What is the role of radiotherapy in the treatment of operable stage I NSCLC?

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What is the role of radiotherapy in the treatment of operable stage I NSCLC?

Introduction

Surgery, at least lobectomy, is the standard of care for patients with operable clinical stage I non-small cell lung cancer. Conventionally fractionated radiotherapy can be used in patients who refuse lobectomy. Hypofractionated stereotactic ablative radiotherapy (SABR) is a new technique whose proponents argue that it may be as effective as lobectomy. In patients with poor lung function or other comorbidities who are judged high risk patients for lobectomy, limited surgery (segmentectomy or wedge resection) or radiotherapy, either conventional or SABR, may be options for curative treatment.

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Radiotherapy versus observation

The evidence that radiotherapy (or surgery for that matter) alters the natural history of stage I NSCLC is indirect and largely derived from its effect on local control. In a non-randomised retrospective analysis of a patient registry, outcomes for 91 patients with operable and inoperable stage I NSCLC (pathologic confirmation not available in 17) were compared: survival was significantly longer in the radiotherapy group (P<0.0001).[1]

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Surgery versus conventional radiotherapy

There has been no modern randomised comparison of surgery with conventional fractionated radiotherapy in patients with operable disease. In a population-based study using results from the North American Surveillance Epidemiology and End Result (SEER) database, the survival of patients having surgery was compared with that of patients treated with radiotherapy, including patients who were eligible to have surgery but refused.[2] The type of radiotherapy was not described, but around half the patients were treated in the period (1988-2002) before the use of SABR for stage I NSCLC became widespread. Patients who had surgery had superior survival compared with those who refused it with a hazard ratio of 0.437 (95% C.I. 0.301-0.632). In a further analysis of the SEER database 2001-2007, restricted to patients over the age of 65, survival following conventional radiotherapy was significantly worse than for patients having lobectomy or sublobar resection.[3]

In a single institution study, survival was better for patients with high risk stage I NSCLC having limited resection versus 3D conformal radiotherapy.[4] This difference was no longer evident after a multivariate analysis including other prognostic factors, or after a propensity-matched analysis of 34 matched pairs. In another single institution study the local control and survival at three years were 76% and 63% respectively for 40 patients having surgery, and 78% and 55% for 39 patients having conventionally fractionated radiotherapy.[5]

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Surgery versus SABR

Two randomised trials (ROSEL and STARS) in which surgery was compared with SABR in patients with operable clinical stage I NSCLC were closed early because of slow accrual.[6] Data from the two trials were pooled and survival based on intention- to- treat was compared between the arms. It should be noted that although survival was the primary endpoint in the STARS trial, it was an a priori defined secondary endpoint in the ROSEL trial. In ROSEL, the primary endpoints were local and regional control. Thirty one patients were randomised to SABR and 27 to surgery. The estimated overall survival at three years was 95% (95% C.I. 85-100) in the SABR group and 79% (95% C.I. 64-97) in the surgery group, with a hazard ratio of 0.14 (95% C.I. 0.017-1.190), p=0.037. There were no significant differences in recurrence free survival between the groups. Six patients died during follow up in the surgery group (two from cancer progression, one from second primary lung cancer, one from a surgical adverse event, and two from comorbidities). One patient in the SABR group died from cancer progression. Not all patients in the ROSEL study had pathologic confirmation of NSCLC. Of the six patients without a preoperative diagnosis on the surgical arm, one proved to have benign disease. Eight patients on the radiotherapy arm had no pathologic confirmation. The authors concluded that “SABR could be an option for treating operable stage I NSCLC. Because of the small sample size and short follow up, additional randomised studies are warranted.”

There are a number of non-randomised studies comparing outcomes in patients receiving surgery versus outcomes in patients receiving SABR for stage I NSCLC. Usually the SABR patients are not fit for surgery and this introduces a bias favouring surgery. In spite of attempts to adjust for differences in prognostic factors between groups, using techniques such as propensity matching and multivariate analysis, the results of these studies are not consistent.

