
        • Gomez D.R.
        • Swisher S.
        • et al.
        Comparative effectiveness of 5 treatment strategies for early-stage non-small cell lung cancer in the elderly.
        Int J Radiat Oncol Biol Phys. 2012; 84: 1060-1070
        • Varlotto J.
        • Fakiris A.
        • Flickinger J.
        • Medford-Davis L.
        • Liss A.
        • Shelkey J.
        • et al.
        Matched-pair and propensity score comparisons of outcomes of patients with clinical stage I non-small cell lung cancer treated with resection or stereotactic radiosurgery.
        Cancer. 2013; 119: 2683-2691
        • Crabtree T.D.
        • Puri V.
        • Robinson C.
        • Bradley J.
        • Broderick S.
        • Patterson G.A.
        • et al.
        Analysis of first recurrence and survival in patients with stage I non-small cell lung cancer treated with surgical resection or stereotactic radiation therapy.
        J Thorac Cardiovasc Surg. 2014; 147 ([Discussion 91–2]): 1183-1191
        • Matsuo Y.
        • Chen F.
        • Hamaji M.
        • Kawaguchi A.
        • Ueki N.
        • Nagata Y.
        • et al.
        Comparison of long-term survival outcomes between stereotactic body radiotherapy and sublobar resection for stage I non-small-cell lung cancer in patients at high risk for lobectomy: a propensity score matching analysis.
        Eur J Cancer. 2014;
        • Shirvani S.M.
        • Jiang J.
        • Chang J.Y.
        • Welsh J.
        • Likhacheva A.
        • Buchholz T.A.
        • et al.
        Lobectomy, sublobar resection, and stereotactic ablative radiotherapy for early-stage non-small cell lung cancers in the elderly.
        JAMA Surg. 2014;
        • Verstegen N.E.
        • Oosterhuis J.W.
        • Palma D.A.
        • Rodrigues G.
        • Lagerwaard F.J.
        • van der Elst A.
        • et al.
        Stage I-II non-small-cell lung cancer treated using either stereotactic ablative radiotherapy (SABR) or lobectomy by video-assisted thoracoscopic surgery (VATS): outcomes of a propensity score-matched analysis.
        Ann Oncol. 2013; 24: 1543-1548
        • Grills I.S.
        • Mangona V.S.
        • Welsh R.
        • Chmielewski G.
        • McInerney E.
        • Martin S.
        • et al.
        Outcomes after stereotactic lung radiotherapy or wedge resection for stage I non-small-cell lung cancer.
        J Clin Oncol. 2010; 28: 928-935
        • Zheng X.
        • Schipper M.
        • Kidwell K.
        • Lin J.
        • Reddy R.
        • Ren Y.
        • et al.
        Survival outcome after stereotactic body radiation therapy and surgery for stage I non-small cell lung cancer: a meta-analysis.
        Int J Radiat Oncol Biol Phys. 2014; 90: 603-611
        • Felip E.
        • Rosell R.
        • Maestre J.A.
        • Rodriguez-Paniagua J.M.
        • Moran T.
        • Astudillo J.
        • et al.
        Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-small-cell lung cancer.
        J Clin Oncol. 2010; 28: 3138-3145
        • Pignon J.P.
        • Tribodet H.
        • Scagliotti G.V.
        • Douillard J.Y.
        • Shepherd F.A.
        • Stephens R.J.
        • et al.
        Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group.
        J Clin Oncol. 2008; 26: 3552-3559
        • Grills I.S.
        • Hope A.J.
        • Guckenberger M.
        • Kestin L.L.
        • Werner-Wasik M.
        • Yan D.
        • et al.
        A collaborative analysis of stereotactic lung radiotherapy outcomes for early-stage non-small-cell lung cancer using daily online cone-beam computed tomography image-guided radiotherapy.
        J Thorac Oncol. 2012; 7: 1382-1393
        • Onishi H.
        • Yoshiyuki S.
        • Yasuo M.
        • Kenji T.
        • Yukinori M.
        • Akifumi M.
        Japanese multi-institutional study of stereotactic body radiation therapy for more than 2000 patients with stage I non-small cell lung cancer.
        Int J Radiat Oncol Biol Phys. 2013; 87: S9
        • Baumann P.
        • Nyman J.
        • Hoyer M.
        • Wennberg B.
        • Gagliardi G.
        • Lax I.
        • et al.
        Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy.
        J Clin Oncol. 2009; 27: 3290-3296
        • Field J.K.
        • Smith R.A.
        • Aberle D.R.
        • Oudkerk M.
        • Baldwin D.R.
        • Yankelevitz D.
        • et al.
        International Association for the study of Lung Cancer Computed Tomography Screening Workshop 2011 report.
        J Thorac Oncol. 2012; 7: 10-19