Treatment advances for medically inoperable non-small-cell lung cancer: emphasis on prospective trials

Review

Treatment advances for medically inoperable non-small-cell lung cancer: emphasis on prospective trials John W Powell, Elisabeth Dexter, Ernest M Scalzetti, Jeffrey A Bogart

Advances in technology have changed the treatment of patients with early stage non-small-cell lung cancer who are not healthy enough for standard surgical resection. Previously, patients with severe underlying cardiopulmonary dysfunction were often dissuaded from pursuing definitive therapy, even though most patients died from their lung cancer and not as a result of comorbid medical illness. Recent advances in the technology to treat early stage disease have led to new-found enthusiasm for treating and studying high-risk patients. This Review focuses on the management of these patients, including use of conformal radiotherapy, stereotactic body radiation therapy, sublobar resection, intraoperative brachytherapy, and radiofrequency ablation. Ongoing challenges are presented and prospective data are emphasised.

Lancet Oncol 2009; 10: 885–94

Introduction

Correspondence to: Prof Jeffrey A Bogart, Department of Radiation Oncology, SUNY Upstate Medical University, 750 E Adams Street, Syracuse, NY 13210, USA [email protected]

The International Agency for Research on Cancer estimated 1·18 million deaths attributable to lung cancer in 2002.1 Although treatment of advanced lung cancer remains a significant challenge, outcomes for patients with early stage disease are encouraging, with 5-year overall survival rates of 68·5% for surgically treated pathological stage IA disease and 59·0% for stage IB disease.2 Largely because of medical comorbidities related to tobacco smoke, around 25% of patients with early stage non-small-cell lung cancer (NSCLC) do not have standard surgical treatment.3 Until recently, this medically inoperable population was poorly studied, partly because of therapeutic nihilism. Advances in radiation oncology, surgery, and interventional radiology can improve the therapeutic index, which has given high-risk patients greater confidence in pursuing definitive therapy. An example is the rapid adoption of stereotactic body radiation therapy (SBRT) in clinical practice (figure 1), and inclusion of SBRT in the treatment guidelines of the National Comprehensive Cancer Network.4 This Review focuses on treatment options for high-risk patients with early stage NSCLC, with emphasis on prospective data and ongoing clinical studies.

regional nodal regions does not seem beneficial. Severe treatment-related complications, including pulmonary toxicity, are unusual in most series, but morbidity is likely under-reported in these retrospective studies. There is a suggestion that pulmonary and esophageal toxicity are increased when the mediastinum is electively irradiated. The interpretation of retrospective studies for early stage NSCLC is difficult because the study population is often poorly defined, and rigorous staging evaluation is rarely done. Nevertheless, conventional radiotherapy seems to cure a small proportion of patients with stage I NSCLC, although there is substantial room for improvement in tumour control.

Department of Radiation Oncology (J W Powell MD, Prof J A Bogart MD), Department of Surgery (E Dexter MD), and Department of Radiology (E M Scalzetti MD) SUNY Upstate Medical University, Syracuse, NY 13210, USA

Three-dimensional conformal radiotherapy Three-dimensional conformal radiation therapy (3DCRT) allows greater confidence in developing multiple-field complex plans. The risk of geographic miss is reduced because the position of both the target and relevant healthy tissue can be visualised. Also, the volume of healthy tissue receiving high doses of radiotherapy can be less than with conventional planning.8

External beam radiotherapy External beam radiotherapy is the most commonly reported treatment alternative for medically inoperable NSCLC. Large reviews of more than 2000 patients have summarised reports of early stage NSCLC after fractionated radiotherapy.5–7 Several trials show that local tumour relapse is the most common cause of treatment failure. Sibley5 notes that 30% of patients died from local relapse and a median local-relapse rate of 40% was reported by Qiao and colleagues.7 Tumour size is known to be a main determinant of local tumour control. Overall, studies show a drop-off in 5-year survival for T2N0 tumours (range 4–24%) compared with T1N0 lesions (range 26–67%). Radiation dose may be associated with improved tumour control, with better outcomes observed with doses greater than 60 to 65 Gy. However, increasing the treated volume by including clinically uninvolved www.thelancet.com/oncology Vol 10 September 2009

Figure 1: Stereotactic body radiation therapy (SBRT) Multiple non-coplanar conformal beams are shown targeting a T1N0 non-small-cell lung cancer of the left lung.

