14 Lesser Resection Versus Radiotherapy for Patients with Compromised Lung Function and Stage I Lung Cancer

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14

Lesser Resection Versus Radiotherapy for Patients with Compromised Lung Function and Stage I Lung Cancer

Jeffrey A. Bogart and Leslie J. Kohman

mance status. Various algorithms are available for assessing whether or not a patient will tolerate a lobectomy. There is no commonly accepted absolute for which patients with signiﬁ cant pulmonary disease will and which will not tolerate surgical resection of their lung cancer. Few of the published articles give speciﬁ cs on how the patients were chosen for alternative therapies.

There is no high level evidence available on this topic.

14.1. Published Data

14.1.1. Observation

Prospective data are not available regarding the role of observation for high-risk patients with early-stage NSCLC. The poor outcome for patients with early-stage NSCLC who do not receive any treatment is illustrated by recent retrospective experiences. Of 128 patients identiﬁ ed with stage I and II NSCLC at the Veterans Administration Medical Center in Indianapolis between 1994 and 1999, 49 (38%) patients did not receive treatment due to either refusal of therapy or comorbid medical problems.⁷ The median survival for this cohort of patients was 14.2 months and the majority of patients died from lung cancer. A separate report from the University of Arkansas included 97 patients who did not undergo resection for stage I and II NSCLC.⁸ Seventy of 97 (72%) of patients did not receive cancer-speciﬁ c therapy.

The median survival was 11 months for these patients compared with 22 months for treated patients. Given the retrospective nature of these The prospect for cure is excellent for ﬁ t patients

treated with anatomical resection for pathological stage IA non-small cell lung cancer (NSCLC).¹ Unfortunately, a substantial subset of patients diagnosed with early-stage NSCLC suffer from cardiopulmonary disease and/or other underlying medical comorbidities, and therefore are not suitable candidates for standard therapy.² Treat- ment options for patients unable to tolerate lobectomy are typically guided by the severity of comorbid disease and traditionally have included limited resection (via open thoracotomy or a thoracoscopic approach) and external beam radiotherapy. Newer approaches including stereotactic radiosurgery and radiofrequency ablation are now utilized with increasing frequency. Recently, brachytherapy has been introduced as an adjuvant to wedge resection.^3,4 Although high-risk patients have been relatively neglected with regards to clinical research, this population is expected to increase in the future given factors such as the aging of the U.S. population and the increasing utilization of lung cancer screening.^5,6 In this chapter, we explore the data (retrospective and prospective) regarding these choices of therapy and describe the rationale and hypothe- ses of current ongoing clinical trials. The baseline management option is observation: the expected outcome of patients not eligible for standard surgical therapy (lobectomy) due to concurrent medical conditions.

By far the major reason that patients are turned down for lung cancer surgery is compromised pulmonary function, although a proportion has severe cardiac illness or overall poor perfor-

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experiences, the impact of patient selection on outcomes cannot be ascertained. Evidence from prospectively collected data in a screening context⁹ shows that even small lung cancers, left untreated, have a very poor outcome: The 8-year fatality rate for the diagnosed but untreated cases of lung cancer 6 to 15mm in diameter was 87%, for 16 to 25mm it was 94%, and for 26 to 30mm it was 88%. The corresponding estimates of cure rates with resection were 71%, 67%, and 55%, respectively. These results for untreated patients come from a group of patients who were eligible for the screening because they were felt on general clinical evaluation to be ﬁ t enough to tolerate lobectomy. Results in a group of patients medically unﬁ t for surgery would be worse because they would include deaths from comorbid conditions.

14.1.2. Comparisons of Surgery with

Radiotherapy in Patients with Compromised Lung Function (Evidence Level 2 to 3)

A prospective comparison of surgery and radiotherapy conducted during the 1960s is limited by the use of antiquated staging and radiotherapy technology and the inclusion of patients with small cell lung cancer, and thus does not provide relevant data for modern-day treatment deci- sions.¹⁰ There are no randomized, controlled studies on this topic.

