What is the role of postoperative radiotherapy (PORT) in resected stage III NSCLC?

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What is the role of postoperative radiotherapy (PORT) in resected stage III NSCLC?

Introduction

Jutta's info icon.png Defining operable and inoperable disease in stage III

The management of Stage III NSCLC has been divided into sections dependent on whether the disease is considered operable or inoperable at the time of diagnosis.

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Stage III NSCLC encompasses a broad spectrum of disease extent from tumour involving a single nodal station identified only postoperatively despite extensive pre-operative staging to involvement of multiple contralateral mediastinal nodes and supraclavicular nodes appreciated on clinical examination. In patients with clinically equivocal involvement, pathological confirmation of nodal status should be made if it will influence management options.

The decision as to operability should be made in a multidisciplinary setting.

Patients with Stage III NSCLC may be deemed inoperable because of patient factors (the patient’s respiratory function or co-morbidities may preclude operative intervention or the patient may choose not to proceed with surgery) or tumour factors (the extent or location of gross disease might make surgical resection technically impossible, for example left sided tumours with mediastinal nodes to the right of the aorta, N3 nodal involvement and most T4 tumours).

In the absence of other factors precluding surgery, patients with N1 disease should be considered for surgery. Patients with confirmed N2 disease should not be treated by surgery as the sole modality, but resectable cases may be considered for a multimodality approach. There is no consensus on the distinction between resectable and unresectable N2 disease. Factors influencing assessment of resectability include nodal size, number of stations involved, extracapsular extension and involvement of the recurrent laryngeal nerve.

Despite gross complete surgical resection of NSCLC, the incidence of local/regional failure is significant. Retrospective and prospective studies, performed in the pre-adjuvant chemotherapy era, report crude local-regional failure rates of 6%-28% for N0 disease, 18% to 49% for N1 disease, and 6% to 65% for N2 disease.[1] The use of adjuvant chemotherapy following the resection of stage II-IIIA NSCLC is associated with a survival advantage and is now considered the standard of care.[2] However, the effect of adjuvant chemotherapy on loco-regional control is not clear.

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Post-operative Radiotherapy

The use of radiotherapy (RT) post surgical resection reduces the risk of local recurrence.[3][4][5][6] The effect of PORT on survival, particularly in patients with pN2 disease, is controversial.

A meta-analysis of 11 randomised controlled trials involving 2343 patients undergoing complete resection of stage I-III disease randomised to PORT or observation demonstrated a significant adverse effect of PORT on survival (hazard ratio 1.18, 95% CI 1.07-1.31, p=0.001) corresponding to an absolute detriment in survival of 5% at two years (95% CI 2%-9%).[7] In exploratory subgroup analyses the most pronounced survival detriment was observed in patients with stage I/II and N0-N1 disease. In patients with stage III, N2 disease, there was no clear evidence of an adverse or beneficial effect of PORT on survival.

The applicability of these results to current day practice is questionable because the treatments utilised in the included studies (particularly the radiation dose, field size and mode of delivery) differ substantially from those available currently.

Data from two more recent non-randomised studies suggest a benefit for PORT in pN2 disease, and confirm a detrimental effect for PORT in pN0 and pN1 disease.

A retrospective study using the Surveillance, Epidemiology and End Results (SEER) database identified 7,465 patients who underwent surgery for stage II or III NSCLC between 1988 and 2002, 47% of whom subsequently received PORT.[8] It was presumed that given the time period involved, modern radiotherapy techniques were employed although no details of treatment technique were provided. The use of PORT did not have a significant impact on survival. However, in subset analysis the use of PORT was associated with a significant increase in survival (HR 0.855; 95% CI 0.762-0.959, p=.0077) for patients with N2 nodal disease. PORT was associated with a significant decrease in survival for patients with N0 (HR 1.176; 95%CI 1.005-1.376. p=.0435) and N1 (HR 1.097, 95% CI 1.015 to 1.186) nodal disease. It must be remembered that the use of PORT was not randomised in this analysis.

In the Adjuvant Navelbine International Trialist Association (ANITA) trial, patients with pN0-pN2 disease were randomised to receive postoperative chemotherapy or observation.[9] Administration of PORT was recommended for patients with pathological node-positive disease, but patients were not randomised to PORT and it was not mandatory. The recommended regimen was 45 -60Gy over five weeks using a high-energy linear accelerator with treatment initiated two weeks after the completion of chemotherapy or within two weeks of randomised in the observation group. Overall 27.6% of patients received PORT, of whom 50% had pN2 disease. A hypothesis-generating sub-analysis of this trial found higher five-year overall survivals in those patients with pN2 disease who received PORT, in both the observation and chemotherapy arms (21% versus 17% and 47% versus 34%, respectively; statistical tests of comparison not conducted). For patients with pN1 disease, those who were assigned to no chemotherapy and received PORT had a better survival than those who did not (median survival 50 versus 26m) but in those who received chemotherapy, the use of PORT was associated with a survival detriment (median survival 47 versus 94m). It must be remembered that local-regional failure was not the primary endpoint of this study and PORT was not randomly assigned.