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A

B

C

D

Figure 2: Image guided radiotherapy (IGRT) Comparison of an IGRT cone-beam CT (A,B,C) with the treatment planning CT (D) to verify target accuracy during treatment of stage I non-small-cell lung cancer.

Dose escalation Simply applying 3DCRT planning with conventional radiation doses (eg 66–70 Gy) resulted in discouraging outcomes for stage I NSCLC (3-year local tumour control of 43%) in a review of 116 patients.9 In the 1990s, prospective studies of 3DCRT from the University of Michigan, Memorial Sloan Kettering Cancer Center (MSKCC), and the Radiation Therapy Oncology Group (RTOG) explored the hypothesis that increasing the nominal total radiotherapy dose, by extending the treatment course, will improve outcomes.10–12 Substantial dose escalation, from 83·8 Gy to 102·9 Gy, was possible when the volume of irradiated lung was restricted. Despite these doses, local relapse remained a substantial problem. 3-year local progression-free survival was 68% in the University of Michigan study, with a 35% failure rate inside the planning target volume, and 2-year locoregional tumour control ranged from 55% to 73% in the RTOG trial. Moreover, a clear dose-response relationship was not established. Even with 3D planning and the volume of treated lung restricted, dose-limiting toxicity was observed when approaching 90 Gy in the RTOG and MSKCC studies. Although acute toxicity was acceptable, the appearance of late severe pulmonary toxicity, including treatment related mortalities, is of concern. Overall, the results of dose-escalated 3DCRT regimens are not promising enough to warrant consideration as primary treatment for stage I NSCLC. The increased cost and time commitment associated with protracted regimens further limit their use.

Dose intensification Decreasing the time to complete a course of radiation treatment (eg, increasing dose intensity) might improve efficacy, partly by reducing the opportunity for tumour repopulation.13 One way to increase dose intensity is to give multiple daily radiotherapy fractions. A regimen of 886

continuous hyperfractionated accelerated radiotherapy (CHART; 54 Gy in 36 fractions over 12 consecutive days) improved survival compared with conventional fractionated radiation, in a phase 3 setting in the UK.14 For 169 patients with stage I/IIA NSCLC (around 20% had clinical T1N0 NSCLC), 4-year survival was 18% with CHART and 12% with conventional radiotherapy.14 An alternate approach to improve treatment efficacy is to increase the dose of radiation given in each treatment, such that therapy is completed in fewer sessions (eg, hypofractionation). In a multi-institutional trial, the Cancer and Leukemia Group B (CALGB) assessed whether 3DCRT could facilitate hypofractionation. The study was designed specifically for high-risk patients with T1N0 or T2N0 (<4 cm) NSCLC.15 A nominal dose of 70 Gy was maintained while treatment was reduced from 29 to 17 daily fractions. Outcomes were encouraging, including a median survival of 38·5 months and 92% local tumour control with 51 months median follow-up. Treatment was well tolerated, with 5% grade 3 non-haematological toxicity. On the basis of this result, further study of accelerated 3DCRT is planned. An accelerated hypofractionated 3DCRT regimen, 60 Gy in daily 4 Gy fractions, has also been studied in patients with high-risk NSCLC, by the National Cancer Institute of Canada, and a report of their completed phase 2 study is pending.16

Stereotactic body radiation therapy (SBRT) Stereotactic body radiation therapy (SBRT) is a form of extreme hypofractionation that uses sophisticated techniques to deliver highly conformal “ablative” doses of radiotherapy. SBRT regimens generally deliver doses higher than 10 Gy per fraction in five or fewer fractions. Only small targets can be treated (typically <5 cm), and the accuracy and reproducibility of treatment is essential. During the treatment planning process, the extent of tumour motion during the breathing cycle must be defined, which can be done with four-dimensional CT imaging. Target volumes should be contoured on the pulmonary windows of the planning CT, and smaller treatment margins are used compared with conventional radiotherapy. A typical plan has six to 12 convergent beams and normal tissue constraints must be considered in the planning process (figure 1). Once measured, respiratory motion is accounted for during treatment by one of several techniques. Breath-holding techniques or abdominal compression devices might be used to limit the extent of tumour excursion. Alternatively, treatment can be gated such that the beam-on time is matched to specific phases of the respiratory cycle.17 Image guided radiotherapy (IGRT) has been important for the development SBRT.18 IGRT systems use 3D imaging, such as cone-beam CT, for target verification with the patient in the treatment position on the radiation couch (figure 2). Thus, real time correction of patient www.thelancet.com/oncology Vol 10 September 2009

