Updated February 2008

Guideline : There is evidence to recommend platinum-based chemotherapy regimens as post-operative adjuvant therapy in the management of patients with completely resected stage II and IIIA NSCLC. Cisplatin-based treatment is preferred, although a carboplatin-based regimen can be used as an alternative if there is a contraindication to cisplatin. There is uncertainty about a benefit to patients with resected stage IB NSCLC, although adjuvant chemotherapy may still be considered in selected individuals such as those with tumors >4cm in diameter.

Level of Evidence: I

Grade of Recommendation: A

A meta-analysis published in 1995 indicated that post-operative chemotherapy did not significantly reduce the risk of death in surgically resected, pathologic stage IB, II and IIIA NSCLC, although there was a trend in favour of adjuvant chemotherapy regimens that included the agent cisplatin.¹

ECOG 3590 and ALPI failed to demonstrate any benefit from adjuvant chemotherapy, either with or without post-operative radiotherapy.^2,3 However, IALT renewed interest in adjuvant therapy, as cisplatin-based combination chemotherapy was shown to improve relapse-free survival by 5.1%, and overall survival by 4.1% at five years.⁴

The recent reports of NCIC CTG BR.10 and ANITA support a role for platinum-based combination chemotherapy as adjuvant therapy in resected NSCLC.^5,6 Both trials demonstrated an improvement in overall survival: NCIC CTG BR.10 15% at 5 years, and ANITA 8.6% at 5 years.

A number of factors may account for the lack of benefit from adjuvant therapy in ECOG 3590 and ALPI, as compared to IALT, NCIC CTG BR.10, and ANITA. These include the potentially detrimental effect of post-operative radiotherapy, the impact of newer chemotherapy agents, and the total dose of chemotherapy delivered.

IALT, NCIC CTG BR.10, and ANITA provide compelling evidence in favour of adjuvant chemotherapy, although appropriate selection of patients for treatment is highlighted by the 0.8% risk in IALT of chemotherapy-related adverse events resulting in death. Both NCIC CTG BR.10 and ANITA also reported treatment-related deaths, accounting for 0.8% and 1.7% of those treated with chemotherapy, respectively.

The initial report of CALGB 9633 in 2004 indicated that adjuvant treatment with the combination of carboplatin and paclitaxel in resected stage IB NSCLC was associated with a 12% improvement in survival at 4 years.⁷ However, an update presented in 2006 demonstrated only a non-significant trend in favour of treatment at 5 years.⁸ While further analyses of CALGB 9633 are planned, the LACE meta-analysis also suggests a lack of benefit for adjuvant chemotherapy in resected stage IB NSCLC.⁹

The Lung Tumour Group recommends routine consideration of adjuvant platinum-based combination chemotherapy in patients with fully resected stage II and IIIA NSCLC, but there is uncertainty about its prescription in those with resected stage IB NSCLC. The magnitude of benefit of adjuvant therapy is likely proportional and dependent on the risk of relapse according to stage. There may be individuals with stage IB NSCLC with features associated with a risk of relapse similar to those with a higher stage of NSCLC. However, those high risk factors that might support selection for adjuvant chemotherapy have not been defined with certainty. Adjuvant chemotherapy may be offered to highly motivated individuals with resected stage IB NSCLC, but a discussion regarding the potential risks and harms of treatment is necessary.

Only chemotherapy regimens used in the most recent trials are evidence-based. The BC Cancer Agency currently views the combination of cisplatin and vinorelbine as standard, as these two agents were employed in IALT, NCIC CTG BR.10 and ANITA. Cisplatin-based treatment is preferred, but in individuals with a contraindication to cisplatin, the combination of carboplatin and paclitaxel is an acceptable alternative.

References:

1. Anonymous: Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. Bmj. 311:899-909, 1995
2. Keller SM, Adak S, Wagner H, et al: A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. Eastern Cooperative Oncology Group.[comment]. New England Journal of Medicine. 343:1217-22, 2000
3. Scagliotti GV, Fossati R, Torri V, et al: Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer.[comment]. Journal of the National Cancer Institute. 95:1453-61, 2003
4. The International Adjuvant Lung Cancer Trial Collaborative Group: Cisplatin-Based Adjuvant Chemotherapy in Patients with Completely Resected Non-Small-Cell Lung Cancer. N Engl J Med 350:351-360, 2004
5. Douillard J-Y, Rosell R, Delena M, et al: ANITA: Phase III adjuvant vinorelbine (N) and cisplatin (P) versus observation (OBS) in completely resected (stage I-III) non-small-cell lung cancer (NSCLC) patients (pts): Final results after 70-month median follow-up. On behalf of the Adjuvant Navelbine International Trialist Association. J Clin Oncol (Meeting Abstracts) 23:7013-, 2005
6. Winton T, Livingston R, Johnson D, et al: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352:2589-97, 2005
7. Strauss GM, Herndon J, Maddaus MA, et al: Randomized Clinical Trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in Stage IB Non-Small Cell Lung Cancer (NSCLC): Report of Cancer and Leukemia Group B (CALGB) Protocol 9633. J Clin Oncol (Meeting Abstracts) 22:7019-, 2004
8. Strauss GM, Herndon JE, II, Maddaus MA, et al: Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): Update of Cancer and Leukemia Group B (CALGB) protocol 9633. ASCO Meeting Abstracts 24:7007-, 2006
9. Pignon JP, Tribodet H, Scagliotti GV, et al: Lung Adjuvant Cisplatin Evaluation (LACE): A pooled analysis of five randomized clinical trials including 4,584 patients. ASCO Meeting Abstracts 24:7008-, 2006