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

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

Introduction

This clinical practice guideline addresses the question of the role of chemotherapy after complete resection of stage II NSCLC. The primary outcome assessed while preparing these guidelines is overall survival. The studies examined have used the 6th edition of TNM staging. Curative treatment for early stage NSCLC is surgery. However 30-60% of patients treated with surgery develops recurrence.[1][2][3] Many of the recurrences are systemic, indicating that adjuvant treatment might be beneficial. The question of adjuvant treatment in patients with positive margins after surgery has not been addressed here. Adjuvant use of Tegafur- Uracil is excluded as these drugs have not been well studied in Caucasian population.

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Chemotherapy after surgery in stage II NSCLC

Several studies have confirmed the benefit of adjuvant chemotherapy in Stage II NSCLC. A large meta-analysis of individual patient data[4] involving 8447 patients from 34 trials (1291 stage II patients) reported a 5% (from 40 to 45%) absolute benefit in overall survival, at five years, in stage II patients, using platinum based chemotherapy. These results are confirmed by results of a pooled analysis (LACE meta-analysis) of individual patient data from five well designed, large, randomised controlled trials which included a total of 4584 patients. Out of this 1616 patients had stage II disease.[5] At a median follow up of 5.1 years the absolute overall survival benefit was 5.4% for the whole population and 10% for stage II patients (from 39% to 49%) with HR of death for stage II patients at 0.83 ( 95% CI 0.73-0.95). This analysis included only patients treated with Cisplatin based chemotherapy as this was shown to be the combination most effective in a previous large meta-analysis. The same study also revealed combination of alkylating agents with Cisplatin to be detrimental and this combination is no longer recommended.[6]


The major characteristics of the five major randomised controlled trials, included in the LACE meta-analysis mentioned above, are shown in Table - Summary of five randomised trials included in the LACE meta-analysis. These constitute the major evidence on which these guidelines are based upon. The first three trials showed a survival benefit with adjuvant Cisplatin based chemotherapy while the last two did not. The Big lung trial was underpowered to demonstrate survival benefit. The IALT is the largest trial and was the first RCT to demonstrate a statistically significant benefit in overall survival.[7] However, in an updated publication, with a median follow up of 7.5 years, the survival benefit in favour of chemotherapy became non-significant.[8] In contrast, results of long term follow up of the JBR 10 trial (median 9.3 years), showed that the survival benefits continued to be significant for the overall population as well as for patients with stage II disease.[9][10] The median age was similar in all the trials. The majority of patients had good performance status (ECOG 0, 1) with only 4.5-7.2% of patients having an ECOG performance status of 2, in trials including them. At least 50% of enrolled patients completed the planned number of chemotherapy cycles across the studies. The dose of Cisplatin varied from 80-120mg/m2 per cycle. Cisplatin was combined with Vinorelbine in two of the trials while in the rest, it was combined with a range of other drugs. These include Etoposide, other Vinca alkaloids, Mitomycin C, Ifosfamide and Prednisolone.

Pre-specified subset analysis of the LACE meta-analysis looking at the combination of Cisplatin and Vinorelbine found this combination to be superior in terms of overall survival when compared to the other combinations. HR 0.80, 95% CI: 0.70–0.91, p<0.001 versus HR 0.95, 95% CI: 0.86– 1.05, p = 0.33.[11] Chemotherapy was reasonably well tolerated with 50% or more patients completing all planned cycles. Toxic deaths reported ranged from 0.8 % (JBR 10) to 2% (IALT)[12]. The absolute survival benefit at five years in the three positive trials ranged from 3.9 % (IALT), 8.6% (ANITA) and 15% (JBR10). Quality of life (QOL) of the patients were reported from the JBR10 trial. It was seen that the QOL was impaired in the immediate period following chemotherapy. However, scores improved to match the control group within a period of nine months. QOL scores for peripheral neuropathy and hearing impairment persisted in the chemotherapy group for up to 30 months.[13] These results have been further confirmed by an updated individual patient data meta-analysis. An absolute improvement in 5-year survival of 5%, from 40-45%, for stage II disease was again demonstrated. The benefit for chemotherapy was also evident in patients who received adjuvant radiotherapy.[14]

The Cancer and Leukemia Group B trial (CALGB 9633) looked at benefit of four cycles of Paclitaxel/Carboplatin as adjuvant treatment in patients with stage IB NSCLC. The regime was well tolerated with no toxic deaths. The trial did not demonstrate any overall survival benefit. However, in an exploratory subset analysis of the trial, patients with tumour diameter >4cm demonstrated a significant survival advantage.[15] These tumours would be classified under IIA in the 7th edition of TNM classification.These groups of patients also may benefit from adjuvant chemotherapy as evidenced by updated meta-analysis data.[14]

There is limited evidence on the long term toxicities of adjuvant chemotherapy. An updated analysis of the IALT study with a follow up of 7.5 years confirmed a benefit of adjuvant chemotherapy within the first 5 years. However after that period there was an increased risk of non-cancer mortality in the group who received chemotherapy ( HR 3.6; 95% CI 2.2-5.9, p< 0.001).[16] However this affected only about 2% of the study population. These results need further validation from long term follow up results of similar studies.