Review

setup errors can be done before (and during) each session, which is crucial when very large doses are given to small targets with tight treatment margins. IGRT also facilitates “adaptive” therapy by showing tumour changes that can happen between treatments. Clinical experience with body radiosurgery was first reported in 1995,19 and recent interest in lung SBRT comes largely from prospective studies at Indiana University.20,21 These trials show that very high radiation doses can be delivered to lung lesions (of limited volume) with SBRT. A phase 1 study used doses as high as 72 Gy in three fractions for T1–3N0 NSCLC, and a subsequent phase 2 study, including 70 patients with stage I NSCLC, used an SBRT regimen of 60 Gy in three fractions for T1 tumours and 66 Gy in three fractions for T2 tumours. Local tumour control was excellent in the phase 2 study (95% at 2 years), but excess severe pulmonary toxicity was noted in patients with centrally located tumours, including four treatment-related deaths. These deaths were partly caused by severe bronchial stenosis and consequential lung collapse. The RTOG recently completed a multi-institutional study assessing the SBRT regimen used at Indiana University: 60 Gy in three fractions for T1N0 and T2N0 (≤5 cm) NSCLC.22 Only patients with peripheral tumours (>2 cm from the Number Stage of patients

bronchial tree) were enrolled. Rigorous central accreditation and quality assurance were mandated. A preliminary report described acceptable treatment-related toxicity, and mature outcomes are awaited.22 Based on the above experiences, a three-fraction SBRT regimen has been widely adopted in North America for treating peripheral stage I NSCLC, but there is considerable variation in clinical practice. A review of 257 patients with stage I NSCLC treated in Japan reported excellent local tumour control (eg, 91·6%) for a wide range of SBRT regimens, as long as the predicted biologically equivalent dose was at least 100 Gy.23 Local relapse increased to around 43% if the biologically equivalent dose was less than 100 Gy. Steep dose-response relationships have also recently been reported for three and four fraction SBRT regimens, emphasising the need for caution in choosing SBRT dose and fractionation.24,25 Although not all trials stratify treatment according to tumour location, the severe toxicity reported for central tumours in the study at Indiana University, and in other trials, has raised serious concerns. The appropriate SBRT regimen for central tumours is not clear, and the RTOG recently initiated a dose escalation study using five fractions.26 A risk-adapted approach has been studied

Medically Any Biopsy Dose Design Median proven, fractionation operable, toxicity follown (%) up ≥grade 3, n (%) (months) n (%)

Chest– Local Dyspnoea, Rib Grade 1–2 Any control fracture, wall pulmonary pneumonitis, n (%) pain, n (%) toxicity, n n (%) n (%) (%) 45 (100)

Kyoto University, Japan28

45

T1–2 N0M0

P

30

45 (100)

4×12 Gy

18 (40)

0

Stanford University, USA29

20*

T1–2 N0M0

P

18†

20 (100)

1×15–30 Gy

NA

4(12·5)‡

Aarhus University, Denmark30

40

T1–2 N0M0

PM

28·8

39 (97·5)

3×15 Gy

0

NA

Indiana University, USA21

70

T1–2 N0M0

P

17·5

70 (100)

3×20–22 Gy

0

14 (20)

RTOG 0236, USA22

55

T1–3 N0M0

PM

8·7

55 (100)

3×20 Gy

0

10 (18)

University of Heidelberg, Germany31

42||

T1–3 N0M0

PR

15

42 (100)

1×19–30 Gy

0

Tohoku University, Japan32

31

T1–2 N0M0

P

32

31 (100)

3×15 Gy or 8×7·5 Gy

Karolinska University, Sweden33

57

T1–2 N0M0

PM

23

38 (67)

3×15 Gy

VU University, 206 Netherlands27

T1–2 N0M0

PD

12

64 (31)

3–8× 7·5–20 Gy

11 (35)

0

39 (19)

NA

NA

NA

94% at 3 y T1: 83% OS at 5 y; T2: 72% OS at 5 y

NA

NA

NA

92% at 1 y§

85% OS at 1 y

NA

12 (30)

NA

16 (40)