Retrospective reports comparing surgery and radiotherapy for high-risk and/or elderly patients have reached differing conclusions. Yano and colleagues, from the National Kyushu Cancer Center in Fukuoka, Japan, retrospectively reviewed treatment results in compromised or poor-risk patients with clinical stage I NSCLC.¹¹ Seventeen patients underwent a limited resection (9 wedge resections and 8 segmentectomies), while 18 patients received radiation therapy. The 5-year survival rates for patients in the limited resection group and the radiation treatment group were 55.0% and 14.4%, respectively. More- over, the reported incidence of severe treatment- related complications was not different between the limited operation group and the radiotherapy group (11.8% vs. 11.1%). Alternatively, Noordijk and colleagues, from Leiden, The Netherlands, described outcomes for patients irradiated for

peripherally located T1-2 N0M0 NSCLC.¹² Patients included did not have surgery because of poor medical condition, advanced age, or patient refusal. These results were compared to a group of 86 patients over 70 years of age treated surgically in the same hospital. The median survivals for patients treated with surgery and radiotherapy were 23 months and 27 months, respectively.

14.1.3. Retrospective Studies Assessing Surgery in Patients with Compromised Lung Function (Evidence Level 2 to 3)

Outcomes for high-risk patients treated with surgical resection vary greatly in retrospective studies. In a report of 116 patients with T1N0 NSCLC, 5-year survival was reduced for patients with chronic cardiopulmonary disease after standard surgery compared with patients without cardiopulmonary disease, 35% versus 53%, respectively.¹³ Higher operative mortality was the main reason for the lower observed survival.

Trials employing limited resection for patients with well-deﬁ ned pulmonary dysfunction report lower operative mortality but similar survival.

Five-year survival was 29% for 73 high-risk patients [mean ASA class II and mean forced expiratory volume in 1s (FEV1) of 1.25] following wedge resection in a report from the Veterans Hospital in Washington, D.C.¹⁴ In a separate study from Emory University, 5-year survival was 31% (excluding one postoperative death) following segmental or wedge resection for 32 patients with an FEV1 less than 1.0.¹⁵ All patients had clinical T1N0 NSCLC, and 31/32 patients had pathological T1N0 tumors.

Retrospective trials that appear to employ more liberal criteria for performing limited surgery report better outcomes. A report from the Arkansas Veterans Administration included 244 patients with T1N0 NSCLC. Five-year survival for the 113 patients treated with limited resection was 51%, and exceeded the outcomes for patients treated with lobectomy.¹⁶ Similarly, Errett and colleagues reported 75% 6-year overall survival with wedge resection compared with 69% 6-year survival following lobectomy.¹⁷ The median FEV1 prior to wedge resection was 1.56L and wedge resection was more frequently

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employed than lobectomy in their series. A large retrospective analysis from Allegheny General Hospital compared segmental resection and lobectomy for stage I NSCLC (18). Four-year survival was comparable in both groups (67 % vs.

62%) and pulmonary function was more likely to be spared following segmental resection, as a decline in diffusing capacity was the only sig- niﬁ cant change observed in this group. A recent report supports the feasibility of safely performing limited resection in patients with pulmonary dysfunction.¹⁹ In a study of 219 patients with stage IA NSCLC, there was no operative mortality with wedge resection (via either an open or thoracoscopic approach), compared with 3% mortality following lobectomy. Five-year survival was 58% for following open wedge resection, 65% following video-assisted wedge resection, and 70%

after lobectomy.

An increased risk of local tumor relapse has been reported for limited resection compared with lobectomy. The local recurrence rate was 22.7% (15/66) with segmentectomy versus 4.9%

(5/103) with lobectomy in a study from Rush Medical Center.²⁰ Miller reported the potential for adjuvant external beam radiotherapy to reduce the risk of local relapse after limited resection for stage I NSCLC, particularly when the lesion crossed an intersegmental plane.¹⁵ In their series, local tumor relapse was reduced from 33%

to 11% (2/18) with the addition of adjuvant external beam radiotherapy.

In an effort to address the risk of local tumor relapse, two retrospective studies have addressed a combined approach of limited resection and permanent ¹²⁵I brachytherapy. D’Amato reported a series of 14 patients, with an average FEV1 of 0.59L (23% predicted) and an average diffusion of carbon monoxide was 6.8mL/min/mm Hg (30% predicted), with peripheral pathological T1N0 NSCLC.³ Surgical margins were pathologically clear and mediastinal nodes were sampled in all patients. Treatment included video-assisted thoracoscopic wedge resection with a polygly- conate mesh containing ¹²⁵I seeds applied to pulmonary resection margins. The short follow-up time (average 7 months and maximum 12 months) precluded an assessment of outcome, but no sig- niﬁ cant operative morbidity or radiation related toxicity was observed. A larger experience was

reported from the New England Medical Center.⁴ Thirty-three patients underwent a limited resection with ¹²⁵I brachytherapy seeds implanted along the resection margin. With a median follow-up of 51 months, the 5-year survival was 47%, 67% for patients with T1N0 tumors, and 39% for patients with T2N0 tumors. Two local and six regional recurrences were observed.