A population-based study using the National Cancer Database, identified 3340 patients treated with PORT using modern radiation therapy techniques between 1998-2006. PORT resulted in a statistically significant reduction in 5 year OS in patients with pN0-pN1 disease but a statistically significant 6.3% improvement in 5yrOS in patients with pN2 disease. The OS benefit in pN2 disease was dependent on radiation dose with patients receiving 45-54Gy having better outcomes that those treated with doses >54Gy. In patients treated with doses >54Gy, OS was similar to those patients not receiving PORT.[10]

These results suggesting a potential benefit for PORT in pN2 disease need to be clarified in prospective randomised trials. Unfortunately, a trial conducted by the Cancer and Leukemia Group (CALGB 9734) in which patients with completely resected stage IIIA (N2) disease received four cycles of adjuvant paclitaxel/carboplatin and were then randomised to adjuvant RT or observation, closed early due to poor accrual.[11]

The Lung Adjuvant Radiotherapy Trial (LUNG ART) is currently recruiting patients in Europe. In this Phase III trial patients with completely resected III-N2 disease are randomised between PORT and no PORT, irrespective of chemotherapy use.[12]

Positive Margins: There is a paucity of data regarding the use of PORT for positive surgical margins. Drawing on experience from the use of RT in other tumour sites, the use of PORT in this setting may be considered.[13]

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Evidence summary and recommendations

Evidence summary Level References
A meta-analysis demonstrates no clear evidence of an adverse or beneficial effect of PORT on survival in patients with pN2 disease. The applicability of this finding to current day practice is questionable.

Last reviewed December 2015

I [7]
Data from three more recent but non-randomised studies suggest a survival benefit for PORT in pN2 disease.

Last reviewed December 2015

III-2 [8], [9], [10]
Evidence-based recommendationQuestion mark transparent.png Grade
Post-operative radiation therapy in patients with pN2 disease is not recommended for routine use because of the lack of prospective randomised clinical trial data demonstrating an improvement in survival. The use of PORT could be considered in selected patients with pN2 disease.

Last reviewed December 2015

C



Practice pointQuestion mark transparent.png

Post-operative radiation therapy may be considered in the setting of a positive margin.
Last reviewed December 2015

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References

  1. Kelsey CR, Marks LB, Hollis D, Hubbs JL, Ready NE, D'Amico TA, et al. Local recurrence after surgery for early stage lung cancer: an 11-year experience with 975 patients. Cancer 2009 Nov 15;115(22):5218-27 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19672942.
  2. NSCLC Meta-analyses Collaborative Group, Arriagada R, Auperin A, Burdett S, Higgins JP, Johnson DH, et al. Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet 2010 Apr 10;375(9722):1267-77 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20338627.
  3. Lung Cancer Study Group.. Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid carcinoma of the lung. N Engl J Med 1986;315: 1377-1382. Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/2877397.
  4. Stephens RJ, Girling DJ, Bleehen NM, Moghissi K, Yosef HM, Machin D. The role of post-operative radiotherapy in non-small-cell lung cancer: a multicentre randomised trial in patients with pathologically staged T1-2, N1-2, M0 disease. Medical Research Council Lung Cancer Working Party. Br J Cancer 1996 Aug;74(4):632-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8761382.
  5. Mayer R, Smolle-Juettner FM, Szolar D, Stuecklschweiger GF, Quehenberger F, Friehs G, et al. Postoperative radiotherapy in radically resected non-small cell lung cancer. Chest 1997 Oct;112(4):954-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9377958.
  6. Van Houtte P, Rocmans P, Smets P, Goffin JC, Lustman-Maréchal J, Vanderhoeft P, et al. Postoperative radiation therapy in lung caner: a controlled trial after resection of curative design. Int J Radiat Oncol Biol Phys 1980 Aug;6(8):983-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/6998936.
  7. 7.0 7.1 PORT Meta-analysis Trialists Group. Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev 2005 Apr 18;(2):CD002142 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15846628.
  8. 8.0 8.1 Lally BE, Zelterman D, Colasanto JM, Haffty BG, Detterbeck FC, Wilson LD. Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database. J Clin Oncol 2006 Jul 1;24(19):2998-3006 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16769986.
  9. 9.0 9.1 Douillard JY, Rosell R, De Lena M, Riggi M, Hurteloup P, Mahe MA, et al. Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or IIIA non-small-cell lung cancer treated with adjuvant chemotherapy: the adjuvant Navelbine International Trialist Association (ANITA) Randomized Trial. Int J Radiat Oncol Biol Phys 2008 Nov 1;72(3):695-701 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18439766.
  10. 10.0 10.1 Corso CD, Rutter CE, Wilson LD, Kim AW, Decker RH, Husain ZA. Re-evaluation of the role of post-operative radiotherapy and the impact of radiation dose for non-small cell lung cancer using the National Cancer Database. J Thorac Oncol 2014 Oct 16 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25325781.
  11. Perry MC, Kohman LJ, Bonner JA, Gu L, Wang X, Vokes EE, et al. A phase III study of surgical resection and paclitaxel/carboplatin chemotherapy with or without adjuvant radiation therapy for resected stage III non-small-cell lung cancer: Cancer and Leukemia Group B 9734. Clin Lung Cancer 2007 Jan;8(4):268-72 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17311692.
  12. Pechoux C et al.. Lung ART: A Phase III Trial with a simple design to address the question of adjuvant conformal radiotherapy in patients at high risk of recurrence after complete resection. www.ifct.fr 2011.
  13. Saynak M, Higginson DS, Morris DE, Marks LB. Current status of postoperative radiation for non-small-cell lung cancer. Semin Radiat Oncol 2010 Jul;20(3):192-200 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20685582.


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Appendices

Further resources

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