85% at 2 y

48% at 2y

58 (82·9)¶

NA

NA

NA

NA

95% at 2 y

54·7% OS at 2 y

NA

NA

NA

NA

NA

NA

NA

0

NA

NA

NA

NA

NA

68% at 3 y 37% OS at 3 y

1 (3·2)

27 (87·1)

29 (93·5)

NA

NA

NA

T1: 78% at 72% OS at 3 y 3 y; T2: 40% at 3 y

12 (21)

NA

10 (17·5)

14 (24·6)

4 (7)

11 (19·3)

96% crude 65% rate crude rate

6 (3)

NA

NA

4 (1·9)

25 (12) 93% at 2 y

4 (12·5)

8 (20)

100

Survival

12·5

6

64% OS at 2 y

P=prospective trial. PR=prospective and retrospective reported together. PM=prospective multicentre. PD=prospective database. OS=overall survival. RTOG=Radiation Therapy Oncolovy Group. T1=American Joint Committee on Cancer tumour stage 1. T2=American Joint Committee on Cancer tumour stage 2. NA=not available. *Data refer only to patients with NSCLC, although study also enrolled patients with lung metastases. †For living patients. ‡Data not limited to early stage NSCLC patients. §For patients receiving greater than 20 Gy. ¶Includes all grade 1–2 toxicity. ||Includes ten patients on a phase 1–2 protocol.

Table 1: Prospective studies of SBRT for early stage NSCLC

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in the Netherlands, and the SBRT regimen varies according to tumour location; the most conservative regimen is used for central lesions, an intermediate regimen for very peripheral tumours proximal to the ribcage, and the Indiana University regimen is used otherwise.27 This approach has yielded excellent local tumour control and acceptable treatment related toxicity in more than 200 patients. Table 1 summarises the results of prospective studies in North America, Europe, and Asia.21,22,27–33 When assessing SBRT trials, differences in patient characteristics (eg, operable vs medically inoperable) and tumour characteristics (eg, tumour size, location, and pathology) need to be considered. Moreover, there is no uniform method of dose reporting: dose may be prescribed to the isocentre or the periphery of the target, and different corrections are used for tissue heterogeneity. The SBRT course is generally well tolerated, although patients with cardiopulmonary compromise can find it difficult to remain motionless in the treatment position for the duration of each session. The full extent of late toxicity might only be appreciated as SBRT becomes more widely adopted in clinical practice. In addition to central tumour location, factors associated with severe toxicity include tumour location and prior treatment (radiotherapy or chemotherapy). Recent reports show higher than expected skin, chest wall, and rib toxicity, including one report with a 48% actuarial 2-year risk of rib fracture.34 Tumour location and treatment technique might dictate the risk of these complications.35 Because of concerns for late toxicity with large fraction sizes, and the risk of late tumour recurrence, long-term results are necessary for a more complete understanding of SBRT.

Surgery Sublobar resection was widely reported as an alternative for some patients with early stage NSCLC, beginning in the 1970s.36 Lobectomy was better than limited resection in healthy patients with stage I NSCLC, although the value of sublobar resection continues to be debated.37–39 Nevertheless, sublobar resection is an appealing “lung-sparing” consideration for high-risk patients with stage I NSCLC that are healthy enough for general anesthesia. Retrospective reports suggest reduced mortality and morbidity, from better sparing of pulmonary function, for limited surgery compared with lobectomy in patients with physiological impairment. The advent of minimally invasive surgery, with video-assisted thorascopic resection (VAR), might further reduce the morbidity and result in shorter hospitalisation, less pain, and quicker recovery compared with thoracotomy.40 Wedge by VAR is limited to easily localised, small peripheral tumours where excising an adequate portion of lung tissue is technically feasible. Segmentectomy by VAR results in the anatomic 888