14.1.4. Prospective Trials Assessing Limited Resection in Patients with Compromised Lung Function (Level of Evidence 2 ++)

The Lung Cancer Study Group conducted a prospective, randomized phase III trial comparing limited resection with lobectomy for patients with peripheral, pathologically documented T1N0 NSCLC. Patients were required to have adequate pulmonary reserve for lobectomy.²¹ Limited resection was associated with a 30%

increase in the overall death rate, a 50% increase in the observed death with cancer rate, and a tri- pling of local recurrence compared to lobectomy.

Local recurrence was, likewise, increased following wedge resection compared with segmentectomy. Moreover, limited pulmonary resection did not reduce perioperative morbidity or mortality, or improve postoperative pulmonary function.

The results of a prospective phase II trial limited to patients with pulmonary dysfunction were recently published.²² The Cancer and Leu- kemia Group B (CALGB) 9335 enrolled high-risk patients with one or more of the following risk factors: FEV1 less than 40%, carbon monoxide diffusing capacity in lung (DLCO) less than 50%, and maximum oxygen consumption(VO₂max) less than 45mmHg. Patients underwent video- assisted wedge resection followed by local (56Gy) radiotherapy if they were found to have pathological T1N0 NSCLC. The primary end point was the proportion of patients whose disease could be completely resected and who received radiotherapy without treatment complications. Overall, video-assisted wedge resection was not techni- cally feasible in 29% of patients. Of 58 eligible patients registered in the study, 32 patients were found to have pathologically staged T1 NSCLC.

The median survival of patients with pathological T1 disease (excluding one postoperative death) was 32 months and 5-year survival was

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29%. Detailed patterns of failure have not been published, although a 29% local relapse rate was observed: 36% for narrowly resected (e.g., margin

<1cm) lesions and 21% for widely resected lesions.

The inﬂ uence of adjuvant radiotherapy on survival and local tumor control is not discernable.

A recently activated prospective phase III trial, headed by the American College of Surgeons Oncology Group, seeks to conﬁ rm the provoca- tive retrospective experience of combined wedge resection and ¹²⁵I brachytherapy. Patients with NSCLC less than 3cm are randomized to treatment with sublobar resection or sublobar resection and intraoperative ¹²⁵I brachytherapy (100Gy). Eligibility criteria are more liberal than the CALGB prospective trial, and advanced age is included in the criteria for protocol entry. The primary end point of the study is 2-year local tumor relapse, and approximately 225 patients will be accrued. Table 14.1 summarizes the results of select surgery series.

14.1.5. Retrospective Trials of Radiotherapy in Patients with Compromised Lung

Function (Level of Evidence 2– to 3)

Published reviews summarize the results of early NSCLC following radiotherapy in retrospective reports. Sibley reviewed the results of 10 studies utilizing megavoltage irradiation to doses of more than 55Gy for medically inoperable stage I NSCLC.²³ Although there was a substantial rate of death from intercurrent disease, the main cause of death in this patient population was lung cancer progression. Overall, 15% of patients were long-term survivors, 30% died from progression of local disease, 30% died from distant metasta-

ses, and 25% died from other causes. Prognostic factors for survival included tumor size and age, and 5-year overall survival ranged from 26% to 67% for T1 lesions and from 4% to 24% for T2 lesions. A correlation between radiation dose and local tumor failure and/or improved survival was suggested in several studies. Toxicity was minimal and 8 of 10 studies reported grade 3+ complica- tion rates less than 2%.

More recently, Rowell and Williams reviewed all published trials of radiotherapy for stage I/IIA NSCLC delivering more than 4000cGy.²⁴ Twenty- seven trials were identifi ed with greater than 2000 patients, including one prospective randomized trial for which a subset analysis was available for patients with clinical stage I/II A NSCLC.⁵ It was noted that the population included in these trials is poorly defi ned: the rationale for nonoperative therapy was stated for only approximately 50% of patients, pretreatment pulmonary function testing was reported in only one trial, CT staging was utilized haphazardly in many studies, and mediastinoscopy was rarely employed. Overall, observations were similar to those of Sibley, in that most patients died from their cancer despite a presumed high rate of comorbid illness, improved survival was observed with smaller tumors, and better results (i.e., response rates) were suggested with higher doses of radiotherapy. In fact, more than one third of patients with T1 tumors survived 5 years. Treat- ment outcome was related to pretreatment weight loss, but in contrast to the fi ndings of Sibley, age was not a prognostic factor. Only one fatal pneu- monitis was reported, although morbidity was likely underreported due to the retrospective nature of these studies.

