What is the role of chemotherapy before surgery in the treatment of operable stage II NSCLC?

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What is the role of chemotherapy before surgery in the treatment of operable stage II NSCLC?

Introduction

This clinical practice guideline addresses the question of the role of chemotherapy before surgery or neoadjuvant chemotherapy in operable stage II lung cancer. This does not address treatment of tumours involving superior sulcus. There are theoretical advantages in using chemotherapy in this setting, although available evidence is non-conclusive. Randomised controlled trials (RCTs) and meta-analysis have been confounded by low number of patients with stage II disease, poor accrual, early closure and significant heterogeneity. Sub group analysis of these trials cannot be considered as conclusive evidence regarding use of neoadjuvant chemotherapy.

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Neoadjuvant chemotherapy

The major evidence on which these guidelines are based comes from five RCTs and two meta-analyses.The salient features of the RCTs are depicted in the Table - Summary of five randomised trials comparing neoadjuvant chemotherapy with surgery alone.

The recently published CHEST trial[1] had progression free survival (PFS) as its primary end point. The HR for PFS and overall survival (OS) was significant in favour of the neoadjuvant chemotherapy arm. Patients with stage IIB/IIIA where grouped together and showed significant benefit for both PFS and OS compared to control group while IB/IIA patients did not have any significant benefit. This contrasts with results of the S9900 trial,[2] which did not show any significant OS difference in the overall population, while subgroup IB/IIA demonstrated a significant OS benefit. The NATCH trial[3] had an adjuvant arm in addition to the neoadjuvant chemotherapy arm. The primary endpoint of this study was disease free survival (DFS). There was no difference in DFS and OS amongst the three groups. Stage II patients receiving neoadjuvant chemotherapy demonstrated a trend towards improved DFS, which failed to reach statistical significance. Interestingly 90% of subjects in the neoadjuvant chemotherapy arm completed all planned chemotherapy compared with 60% in the postoperative arm. Surgical outcomes and postoperative mortality were similar. The European intergroup trial MRC-LU22 EORTC NVALT trial[4] did not demonstrate any overall survival benefit with neoadjuvant chemotherapy. Neoadjuvant chemotherapy did not have any impact on the quality of life. The FTCG study[5] did not demonstrate any survival benefit in the population studied. However ,subset analysis revealed survival benefit in stage I/II disease. The compliance rates were very good across the trials, ranging from 75-90%. The response rates ranged from 34% to 64%. A systematic review and meta-analysis[6] including 988 patients across seven RCTs demonstrated an overall survival benefit (HR 0.82, 95% CI 0.69-0.97;P=0.02). This equated to an absolute improvement in overall survival of 7% at five years in patients with stage II disease. Updated analysis including the LU22 trial[4] demonstrated a shift in HR to 0.88 (0.76-1.01) with the benefits not maintaining statistical significance. However, these meta-analyses were not based in individual patient data and meaningful subgroup analysis could not be undertaken for early stage disease due to significant heterogeneity amongst the trials. The benefits of neoadjuvant chemotherapy are similar to that of adjuvant chemotherapy with absolute benefit of 6% at five years from meta-analysis.[6] A more recent individual patient meta-analysis provides a clearer picture across these studies.[7] This individual patient meta-analysis included 15 randomised controlled trials involving 2385 patients, majority across stages 1B- IIIA. Out of 1194 patients for whom staging information was available, 330 (28%) were stage II patients. A clear overall survival benefit was demonstrated with a HR of 0.87, 95 % confidence interval 0.78-0.96,P=0.007.There was a 13% decrease in relative risk of death with an absolute survival improvement of 5% at 5 years from 40% to 45% overall and 30% to 35% in stage II. This benefit was independent of other variables tested, including chemotherapy regimen, patient demographics and tumour characteristics. There was no demonstrable effect on the operability rate or on the likelihood of achieving a complete resection with administration of chemotherapy before surgery.

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Evidence summary and recommendations

Evidence summary Level References
Individual patient meta-analysis shows benefit in overall survival for chemotherapy given before surgery.

Last reviewed December 2015

I [7]
Individual studies looking at chemotherapy use before surgery in stage II disease have inconsistent end points and lack power due to poor accrual and early closure.

Last reviewed December 2015

II [3], [2], [1]
Majority of individual trials do not show statistically significant benefit in stage II disease.

Last reviewed December 2015

II [5], [3], [4], [2]
Chemotherapy given before surgery does not adversely affect the quality of life.

Last reviewed December 2015

II [4]
Compliance to chemotherapy given before surgery (neo-adjuvant) is better compared to chemotherapy given after surgery(adjuvant).

Last reviewed December 2015

II [3]
The survival benefits of neoadjuvant chemotherapy are similar whether given before or after surgery.

Last reviewed December 2015

I [6], [8]
Evidence-based recommendationQuestion mark transparent.png Grade
Chemotherapy before surgery may be considered as an option for patients with operable stage II NSCLC.

Last reviewed December 2015

B
Evidence-based recommendationQuestion mark transparent.png Grade
Chemotherapy before surgery in operable stage II disease, with 3-4 cycles of platinum-based regimes, may be considered in select patients, who are unlikely to receive it as adjuvant therapy.

Last reviewed December 2015

B


Practice pointQuestion mark transparent.png

No benefit in improved operability rates has been demonstrated in using chemotherapy before surgery. Survival benefit of chemotherapy seem to be similar when given either before or after surgery. Chemotherapy before surgery may be considered for those patient who are expected to have prolonged delay in surgery.
Last reviewed December 2015

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References

  1. 1.0 1.1 Scagliotti GV, Pastorino U, Vansteenkiste JF, Spaggiari L, Facciolo F, Orlowski TM, et al. Randomized Phase III Study of Surgery Alone or Surgery Plus Preoperative Cisplatin and Gemcitabine in Stages IB to IIIA Non-Small-Cell Lung Cancer. J Clin Oncol 2012 Jan 10;30(2):172-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22124104.
  2. 2.0 2.1 2.2 Pisters KM, Vallières E, Crowley JJ, Franklin WA, Bunn PA Jr, Ginsberg RJ, et al. Surgery with or without preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer: Southwest Oncology Group Trial S9900, an intergroup, randomized, phase III trial. J Clin Oncol 2010 Apr 10;28(11):1843-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20231678.
  3. 3.0 3.1 3.2 3.3 Felip E, Rosell R, Maestre JA, Rodríguez-Paniagua JM, Morán T, Astudillo J, et al. Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-small-cell lung cancer. J Clin Oncol 2010 Jul 1;28(19):3138-45 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20516435.
  4. 4.0 4.1 4.2 4.3 Gilligan D, Nicolson M, Smith I, Groen H, Dalesio O, Goldstraw P, et al. Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet 2007 Jun 9;369(9577):1929-37 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17544497.
  5. 5.0 5.1 Depierre A, Milleron B, Moro-Sibilot D, Chevret S, Quoix E, Lebeau B, et al. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer. J Clin Oncol 2002 Jan 1;20(1):247-53 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11773176.
  6. 6.0 6.1 6.2 Burdett S, Stewart LA, Rydzewska L. A systematic review and meta-analysis of the literature: chemotherapy and surgery versus surgery alone in non-small cell lung cancer. J Thorac Oncol 2006 Sep;1(7):611-21 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17409927.
  7. 7.0 7.1 NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet 2014 Feb 24 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24576776.
  8. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995;311(7010):899-909 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7580546.

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Appendices

Further resources

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