dissection of the segment of lung encompassing the cancer. The advantage over simple wedge resection is dissection of regional or hilar lymph nodes, resulting in more accurate staging. Outcomes following limited surgical resection vary greatly in retrospective studies and might reflect the criteria used to select the study population. Survival seems to be least encouraging in studies that use strict measures of pulmonary dysfunction. For example, 5-year survival was 31% (excluding one postoperative death) following segmental or wedge resection for 32 patients with T1NO NSCLC and a forced expiratory volume in 1 s (FEV1) of less than 1·0 L.41 Similar outcomes were also noted in a larger trial following wedge resection in patients with a mean FEV1 of 1·25 L.42 However, studies that use less strict criteria for performing limited surgery report better outcomes. In one series, 6-year overall survival was 75% following wedge resection, exceeding the results of lobectomy. The median FEV1 before wedge resection was 1·56 L, and wedge resection was done more often than lobectomy.43 One limitation of sublobar resection is the increased risk of local relapse. For example, local relapse was 22·7% with segmentectomy versus 4·9% with lobectomy in a study from Rush Medical Center,44 and Miller reported local relapse in a third of patients when the tumour crossed an intersegmental plane.40 The distinction between segmentectomy, where anatomic boundaries are observed, and wedge resection might be important in determining the likelihood of local relapse. Margin status might also be associated with the risk of local relapse, and a minimum margin of 1–2 cm seems preferable.45,46 The first prospective multi-institutional trial specific to high-risk patients with stage I NSCLC was designed by the CALGB to assess the feasibility of wedge VAR.47 After VAR, patients with pathological T1N0 NSCLC remained on study and received external beam radiotherapy. An important aspect of this trial is that strict criteria for pulmonary dysfunction were required for protocol entry: FEV1 of less than 40% of predicted value, carbon monoxide diffusing capacity in lung of less than 50% of predicted value, maximum oxygen consumption less than 15 mL/kg per min, or arterial carbon dioxide level higher than 45 mm Hg. VAR did not meet predefined feasibility criteria; operative failure rate was 29% (19 patients), including the need to convert to open thoracotomy in 17% (ten patients).47 Unfortunately, the role of adjuvant external radiotherapy was not defined in this study. Nevertheless, this is the only prospective surgical study for patients with well defined pulmonary dysfunction. Median survival was around 32 months and 5-year overall survival about 29% for patients with pathologic T1N0 NSCLC (excluding one postoperative death).47 These data are a benchmark for other prospective studies of high-risk NSCLC. Complications of wedge VAR were well described in the CALGB study and included 4% deaths from cardiowww.thelancet.com/oncology Vol 10 September 2009

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respiratory failure (two patients), 4% respiratory failure requiring mechanical ventilation (two patients), 6% pneumonia (three patients), and 10% prolonged air leak (five patients).47 For comparison, in a large retrospective report, complications including respiratory failure, empyema, air leak, myocardial infarction, and pneumonia were observed in 16% (six patients) treated with VAR and 28% (16 patients) treated with open sublobar resection.40

Intraoperative brachytherapy Intraoperative brachytherapy is a logical alternative to adjuvant external beam radiotherapy. Radiation dose is applied directly to the tumour bed, so precise targeting of the region at risk is better than with external radiotherapy, and a reduced volume of surrounding functional lung is exposed to radiation. As a practical benefit, patients are not required to undergo additional therapy following surgical intervention. Brachytherapy can be done with an open or minimally invasive approach. Indications are similar to those described for limited resection. Although general anaesthesia is necessary, treatment of patients with very poor lung function has been reported, including one series with an average pretreatment FEV1 of 0·59.48 Intraoperative brachytherapy is usually done with Iodine-125 (¹²⁵I), a radionuclide with a half-life of 60 days, which emits low-energy gamma rays. Two techniques for permanently implanting ¹²⁵I seeds have been described.49,50 In the largest study, seeds were sewn in an evenly spaced pattern onto a mesh of polyglycolic acid.49 The mesh was applied so that it straddled the resection staple line after sublobar resection. Alternatively, a double suture technique can be used where ¹²⁵I seeds are intermittently embedded in suture-material-like beads on a string.50 A string of seeds is then sutured along each side of the resection margin. Typically, the implant is designed to provide a dose of 100 Gy to a depth of 5 mm with the mesh technique, or 100 Gy to a depth of 7 mm along the resection margin if the double strand technique is used.51 Final dosimetry is generally done on the basis of seed position on postoperative imaging. Provocative results have been reported in series of intraoperative brachytherapy, with the largest study from investigators at Allegheny General Hospital and the University of Pittsburgh (Pittsburgh, PA, USA). In a retrospective comparison of patients who had sublobar resection with or without ¹²⁵I brachytherapy, local relapse was reduced in the brachytherapy cohort (2% vs 19%), whereas other outcomes were similar.52 A recent update included 145 patients treated with sublobar resection and brachytherapy; only six local relapses (defined as within the same lobe) were observed, with a median follow-up of 38 months.49 Results were similar whether thoracotomy or VAR was used and did not vary by the extent of resection margin. A separate report analysed larger lesions (eg, T2N0) and found no difference in local relapse between patients treated with www.thelancet.com/oncology Vol 10 September 2009