TABLE 14.1. Selected reports of surgery for high-risk early-stage NSCLC.

Reference Method n Stage Surgery OS Level of evidence

Pastorino¹³ R 116 IA Lobe/Pn 35% (5 years) 3

Miller¹⁵ R 31 IA Wed (21)/Seg (10) 31% (5 years) 3

Errett¹⁷ R 100 I Wedge 69% (6 years) 3

Read¹⁶ R 113 IA Seg (106)/Weg (7) 51% (5 years) 3

Landreneau¹⁹ R 102 IA Wed (42)/VATS (60) 58%/65% (5 years) 3

Shennib²² P 31 IA VATS^a 29% (5 years) 2++

Abbreviations: Lobe, lobectomy; OS, overall survival; P, prospective; Pn, pneumonectomy; R, retrospective; Seg, segmental resection; VATS, video- assisted thorascopic resection; Wed, wedge.

aPostoperative radiotherapy planned.

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The largest reported retrospective radiotherapy series employing conventional radiotherapy planning, from Queensland Radium Institute, consists of 347 patients with T1N0 and T2N0 tumors.²⁵ The median age for the group was 70 years, and all patients were treated to 50Gy in 20 fractions over 4 weeks. Survival correlated with tumor size with 5-year survival rates of 32% and 21% for T1 and T2 tumors, respectively. Despite the use of clinical staging, results from this large series are similar to those reported for patients with cardiopulmonary dysfunction undergoing limited surgery for comparably sized tumors.

14.1.6. Prospective Trials of Radiotherapy in Patients with Compromised Lung Function (Level of Evidence 2 +)

The advent of three-dimensional conformal therapy helps to ensure appropriate coverage of the intended target, while at the same time limit- ing radiation exposure to the surrounding normal structures. Few trials have been designed exclu- sively for high-risk stage I NSCLC, but recently reported prospective dose escalation trials have included this population. A phase I/II Radiation Therapy Oncology Group (RTOG) study administered escalating radiation doses with conformal techniques depending on the percentage of lung volume irradiated. In the small volume bin (i.e., 20Gy to <25% total lung volume), dose was sequentially increased from 70.9Gy to 90.3Gy.²⁶ Clinical stage I NSCLC composed 44% (77/177) of the study population. Median follow-up ranged from 13.4 months to 18 months, with an esti- mated median survival approaching 27 months for patients with clinical stage I NSCLC. A dose escalation study at the University of Michigan demonstrated that doses as great as 102.9Gy could be delivered with conventional fraction- ation when the volume of irradiated lung was restricted.²⁷ The median survival for patients with stage I /II NSCLC was 20 months and local tumor control was 61% if doses greater than or equal to 92Gy were applied.

Radiotherapy treatment schemes that acceler- ate completion of the treatment course may be more effective than conventionally fractionated (e.g., protracted) regimens. A randomized trial in the United Kingdom compared continuous

hyperfractionated accelerated radiotherapy (CHART), 54Gy in 36 fractions of 1.5Gy over 12 days, to conventional radiotherapy, 60Gy over 6 weeks.²⁸ While the majority of patients had stage III disease, 169 patients with stage I/IIA NSCLC were included. However, only a small subset of patients with early stage disease (∼20%) had clinical T1N0 lesions. Two-year survival was signiﬁ - cantly improved with CHART for patients with stage I/II disease, 37% versus 24%, and the dif- ference remained at 4 years (18% vs. 12%).

Accelerated once-daily (e.g., hypofractionated) conformal radiotherapy is currently being explored in a phase I prospective clinical trial conducted by the Cancer and Leukemia Group B (CALGB). Eligibility is limited to high-risk patients with stage I NSCLC (i.e., <4cm). The radiation fraction size is progressively increased from 2.41Gy to 4.11Gy while the total nominal dose is kept at 70Gy and the total treatment time is reduced to 3.5 weeks. This schedule yields a stepwise reduction in the treatment time, with a corresponding potential increased biological effect.

