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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. However, no firm recommendation can be made regarding adjuvant chemotherapy in this subgroup.

These groups of patients 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] These results need to confirmed from 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 adjuvant cisplatin-based chemotherapy after surgery. 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. I [14]
Evidence-based recommendationQuestion mark transparent.png Grade
Patients with completely resected stage II NSCLC should be offered 3-4 cycles of adjuvant cisplatin based chemotherapy. 		A


Practice pointQuestion mark transparent.png

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

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

No recommendation can be made for patients who have had less than a lobectomy.

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.

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

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

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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[20] 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,[21] which did not show any significant OS difference in the overall population, while subgroup IB/IIA demonstrated a significant OS benefit. The NATCH trial[22] 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[23] 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[24] 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[25] 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[23] 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.[25] However, the overall evidence is insufficient to recommend neoadjuvant chemotherapy as standard therapy for operable stage II NSCLC. Individual patient meta-analysis of all the available trials may help to clarify this question further across all the sub-groups. A more recent individual patient meta-analysis provides a clearer picture across these studies.[26] 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. I [26]
Individual studies looking at chemotherapy use before surgeryThe evidence of benefit for neoadjuvant chemotherapy in stage II disease is unclear with trials having have inconsistent end points and lacking power due to poor accrual and early closure. II [22], [21], [20]
Majority of individual trials do not show statistically significant benefit in stage II disease. II [24], [22], [23], [21]
Neoadjuvant Chemotherapy given before surgery does not adversely affect the quality of life. II [23]
Compliance to neoadjuvant chemotherapy is better compared to adjuvant chemotherapy. II [22]
Meta-analysis showed overall survival benefit, however subset analysis for stage II disease was not undertaken due to heterogeneity of individual trials included. I [25]
The benefits of neoadjuvant chemotherapy are similar to that of adjuvant chemotherapy I [25], [6]
Evidence-based recommendationQuestion mark transparent.png Grade
Chemotherapy before surgery is not recommended as standard of care for patients with operable stage II NSCLC. 		B
Evidence-based recommendationQuestion mark transparent.png Grade
Chemotherapy before surgery may be considered as an option for patients with operable stage II NSCLC. 		A
Evidence-based recommendationQuestion mark transparent.png Grade
Chemotherapy before surgery in operable stage II disease, with at least three 3-4 cycles of platinum-based regimes, may be considered in select patients, who are unlikely to receive it as adjuvant therapy. 		CA

"CA" is not in the list (A, B, C, D, GPP, PP, C/GPP, A (ESPEN grade), N/A, Strong, ...) of allowed values for the "Recommendation grade" property.



Practice pointQuestion mark transparent.png

No benefit has been demonstrated in using chemotherapy before surgery to improve resection rates.

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.

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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 Available from: 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 Available from: 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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20464750.
  5. ↑ 5.0 5.1 .
  6. ↑ 6.0 6.1 6.2 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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/7580546.
  7. ↑ 7.0 7.1 .
  8. ↑ 8.0 8.1 .
  9. ↑ 9.0 9.1 .
  10. ↑ 10.0 10.1 .
  11. ↑ 11.0 11.1 .
  12. ↑ 12.0 12.1 .
  13. ↑ .
  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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25730344.
  15. ↑ .
  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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25193990.
  17. ↑ .
  18. ↑ .
  19. ↑ .
  20. ↑ 20.0 20.1 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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22124104.
  21. ↑ 21.0 21.1 21.2 .
  22. ↑ 22.0 22.1 22.2 22.3 .
  23. ↑ 23.0 23.1 23.2 23.3 .
  24. ↑ 24.0 24.1 .
  25. ↑ 25.0 25.1 25.2 25.3 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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17409927.
  26. ↑ 26.0 26.1 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 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24576776.
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