Updated November 2011
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.
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.1 However, the trials included in this study used older chemotherapy combinations and an analysis looking specifically at regimens that included cisplatin showed a trend in favour of adjuvant chemotherapy.
Subsequently, ECOG 3590 and ALPI failed to demonstrate any benefit from adjuvant chemotherapy.2,3 There was some concern however due to the use of post-operative radiotherapy in these trials and the negative impact this may have had on outcomes based on the Post-Operative RadioTherapy meta-analysis that suggested that radiotherapy may be detrimental in resected NSCLC. 4 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.5
Data from NCIC CTG BR.10 and ANITA support a role for platinum-based combination chemotherapy as adjuvant therapy in resected NSCLC.6,7 These trials had stringent enrolment criteria and used a cisplatin and vinorelbine regimen only. NCIC CTG BR.10 enrolled patients with Stage IB and II disease whereas ANITA included Stages IB-IIIA. Both trials demonstrated an improvement in overall survival with the addition of cisplatin and vinorelbine adjuvant therapy: 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 seen in previous trials 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 cisplatin-based 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.
While the majority of adjuvant trials have focused on the use of cisplatin, carboplatin has also been evaluated. 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.8 However, further follow up demonstrated only a non-significant trend in favour of treatment at 5 years. A subgroup analysis conducted of this study suggested that patients with tumours > 4 cm benefited from adjuvant therapy. It is unclear where this trial was negative because of the lower risk population (IB) or the selected chemotherapy (carboplatin-based).
The Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis assessed the use of adjuvant cisplatin-based chemotherapy. This analysis confirmed the benefit of post-operative chemotherapy in Stage II and III NSCLC.9
Various biomarkers have been evaluated retrospectively to identify a population for adjuvant treatment including ERCC1, MSH1, p27, p53, Bax, K-ras, EGFR, beta tubulin and gene signatures. None have been validated for clinical use and selection for adjuvant treatment using markers remains experimental.
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.
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
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
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
Postoperative radiotherapy for non-small cell lung cancer. PORT Meta-analysis Trialists Group. Cochrane Database Syst Rev.2000;(2):CD002142. Review. Update in: Cochrane Database Syst Rev. 2003;(1):CD002142
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
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
Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, Grodzki T, Pereira JR, Le Groumellec A, Lorusso V, Clary C, Torres AJ, Dahabreh J, Souquet PJ, Astudillo J, Fournel P, Artal-Cortes A, Jassem J, Koubkova L, His P, Riggi M, Hurteloup P. 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
Strauss GM, Herndon JE 2nd, Maddaus MA, Johnstone DW, Johnson EA, Harpole DH, Gillenwater HH, Watson DM, Sugarbaker DJ, Schilsky RL, Vokes EE, Green MR. 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
Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, Dunant A, Torri V, Rosell R, Seymour L, Spiro SG, Rolland E, Fossati R, Aubert D, Ding K, Waller D, Le Chevalier T; LACE Collaborative Group. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008 Jul 20;26(21):3552-9.