Hypofractionated therapy with charged particles has also been evaluated prospectively for early-stage NSCLC. Protons and carbon ions have physical advantages over conventional X-ray beams and may be shaped to deliver a high dose of radiation to a central lung tumor with relative sparing of the surrounding functioning lung tissue. Accordingly, these treatments should help minimize the extent and severity of pulmonary injury and may beneﬁ t patients with severe underlying pulmonary disease. A phase II trial from Loma Linda enrolled 68 patients with stage I NSCLC.²⁹ Proton therapy at doses ranging from 51 to 60 cobalt Gy equivalent (CGE) in 10 fractions/2 weeks was utilized. With a median follow- up of 30 months, 3-year local tumor control and disease-speciﬁ c survival were 74% and 73%, respectively, and symptomatic radiation pneu- monitis was not observed. Superior local tumor control was obtained for clinical T1N0 lesions (87%), compared with T2N0 disease (49%). A phase I/II study evaluating hypofractionated delivery of carbon ion particles included 81 patients treated to a dose of 59 to 94 CGE in 9 to 18 fractions.³⁰ Thirty-seven of 81 patients remain alive after a median follow-up of 40 months, and

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23% absolute local tumor relapse was noted.

Whether charged particle therapy is more efﬁ ca- cious than photon irradiation delivered with advanced technologies (e.g., three-dimensional conformal therapy) has not been assessed and charged particle therapy is not widely available given the prohibitive cast of such facilities.

14.1.7. Body Stereotactic Radiosurgery (Level of Evidence 2 +)

The preliminary results of prospective studies exploring stereotactic radiosurgery have recently been reported. A phase I dose escalation trial assessing stereotactic radiosurgery was conducted at Indiana University.³¹ Eligible patients included those with clinically staged T1 or T2 (tumor size <7cm) N0M0 biopsy-conﬁ rmed NSCLC. All patients had comorbid medical problems that precluded thoracotomy. The median age was 75 years. Radiosurgery was administered in three separate fractions over 2 weeks. The dose was safely increased from 800cGy per fraction (2400cGy total) to 2000cGy per fraction (6000cGy total) for patients with both T1 and T2 lesions.

The overall response rate (n = 37) was 87% (com- plete response, 27%). Six local tumor recurrences were observed after a median follow-up 15.2 months. A phase II multi-institutional trial based on the Indiana University experience was recently activated by the RTOG. Single fraction radiosurgery has been explored in Europe, and Hof and colleagues conducted a phase I/II study of stereotactic radiosurgery in 10 patients with stage I NSCLC.³² Total doses applied ranged from 19 to 26Gy. Local tumor control was obtained in 8 of 10 lesions with a median follow-up period of 14.9 months and actuarial overall survival was 64% at

24 months. Distant metastases developed in ﬁ ve patients and mediastinal lymph node relapse was found in an additional patient. Table 14.2 summarizes the results of select radiotherapy series.

14.2. Summary of Published Data and Their Impact on Clinical Practice

The available published clinical data are not of sufﬁ cient quality to provide deﬁ nitive guidance for patients with early stage NSCLC. Trials of surgery and radiotherapy vary greatly regarding patient selection, thoroughness of staging [e.g., mediastinoscopy, positron emission tomography (PET) scan], tumor location, and tumor burden.

The published evidence is generally of level 2 to 3, the results are conﬂ icting, and no recommendation can be made. The choice of therapy should be individualized by patient and the experience of the institution.

The results of the LCSG phase III trial clearly indicate lobectomy should be considered the optimal surgical procedure for stage I NSCLC.

Therefore, patients should be thoroughly evaluated and pulmonary rehabilitation should be considered for patients with marginal pulmonary function. The level of evidence is 1– and the grade of recommendation is A.

TABLE 14.2. Selected reports of radiotherapy for early-stage NSCLC.

Reference Method n Stage Dose/Fx size LC OS Level of evidence

Gauden²⁵ R 167 IA 50/2.5 – 32% (5 years) 3

Henning²⁷ 3D/P 11 I 92.4–102.9/2.1 76% (2 years) – 2+

Bradley²⁶ 3D/P 77 I 70.9–90.3/2.15 65% (3 years)^a 36% (3 years)^a 2++

Bush²⁹ Proton 27 I 50.1–73.8 CGE/5.1 87% (2 years) 86% 2+

Timmerman³¹ SRS/P 37 I 24–60/8–20 31/37 – 2+

Abbreviations: 3D, conformal radiotherapy; CGE, cobalt GY equivalent; LC, local tumor control; OS, overall survival; P, prospective; R, retrospective; SRS sterotactic radiosurgery.

aEstimated from survival curve.