Summary weighted average outcome data from a systematic review of 45 reports of SABR for stage I NSCLC comprising 3201 patients revealed a two year survival of 70% (95% C.I. 67-72).[7] This was similar to the 68% survival at two years (95%C.I. 66-70) for patients treated with surgery on a separate database from an earlier time period. Two year weighted average local control following SABR based on data from 29 studies in which it was reported was 91% (95% C.I. 90-93). These outcomes were not adjusted for comorbidity or other prognostic factors.

Although described as a meta-analysis, the study of Zheng et al is a comparison of outcomes reported in single arm SABR cohort studies versus outcomes in single arm surgery cohort studies from the same time period.[8] After adjusting for the effects of age and operability, there were no differences in overall survival comparing SABR with lobectomy (HR = 0.52, 95% C.I. 0.20-1.36, P = 0.15) or SABR with sublobar resection (HR = 0.49, 95% C.I. 0.19-1.30, P = 0.18).

Two population based studies using SEER data have compared outcomes in older patients (66 years and over) having surgery or SABR. In the first study (2001-2007), there was no significant difference in survival between 99 propensity matched pairs of patients having lobectomy or SABR with HR = 0.71 (95% C.I. 0.45-1.12, P = 0.14).[3] In the second study (2007-2009) survival and toxicity were compared in propensity score matched patients undergoing SABR (n=367) or lobectomy/sublobar resection (n=711).[9] Overall mortality was lower with SABR at 3 months (2.2% vs 6.1%, P = 0.005), but at 24 months it was higher (40.1% vs 22.3%, P < 0.001). Acute toxicity in the first month was lower with SABR (7.9% vs 54.9%, P < 0.001), but at 24 months there were no differences between treatments.

In a registry-based study limited to patients 75 or older, outcomes following resection or SABR were compared using a matched-pair analysis. At three years survival was 61% in the surgical group, and 47% in the SABR group (P=0.22).[10]

A systematic review of outcomes following surgery or SABR in patients with severe chronic obstructive pulmonary disease (COPD) (FEV1 < 50% predicted) concluded that survival was comparable with both forms of treatment, but three year survivals were highly variable ranging from 43 to 70%.[11]

Institution-based studies comparing SABR with surgery are usually small and underpowered, especially after propensity-score based matching. Some report a survival advantage for surgery patients[12][13][14] and others no difference after adjusting for prognostic factors.[15][16][17][18]

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Surgery or SABR for patients unsuitable for lobectomy

There has been no direct comparison of segmentectomy or wedge resection versus radiotherapy. There are three retrospective non-randomised studies which have reported local control and survival following limited surgery or SABR in patients unsuitable for lobectomy.

In the first study, which used data from the SEER 2001-2007 cohort, there were no survival differences between 112 propensity score based matched pairs having sublobar resection or SABR (HR = 0.82, 95% C.I. 0.53-1.27, P = 0.38).[3]

In the second study, unadjusted survival was superior in patients having wedge resection compared with SABR.[19]

The third study, from Japan, reported no significant differences in survival between sublobar resection and SABR after propensity score matching.[20]

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Evidence summary and recommendations

Evidence summary Level References
In patients with operable stage I NSCLC, surgery is associated with superior survival compared with conventionally fractionated radiotherapy.

Last reviewed December 2015

III-2 [3]
In patients with operable stage I NSCLC, SABR may be associated with similar survival compared with surgery in the medium term.

Last reviewed December 2015

II [6]
Evidence-based recommendationQuestion mark transparent.png Grade
In patients with operable stage I NSCLC, surgery is recommended over conventional radiotherapy, but SABR may be a reasonable option for patients refusing an operation, or who are high risk for a lobectomy.

Last reviewed December 2015

D


Practice pointQuestion mark transparent.png

Radiotherapy is an alternative treatment option for patients with stage I NSCLC who refuse surgery or are not fit for a standard lobectomy. There is insufficient evidence to recommend which method of radiotherapy (conventional or SABR) is preferable. In patients with peripherally situated tumours five cm or less in diameter, SABR is a reasonable treatment option. For larger tumours or those in less favourable anatomical sites near organs at risk, it may be reasonable, for patient convenience, to moderately accelerate treatment e.g. 50-55Gy in 20 fractions (extrapolating from Price et al 2012).
Last reviewed December 2015