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Evidence summary and recommendations

Evidence summary Level References
In patients with operable stage II NSCLC, the evidence supports the use of 3-4 cycles of cisplatin-based chemotherapy after surgery

Last reviewed December 2015

I, II [11], [6], [17], [5], [7], [8], [10], [12], [18], [9], [19]
The benefit of chemotherapy after surgery is present in patients who received radiotherapy as part of the loco-regional treatment.

Last reviewed December 2015

I [14]
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Patients with completely resected stage II NSCLC should be offered 3-4 cycles of adjuvant cisplatin based chemotherapy.

Last reviewed December 2015

A


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The chemotherapy combination of cisplatin and vinorelbine was the most widely studied regimen which showed benefit.
Last reviewed December 2015


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There is insufficient evidence to support adjuvant chemotherapy for patients with ECOG performance status of ≥ 2.
Last reviewed December 2015


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No recommendation can be made for patients who have had less than a lobectomy.
Last reviewed December 2015


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Based on the 7th edition of TNM classification tumour size of >5cm would fall under stage IIA. These patients may be considered for adjuvant chemotherapy.
Last reviewed December 2015


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Chemotherapy benefit is seen even in patients who have received radiotherapy as part of loco-regional therapy in addition to surgery.
Last reviewed December 2015


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Potential long term side effects need to be considered while deciding on chemotherapy after surgery.
Last reviewed December 2015

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References

  1. Ponn RB, Lo Cicero J III, Rusch VW. BDT: Surgical treatment of nonsmall cell lung cancer. In: Shields TW, Lo Cicero J III, Ponn R, Rusch VW, editors. General Thoracic surgery. 6th ed. Philadelphia: Lippincott Williams & Wilkins 2005;p.1548-1587.
  2. Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997 Jun;111(6):1710-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9187198.
  3. Rosell R, Felip E, Maestre J, Sanchez JM, Sanchez JJ, Manzano JL, et al. The role of chemotherapy in early non-small-cell lung cancer management. Lung Cancer 2001 Dec;34 Suppl 3:S63-74 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11740997.
  4. Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy and supportive care versus supportive care alone for advanced non-small cell lung cancer. Cochrane Database Syst Rev 2010 May 12;(5):CD007309 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20464750.
  5. 5.0 5.1 Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008 Jul 20;26(21):3552-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18506026.
  6. 6.0 6.1 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.
  7. 7.0 7.1 Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004 Jan 22;350(4):351-60 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14736927.
  8. 8.0 8.1 Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, et al. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant Cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol 2010 Jan 1;28(1):35-42 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19933916.
  9. 9.0 9.1 Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005 Jun 23;352(25):2589-97 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15972865.
  10. 10.0 10.1 Butts CA, Ding K, Seymour L, Twumasi-Ankrah P, Graham B, Gandara D, et al. Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10. J Clin Oncol 2010 Jan 1;28(1):29-34 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19933915.
  11. 11.0 11.1 Douillard JY, Tribodet H, Aubert D, Shepherd FA, Rosell R, Ding K, et al. Adjuvant cisplatin and vinorelbine for completely resected non-small cell lung cancer: subgroup analysis of the Lung Adjuvant Cisplatin Evaluation. J Thorac Oncol 2010 Feb;5(2):220-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20027124.
  12. 12.0 12.1 Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association (ANITA)): a randomised controlled trial. Lancet Oncol 2006 Sep;7(9):719-27 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16945766.
  13. Bezjak A, Lee CW, Ding K, Brundage M, Winton T, Graham B, et al. Quality-of-life outcomes for adjuvant chemotherapy in early-stage non-small-cell lung cancer: results from a randomized trial, JBR.10. J Clin Oncol 2008 Nov 1;26(31):5052-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18809617.
  14. 14.0 14.1 14.2 Burdett S, Pignon JP, Tierney J, Tribodet H, Stewart L, Le Pechoux C, et al. Adjuvant chemotherapy for resected early-stage non-small cell lung cancer. Cochrane Database Syst Rev 2015 Mar 2;3:CD011430 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25730344.
  15. Strauss GM, Herndon JE 2nd, Maddaus MA, Johnstone DW, Johnson EA, Harpole DH, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008 Nov 1;26(31):5043-51 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18809614.
  16. Rotolo F, Dunant A, Le Chevalier T, Pignon JP, Arriagada R, IALT Collaborative Group. Adjuvant cisplatin-based chemotherapy in nonsmall-cell lung cancer: new insights into the effect on failure type via a multistate approach. Ann Oncol 2014 Nov;25(11):2162-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25193990.
  17. 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.
  18. Scagliotti GV, Fossati R, Torri V, Crinò L, Giaccone G, Silvano G, et al. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst 2003 Oct 1;95(19):1453-61 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14519751.
  19. Waller D, Peake MD, Stephens RJ, Gower NH, Milroy R, Parmar MK, et al. Chemotherapy for patients with non-small cell lung cancer: the surgical setting of the Big Lung Trial. Eur J Cardiothorac Surg 2004 Jul;26(1):173-82 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15200998.

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Appendices

Further resources

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