Lobectomy should be considered the optimal surgical procedure for stage I NSCLC; preop- erative pulmonary rehabilitation should be considered for patients with marginal pulmonary function (level of evidence 1–; grade of recommendation A).

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The outcome of limited surgical resection and radiotherapy are greatly dependent on patient selection. Stage IA patients with deﬁ ned poor lung function and/or medical comorbidity pre- cluding anatomical resection appear to have an approximate 30% expectation for long-term survival with either limited resection or aggressive radiotherapy delivered with modern techniques.

Segmental resection with wide surgical margins results in a lower risk of local tumor relapse compared with wedge resection and may reduce the risk of local tumor failure compared with conventionally fractionated radiotherapy. Moreover, local tumor control following radiotherapy relates directly with tumor volume, and a surgical approach may be advantageous for larger tumors (e.g., >3.5–4cm) if adequate margins can be obtained. Newer radiotherapy approaches, including accelerated conformal treatment and stereotactic body radiosurgery, may improve results compared with traditional radiotherapy.

The quality of evidence is 2 to 3, and the grade of recommendation is C. Large-scale multi- institutional trials are necessary for conﬁ rma- tion. The treatment decision should be based on the experience of the center and patient prefer- ence, guided by estimates of relative toxicity.

Whether adjuvant radiotherapy reduces local tumor failure and improves outcomes after limited surgery remains to be determined. While local tumor relapse is clearly increased following limited resection compared with lobectomy, CALGB 9335 did not establish the value of external beam radiotherapy. The concerns raised regarding the potential detrimental effects of postoperative radiotherapy in the PORT meta- analysis (particularly for N0 disease) may be germane, particularly if large radiotherapy portals are utilized.³³ Initial retrospective trials of adjuvant brachytherapy report promising results, but prospective data from the recently activated ACOSOG trial will not be available for several years. No recommendation can be made regarding the role of adjuvant radiotherapy at this time.

14.2.1. Our Personal View of the Data and Future Trends

All patients with potentially resectable lung cancer and compromised pulmonary function should be evaluated in a multidisciplinary lung cancer clinic, with input by an experienced chest radiologist, thoracic surgeon, radiation oncologist, pulmonologist, and medical oncologist. All continuing smokers should have intense and ongoing smoking cessation counseling begin- ning with their ﬁ rst visit. High-risk patients should be immediately enrolled in a pulmonary rehabilitation program. Sometimes the combina- tion of smoking cessation and pulmonary rehabilitation will render a patient ﬁ t enough for lobectomy or at least segmentectomy. If not, thorough staging (PET scan, sometimes mediastinoscopy) will determine the clinical stage as accurately as possible.

Options for patients who cannot undergo standard resection include wedge resection (open or thoracoscopic), wedge resection with adjuvant radiotherapy, wedge resection with brachytherapy, primary radiotherapy (hypofractionation, intensity–modulated radiation therapy (IMRT), respiratory gating, stereotactic radiosurgery), radiofrequency ablation (experimental), and any of the preceding combined with chemotherapy, including radiosensitizing chemotherapy. All patients should be considered for inclusion in one of several current and upcoming clinical trials evaluating these modalities in a prospective and occasionally randomized fashion.

Patients at high-risk for receiving anesthesia and patients with extremely limited pulmonary reserve will generally be treated nonsurgically.

Central lesions that are not amenable to limited resection are also generally treated non surgically.

Modestly hypofractionated three-dimensional conformal radiotherapy is generally employed outside of the clinical trial setting. The extent of hypofractionation/acceleration is guided by the volume of irradiated lung. Patients treated with radiotherapy are also evaluated for respiratory gating in order to limit the effect of tumor motion.

Patients who have potential for surgical resection should have smoking cessation and pulmonary rehabilitation and a complete cardiac The value of adjuvant radiotherapy on local

tumor control and improved survival after limited surgery remains to be determined.

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evaluation. At the time of wedge resection, place- ment of large hemoclips at the apex of the wedge or the area of closest margin will facilitate postoperative radiotherapy.

Given the heterogeneous nature of the high- risk patient population, comparative prospective, randomized trials of surgery and radiotherapy may not be feasible. The mature results of ongoing trials exploring accelerated conformal radiotherapy, stereotactic radiosurgery, and wedge resection and brachytherapy will provide important information to help guide local therapy. Whether systemic chemotherapy may be of beneﬁ t has not been addressed, but this issue is of increasing consideration particularly given the results of recent trials demonstrating a survival beneﬁ t for the addition of chemotherapy to surgical resection for early-stage NSCLC.^34,35

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