Treatment of late stage non-small cell lung cancer: we have more work to do.

The successful treatment of non-small cell lung cancer (NSCLC), like most solid tumors, still relies on complete surgical resection. However, a meaningful disease-free interval with surgery alone has been typically restricted to early stages I and II. Over the years, we have made slight improvements in the overall survival and quality of life for patients with more advanced stages, although these improvements have been relegated to patients with a "decent" performance status who can tolerate more intense combined modality therapy or chemotherapy alone.

The common theme that has emerged from the successful treatment of NSCLC and other solid tumors has been the benefit of a comprehensive multidisciplinary evaluation and treatment plan at the beginning of treatment. In recent years, chemotherapy and radiation have shown their value in neoadjuvant and adjuvant settings. This improvement has been due to newer and more effective chemotherapeutic agents, and the benefit has been extended even to early stage IB patients. (1-4)

The article by Kiernan et al (5) raises some intriguing questions with regard to the treatment of late stage NSCLC. Traditionally, the role of surgery alone has been of doubtful benefit in patients with mediastinal lymph node involvement (N2 disease). The benefit of resection has been even less convincing for stage IV disease. It should be noted that in Kiernan's paper, the patients with stage IV disease were classified on the basis of disease involvement of multiple lung lobes rather than metastatic disease in distant organs.

Lately, there have been reports of patients with solitary hematogenous metastatic disease who benefited from aggressive treatment with surgical resection. These patients had solitary brain or adrenal metastases. These reports shared some common observations of Kiernan and his group and echoed the finding that good presurgical performance status was crucial to a favorable outcome. Also, there were hints of further advantages when multimodality treatment was tolerated. (6,7)

The other major theme that has emerged from the studies reporting successful treatment of advanced NSCLC was that patients with low metastatic tumor burden (either a single site or limited nodal spread) did well with complete gross resection. This observation has also been shared with other solid tumors such as colon and breast, in which metastatectomy of isolated distant metastasis improved outcome. (8,9)

The interpretation of data of Kiernan et al is limited by the fact that this is a retrospective study. The sample size for the subgroup analysis of those patients receiving neoadjuvant therapy was small. Improved outcome was also highly correlative with a good performance status and raised the question whether these patients would have done well with just chemotherapy and radiation alone. However, Kiernan et al did not overstate or overinterpret their data; they merely reported a noteworthy observation regarding surgical treatment in late stage non-small cell lung cancer.

The next step is to carry forth with a larger prospective study, with standardized chemotherapy and radiation regimens, with or without surgery. If the observations of Kiernan et al hold true after such a prospective study, then we need to reconsider our staging classification system to take into account the patient's performance status and tumor burden as important parts of the overall stage. A distinction may also need to be made between limited versus extensive metastatic burden.

There is still much more room for improvement in the treatment of late stage non-small cell lung cancer; however, with newer, less toxic chemotherapy, novel biological agents, and better surgical outcome, one must be optimistic about the difficult work ahead of us.

References

1. Vokes EE, Green MR. Clinical studies in non-small cell lung cancer: the CALG experience. Cancer Invest 1998;16:72-79.

2. Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected non-small cell lung cancer. N Engl J Med 2005;352:2589-2597.

3. Pister K. Adjuvant Chemotherapy for non-small-cell lung cancer: the smoke clears. N Engl J Med 2005;352:2640-2642.

4. Dillman RO, Herndon J, Seagren SL, et al. Improved survival in stage III non-small cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 1966;88:1210-1215.

5. Kiernan PD, Sheridan MJ, Lamberti J. Late stage (III and IV) non-small cell cancer of the lung: results of surgical resection at Inova Fairfax Hospital. South Med J 2005;98:1088-1094.

6. Schuchert MJ, Luketich JD. Solitary sites of metastatic disease in non-small cell lung cancer. Curr Treat Options Oncol 2003;4:65-79.

7. Downey RJ. Non-small cell lung cancer with a solitary hematogenous metastasis. Thorac Surg Clin 2004;14:265-269.

8. Okamoto T, Maruyama R, Shoji F, et al. Long-term survivors in stage IV non-small cell lung cancer. Lung Cancer 2005;47:85-91.

9. Lin NU, Bellon JR, Winer EP. CNS metastases in breast cancer. J Clin Oncol 2004;22:3608-3617.

Coty Ho, MD

From Wake Forest University Comprehensive Cancer Center, Winston-Salem, NC.

Reprint requests to Dr. Ho, Wake Forest University Comprehensive Cancer Center, Medical Center Boulevard, Winston-Salem, NC 27157-1082.

Accepted August 15, 2005.