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References

  1. Birim O, Kappetein AP, Goorden T, van Klaveren RJ, Bogers AJ. Proper treatment selection may improve survival in patients with clinical early-stage nonsmall cell lung cancer. Ann Thorac Surg 2005 Sep;80(3):1021-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16122477.
  2. Monirul Islam KM, Shostrom V, Kessinger A, Ganti AK. Outcomes following surgical treatment compared to radiation for stage I NSCLC: a SEER database analysis. Lung Cancer 2013 Oct;82(1):90-4 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23910907.
  3. 3.0 3.1 3.2 3.3 Shirvani SM, Jiang J, Chang JY, Welsh JW, Gomez DR, 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 Dec 1;84(5):1060-70 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22975611.
  4. Yendamuri S, Komaki RR, Correa AM, Allen P, Wynn B, Blackmon S, et al. Comparison of limited surgery and three-dimensional conformal radiation in high-risk patients with stage I non-small cell lung cancer. J Thorac Oncol 2007 Nov;2(11):1022-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17975494.
  5. Hsie M, Morbidini-Gaffney S, Kohman LJ, Dexter E, Scalzetti EM, Bogart JA. Definitive treatment of poor-risk patients with stage I lung cancer: a single institution experience. J Thorac Oncol 2009 Jan;4(1):69-73 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19096309.
  6. 6.0 6.1 Chang JY, Senan S, Paul MA, Mehran RJ, Louie AV, Balter P, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol 2015 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25981812.
  7. Soldà 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 Oct;109(1):1-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24128806.
  8. 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 Nov 1;90(3):603-11 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25052562.
  9. Yu JB, Soulos PR, Cramer LD, Decker RH, Kim AW, Gross CP. Comparative effectiveness of surgery and radiosurgery for stage I non-small cell lung cancer. Cancer 2015 Apr 6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25847699.
  10. Palma D, Visser O, Lagerwaard FJ, Belderbos J, Slotman B, Senan S. Treatment of stage I NSCLC in elderly patients: A population-based matched-pair comparison of stereotactic radiotherapy versus surgery. Radiother Oncol 2011 Jul 18 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21775007.
  11. Palma D, Lagerwaard F, Rodrigues G, Haasbeek C, Senan S. Curative Treatment of Stage I Non-small-cell Lung Cancer in Patients with Severe COPD: Stereotactic Radiotherapy Outcomes and Systematic Review. Int J Radiat Oncol Biol Phys 2011 Jun 1 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21640513.
  12. Robinson CG, Dewees TA, El Naqa IM, Creach KM, Olsen JR, Crabtree TD, 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 Feb;8(2):192-201 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23287852.
  13. Crabtree TD, Puri V, Robinson C, Bradley J, Broderick S, Patterson GA, 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 Apr;147(4):1183-1191; discussion 1191-2 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24507980.
  14. Hamaji M, Chen F, Matsuo Y, Kawaguchi A, Morita S, Ueki N, et al. Video-Assisted Thoracoscopic Lobectomy Versus Stereotactic Radiotherapy for Stage I Lung Cancer. Ann Thorac Surg 2015 Feb 5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25661580.
  15. Jimenez MF, van Baardwijk A, Aerts HJ, De Ruysscher D, Novoa NM, Varela G, et al. Effectiveness of surgery and individualized high-dose hyperfractionated accelerated radiotherapy on survival in clinical stage I non-small cell lung cancer. A propensity score matched analysis. Radiother Oncol 2010 Dec;97(3):413-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20851487.
  16. 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 Aug 1;119(15):2683-91 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23605504.
  17. Mokhles S, Verstegen N, Maat AP, Birim Ö, Bogers AJ, Mokhles MM, et al. Comparison of clinical outcome of stage I non-small cell lung cancer treated surgically or with stereotactic radiotherapy: Results from propensity score analysis. Lung Cancer 2015 Jan 15 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25622781.
  18. van den Berg LL, Klinkenberg TJ, Groen HJ, Widder J. Patterns of Recurrence and Survival after Surgery or Stereotactic Radiotherapy for Early Stage NSCLC. J Thorac Oncol 2015 May;10(5):826-31 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25629639.
  19. Grills IS, Mangona VS, 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 Feb 20;28(6):928-35 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20065181.
  20. 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 Nov;50(17):2932-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25281527.


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Appendices

Further resources

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