sublobar resection and brachytherapy or with lobectomy.53 A series using the double suture technique from Tufts Medical Center (Boston, MA, USA) included 35 high-risk patients.50 With median survival of 51 months, only two local relapses were observed, although six additional patients relapsed in the mediastinum or chest wall.50 As expected, survival in these series is largely related to patient selection and tumour size, with 5-year survival ranging from 18% to 67%.48–53 The toxicities observed after sublobar resection plus brachytherapy are generally acceptable and are comparable to sublobar resection alone with respect to hospital stay, recovery, and long-term pulmonary compromise. Perioperative mortality ranges from 0–3·4%.48–53 Complications related to seed migration or excess dosing to critical structures, such as pulmonary artery rupture, have rarely been observed.54 Although radioactive sources are used, a recent analysis showed little radiation exposure to physicians and hospital staff during the procedure.55 Although the results of brachytherapy are impressive, extensive experience is limited to a few institutions and it is not clear whether less experienced investigators would have the same results. A phase 3 study, by the American College of Surgeons Oncology Group (ACOSOG), is comparing sublobar resection versus sublobar resection plus ¹²⁵I brachytherapy in high-risk patients withT1N0 NSCLC.51 This trial should provide robust data regarding both the efficacy and toxicity of sublobar resection.

Radiofrequency ablation Radiofrequency ablation (RFA) is a percutaneous image-guided procedure for treating both primary and metastatic tumours. RFA is approved by the US Food and Drug Administration (FDA) for tumour treatment in general; it has not received specific approval for use in the lungs, although experience in treating lung tumours is rapidly growing.56,57 Lung tumours are suited to RFA because of the insulating effect of air surrounding the solid tumour. RFA is done percutaneously under CT A

B

Figure 3: Radiofrequency ablation (RFA) RFA probe in non-small-cell lung cancer of the right upper lobe (A), and ground glass changes adjacent to lung lesion directly after RFA (B).

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guidance. Placement of the needle-electrode is similar to needle placement for biopsy; however, care in positioning the needle-electrode is crucial. RFA devices deploy tines that should encompass the targeted lesion with an extension of about 1 cm of surrounding lung tissue, and better tumour control has been suggested with larger ablation volumes.58 Radiofrequency energy is then applied and tissue is monitored for changes in temperature or impedance that indicate thermal coagulation. Ground-glass opacification is typically seen on CT in the surrounding lung tissue after the procedure (figure 3). RFA is often considered as primary therapy in patients who are not good candidates for limited surgery or definitive radiotherapy, and can be used to treat locally recurrent lesions after radiotherapy or limited surgery. RFA might be more convenient than alternative options because treatment can be completed in a single session (although repeat applications can be done) and a hospital stay is not usually necessary. The procedure currently seems best suited for peripheral lesions surrounded by lung parenchyma. Lesions that are centrally located near large blood vessels are not ideally treated with RFA because of the “heatsink” effect, where heat is dissipated by bloodflow. Large central airways can be damaged by the procedure and some studies require tumours to be located at least 1 cm from the trachea, main bronchi, oesophagus, heart, and major central blood vessels.59 Additionally, lesions near the diaphragm, lung apex, and scapula might be technically difficult to access. A current assessment of the efficacy of RFA for high-risk stage I NCSLC is challenging because most reports include predominantly metastatic lung lesions. However, some aspects of patient selection, and the toxicity profile of the technique have been reasonably well described. Tumour size seems to be an important

determinant of long-term tumour control, with higher rates of relapse noted in tumours larger than 2–3 cm.58,60 For example, in the report including the largest series of patients with stage I NSCLC (n=75), 5-year progression-free survival was 47% in tumours less than 3 cm, compared with 25% for larger tumours.60 Investigators have speculated that improved control of larger tumours might be possible with technical improvement in RFA devices or by combining the procedure with other treatments. Prospective data is becoming available, and the RAPTURE trial61 prospectively assessed RFA for metastatic and primary lung tumours (<3·5 cm) in seven centres in the USA, Europe, and Australia. Overall, the technical success rate for placement of the RFA device was 99%, and no treatment-related deaths were observed. Complete response at 1 year was defined as a 30% decrease in longest diameter and no evidence of tumour growth or contrast enhancement, and was scored for 88% of assessable patients. Although only 13 patients with stage I NSCLC were included, 2-year overall survival was an impressive 75%.61 Another prospective study included nine patients with NSCLC, although the stage was not specified and most patients had multiple lung tumours.58 Overall, the authors reported 7% incomplete local treatment at 18 months. Possible toxic effects were highlighted by an FDA-issued public health notification of deaths and serious injury attributable to RFA for lung tumours. Clinicians were recommended to use caution when delivering RFA to the lung, and patients were advised to enrol in clinical trials if possible. Overall mortality ranging from 0–5·6% has been reported after RFA to the lung.58,60–67 Pneumothorax is commonly observed after treatment, although only a small proportion of patients require percutaneous chest-tube placement. Other complications can arise from thermal injury to adjacent structures, resulting in

