What is the clinical benefit of the addition of neoadjuvant radiotherapy to neoadjuvant chemotherapy in stage IIIA (N2) NSCLC?

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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.

Neoadjuvant chemotherapy followed by surgical resection became a standard of care internationally in clinical N2 NSCLC[1][2][3] based on the very poor survival of patients treated with surgery alone in this setting.[4][5][6][7] Theoretical improvements in resectability, local control and subsequent survival with the addition of radiotherapy to neoadjuvant chemotherapy must be balanced against the potentially increased morbidity and mortality of surgery in this setting.



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Randomised controlled trials of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy

Girard et al (IFCT – 0101)[8] randomised 46 patients with resectable cIIIA-N2 NSCLC in a phase II study with primary endpoint of feasibility. Response rate was significantly higher after neoadjuvant chemoradiotherapy versus chemotherapy alone (87% versus 57%, p = 0.049).

Despite two completed phase 3 studies published only in abstract form[9][10] and a third well designed trial attempted by the RTOG and abandoned due to poor accrual[11] only one phase 3 study (enrolling a majority of cIIIB patients) has ever been published.

Thomas et al[12][13] randomised 558 patients with cIII (67% cIIIB) NSCLC between 1995 and 2003 at multiple German institutions, to:

  1. three cycles of cisplatin and etoposide, followed by
  2. twice-daily RT [45Gy] with concurrent carboplatin and vindesine, and then
  3. surgical resection (and further RT [24Gy] if less than R0 resection)

versus

  1. three cycles of cisplatin and etoposide, followed by
  2. surgery, and
  3. adjuvant radiotherapy (54Gy and further 24Gy if less than R0 resection).

On an intention to treat basis 37% versus 32% (NS) achieved complete resection. In those undergoing resection, complete resection was more often possible in the intervention group (75% versus 60% [p=0.008]). In patients with complete resection, mediastinal downstaging (46% versus 29% [p=0.02]) and pathological response (60% versus 20% [p<0.0001]) favoured the preoperative chemoradiation group.

Despite this evidence of improved loco-regional response, there was no difference in PFS (primary endpoint). Of interest, post operative mortality favoured the control group (5% versus 9% [p=0.11]), the trend being stronger after pneumonectomy (6% versus 14% [NS]), which was required in 35% in both arms.

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Evidence summary and recommendations

Evidence summary Level References
Neoadjuvant chemotherapy, with or without radiotherapy, is feasible. III-1, II [8], [12], [13]
In patients with stage cIIIA (N2) NSCLC planned for surgery, preoperative chemoradiation compared to preoperative chemotherapy alone increases pathological response and mediastinal downstaging. III-1, II [8], [12], [13]
In unselected patients with stage cIIIA (N2) NSCLC planned for surgery, preoperative chemoradiation compared to preoperative chemotherapy alone has not been shown to improve PFS or OS. III-1, II [8], [12], [13]
Recommendation Grade
In selected patients (excellent performance status and cardio respiratory reserve) with stage cIIIA (N2) NSCLC, planned for surgery that will entail less than pneumonectomy, it is reasonable to offer neoadjuvant chemoradiotherapy.
C


Practice point(s)

Surgery alone is not advised in cIIIA (N2) disease.

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References

  1. Scottish Intercollegiate Guidelines Network. Sign 80: Management of patients with lung cancer. A national clinical guideline. Edinburgh: Scottish Intercollegiate Guidelines Network; 2005 [Abstract available at http://www.sign.ac.uk/guidelines/fulltext/80/index.html].
  2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer. NCCN 2011;Version 3 [Abstract available at http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf].
  3. Australian Cancer Network Management of Lung Cancer Guidelines Working Party. Clinical Practice Guidelines for the Prevention, Diagnosis and Management of Lung Cancer. The Cancer Council Australia and Australian Cancer Network, National Health and Medical Research Council Canberra 2004.
  4. Roth JA, Fossella F, Komaki R, Ryan MB, Putnam JB Jr, Lee JS, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst 1994 May 4;86(9):673-80 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8158698].
  5. Roth JA, Atkinson EN, Fossella F, Komaki R, Bernadette Ryan M, Putnam JB Jr, et al. Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. Lung Cancer 1998 Jul;21(1):1-6 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9792048].
  6. Rosell R, Gómez-Codina J, Camps C, Maestre J, Padille J, Cantó A, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med 1994 Jan 20;330(3):153-8 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8043059].
  7. Rosell R, Gómez-Codina J, Camps C, Javier Sánchez J, Maestre J, Padilla J, et al. Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: a 7-year assessment of a randomized controlled trial. Lung Cancer 1999 Oct;26(1):7-14 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10574676].
  8. 8.0 8.1 8.2 8.3 Girard N, Mornex F, Douillard JY, Bossard N, Quoix E, Beckendorf V, et al. Is neoadjuvant chemoradiotherapy a feasible strategy for stage IIIA-N2 non-small cell lung cancer? Mature results of the randomized IFCT-0101 phase II trial. Lung Cancer 2010 Jul;69(1):86-93 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19879013].
  9. Tada H, Tanaka M, Katakami N, Kurata T, Mitsudomi T, Negoro S, Kudoh S, Nishiyama H, Nishimura Y, and Nakagawa K. Phase III study of induction chemotherapy (docetaxel and carboplatin) with or without radiotherapy followed by surgery in patients with stage IIIA (pN2) non-small cell lung cancer (NSCLC):WJTOG9903. Journal of Clinical Oncology 2009;27:15 SUPPL. 1 (7556) [Abstract available at http://www.embase.com.ezproxy1.library.usyd.edu.au/search/results?subaction=viewrecord&rid=2&page=1&L70242257].
  10. Fleck J, Camargo J, Godoy D, Teixeira P, Graga-Filho A, Barletta A. Chemoradiation therapy alone versus chemotherapy alone as a neoadjuvant treatment for stage III non-small-cell lung cancer. Preliminary report of a phase III, randomized trial. Proc Am Soc Clin Oncol 1993;11:1108.
  11. Radiation Therapy Oncology Group. RTOG 0412 Protocol Information (updated 2011 August 4; cited 2012 April 4). 2012 [Abstract available at http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0412].
  12. 12.0 12.1 12.2 12.3 Semik M, Riesenbeck D, Linder A, Schmid C, Hoffknecht P, Heinecke A, et al. Preoperative chemotherapy with and without additional radiochemotherapy: benefit and risk for surgery of stage III non-small cell lung cancer. Eur J Cardiothorac Surg 2004 Dec;26(6):1205-1210 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15678591].
  13. 13.0 13.1 13.2 13.3 Thomas M, Rübe C, Hoffknecht P, Macha HN, Freitag L, Linder A, et al. Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III non-small-cell lung cancer. Lancet Oncol 2008 Jul;9(7):636-48 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18583190].

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Appendices

Further resources

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