Study Follow-up design (months)

Number Number of patients of patients with stage I NSCLC

Local control Mean tumour size (cm)

Survival

Survival for patients with stage I NSCLC

Mortality Pneumothorax, Pneumothorax Pleural effusion, (%) n (%) requiring intervention, n n (%) (%)

Multiple institutions61

PM

NA

106

13

NA

88% CR*

NA

75% OS at 2 y

0

Okayama, Japan63

R

21·8 median

20

20

NA

NA

74% OS at 3 y

74% OS at 3 y

0

13 (57)

1 (5)

Providence, USA60 R

20·5 median

153

75

2·7†

47% at 5 y

NA

27% OS at 5 y

2·6

52 (28)

18 (9·8)

NA

68% OS at 2 y

NA

12 (63)

NA

NA

27 (20)

15 (10·9) 4 (17)

Pittsburgh, USA64

R

15 median

19

19

2·6

58% crude

68% OS at 2 y

0

Caserta, Italy65

R

NA

33

NA

3·4

97% crude rate 69% crude OS at 6 months

NA

0

3 (9)

0

3 (9)

Jeonju, South Korea66

R

12·5 mean

30

10

5·2

38% CR‡

40% crude OS

80% crude OS

3·3

9 (30)

2 (6·6)

2 (6·6)

Villejuif, France58

P

12 minimum

60

NA

1·7

93% at 18 months

71% OS at 1·5 y

NA

0

40 (54)

17 (23)

45 (60)

P=prospective. PM=prospective multi-institutional. R=retrospective. NA=not available. OS=overall survival. *CR defined as target tumours showing at least a 30% decrease in longest diameter compared with the diameter measured at 1-month CT, no evidence of tumour growth from the zone of ablation, and no evidence of contrast enhancement. †Data for subset of patients treated with local control as primary goal (as opposed to palliation). ‡CR defined as complete necrosis based on imaging findings.

Table 2: Reports of radiofrequency ablation (RFA) for pulmonary malignancy including early stage NSCLC (data reflects entire cohort unless noted)

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pain and perforation, and intrapulmonary haemorrhage, haemoptysis, pleural effusion, and pleuritic chest pain have been reported. Complications are usually mild and self-limited. Treatment of large masses can lead to a flu-like illness. Skin burns at the needle entry site have been described but are generally avoidable with careful technique. Table 2 summarises studies of RFA for stage I NSCLC.58,60,61,63–66 Preliminary results are encouraging, but longer follow-up in larger cohorts of stage I NSCLC patients will be necessary to establish the therapeutic index. An ongoing ACOSOG pilot prospective trial is assessing the safety and efficacy of RFA in high-risk T1N0 NSCLC.68

A

B

C

D

Challenges Although substantial progress has been made in the recognition and study of high-risk NSCLC, several issues remain to be settled. The first challenge is to define which patients should be considered medically inoperable. Evaluating the literature, it is often not possible to establish selection criteria for “inoperability” in retrospective reports, and even prospective studies have varying selection methods. Clinical practice guidelines for physiological assessment of patients being considered for lung cancer surgery were recently updated by the American College of Chest Physicians (ACCP).69 No treatment has been shown to be as effective as anatomical resection for early stage NSCLC. Therefore, patients should generally be assessed by a thoracic surgeon before proceeding with non-operative therapy, and pulmonary rehabilitation should be considered for borderline patients. Comparison of outcomes between clinical studies assessing alternate therapies for high-risk patients is challenging, because the selection of patients might substantially affect reported outcomes and toxicity. For example, 5-year survival was only 41% for patients with severe chronic obstructive pulmonary disease (and no known malignancy) who were part of a pulmonary rehabilitation programme.70 Outcomes are often biased in favour of surgical series, in which patients need to be healthy enough to tolerate general anaesthesia. Moreover, results might be provided according to pathological stage rather than clinical stage. Additional variables such as tumour size, location (peripheral vs central), histology, and gender need to be considered when comparing outcomes reported in the literature. The optimum endpoint to compare treatments is not defined, but local tumour control and relapse-free survival might be more valid than overall survival. The introduction of the revised staging system refines the definition of stage I NSCLC and should facilitate comparison of treatment results. Other than the ACOSOG trial assessing brachytherapy, few direct comparative trials have been done. The results of recently completed and ongoing prospective www.thelancet.com/oncology Vol 10 September 2009

Figure 4: Radiographic changes following radiotherapy CT appearance of left lung lesion at biopsy (A), 1 year (B), 2 years (C), and 3 years (D) after radiotherapy.

trials will be important to help guide therapeutic options for high-risk patients. The ACCP guidelines published in 2007 recommended sublobar resection over nonsurgical options for high-risk early stage NSCLC; however, evidence in support of SBRT has grown substantially and this recommendation might no longer be valid.71 In fact, results in compromised patients have led to pilot studies of SBRT in selected patients who are suitable candidates for lobectomy. A prospective comparison of SBRT and limited resection—assessing efficacy, toxicity, and quality of life—in patients with pulmonary compromise seems warranted. In any case, multidisciplinary assessment with full discussion of treatment options should be done routinely for patients with high-risk early stage NSCLC. Appropriate follow-up after non-surgical treatment for early stage NSCLC remains to be defined. Unlike surgical intervention, complete radiographic disappearance of a tumour is not typical following radiotherapy or RFA. Although treatment-induced pulmonary changes happen over time (figure 4), differentiating a recurrent tumour from pulmonary fibrosis can be challenging. FDG-PET imaging might help detect a recurrent tumour after RFA and radiotherapy, but abnormal activity can be observed with FDG-PET imaging several years after treatment.72,73 Recent prospective studies have integrated routine FDG-PET for initial staging and follow-up and should help define the applicability of FDG-PET imaging. Intensive local therapy seems to change the natural history of high-risk NSCLC. As local relapse decreases 891

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Search strategy and selection criteria References for this Review were found by searches of Medline, PubMed, and references from relevant articles by use of the search terms “medically inoperable”, “non-small cell lung cancer”, and terms for the specific treatments of interest. Abstracts and reports from meetings were included. The website Cancer.gov was used to help select ongoing prospective clinical trials. Only articles published in English, between January, 1990, and January, 2009, were included.

and patients live longer, the risk of developing distant metastases increases. The role of systemic chemotherapy or molecular targeted agents is not well defined for healthy patients with node-negative early stage NSCLC, although subset analysis from a randomised CALGB study suggested that patients with tumours larger than 4 cm might benefit from adjuvant chemotherapy.74 Drugs with activity against the epidermal growth-factor receptor and vascular endothelial growth-factor receptor have a defined benefit in advanced NSCLC and are now studied in earlier stage disease.75,76 There is currently no substantive prospective data regarding systemic therapy for medically inoperable stage I NSCLC, and future studies will need to address the integration of systemic therapy for this population.

Conclusion Advances in the past decade have changed the therapeutic approach to patients with high-risk early-stage lung cancer. The notion that this population is too frail to undergo definitive treatment has largely been abandoned, and efforts have shifted toward defining the relative merits of treatment alternatives. Results of prospective trials will provide further insight regarding appropriate treatment approaches for these patients. In the meantime, treatment for compromised patients with stage I NSCLC must be individualised on the basis of comprehensive multidisciplinary assessment. Contributors JWP and JAB were responsible for the literature search, tables, figures, and writing of the paper. ED and EAS contributed to the figures and writing. Conflicts of interest The authors declared no conflicts of interest. References 1 Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55: 74–108. 2 Mountain CF. A new international staging system for lung cancer. Chest 1986; 89: 225–33. 3 Bach PB, Cramer LD, Warren, JL, Begg CB. Racial differences in the treatment of early-stage lung cancer. N Engl J Med 1999; 341: 1198–205. 4 National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. http://www.nccn.org/professionals/ physician_gls/PDF/nscl.pdf (accessed Jan 2, 2009).

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