This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hanna, N. H. Articles by Einhorn, L. H. Search for Related Content PubMed PubMed Citation Articles by Hanna, N. H. Articles by Einhorn, L. H. Social Bookmarking                            What's this?

Postoperative Chemotherapy for N2 Non–Small-Cell Lung Cancer: Conclusions Are Not Black and White, but Gray

Indiana University, Indianapolis, IN

To the Editor:

We read with interest the recent article by Lally et al in the July first issue of the Journal of Clinical Oncology.¹ The author's review of the outcomes from postoperative radiation therapy (PORT) in patients with resected non–small-cell lung cancer (NSCLC) from the Surveillance, Epidemiology and End Results (SEER) database contributes to this body of literature. Overall, this is a fair and balanced presentation. However, we disagree with the authors conclusion which states, "...PORT use is associated with an increase in survival in patients with N2 nodal disease." The SEER database analysis should not be taken as proof of this claim, as there are several potential flaws that we would like to address.

The authors correctly point out that the previous meta-analysis published in 1998 indicated that PORT was detrimental for patients with stage I and II disease.² This was presumed to be due to an increase in radiation-related intercurrent illness rather than an increase in cancer-related deaths. Outdated radiation techniques and planning were largely blamed for these poor outcomes. However, it should be emphasized that in the era from 1988 to 2002 (from which this analysis was performed), modern radiation techniques and computed tomography planning still resulted in a detrimental effect on survival for patients with stage I and II disease. Therefore, one conclusion that is clear is that radiation is detrimental in the postoperative setting for patients with stage I or II disease. A logical extension of this is that PORT is also potentially harmful to some patients with N2 disease. The authors excluded patients from this analysis who died within 4 months of surgery. In addition, 80 patients who died of unknown causes were excluded from the analysis. Since PORT can be detrimental, presumably due to intercurrent cardiopulmonary disease, these exclusions might create a bias, as a certain percentage of these patients may have died due to PORT toxicity.

The retrospective nature of the SEER analysis fails to account for the heterogeneity in N2 NSCLC, which includes the number of lymph nodes and lymph node stations involved, the type of surgery required (lobectomy v pneumonectomy), the type of lymph node dissection performed (complete v systematic sampling) and the comorbidities of the patient. If we adopt the use of PORT in patients with N2 disease based on these data, to whom should this therapy be given? Everyone with resected N2? Only those with multiple lymph nodes or only those with multiple stations of lymph nodes? This type of analysis would be a minimum requirement before recommending PORT in routine practice. Such criteria should be carefully considered when PORT is given following thoracotomy, especially given the increased risks to this patient population, largely comprising smokers with compromised pulmonary function.

A more practical question is the timing of PORT in the current era of adjuvant chemotherapy. Given the previously negative US Intergroup of adjuvant therapy with concurrent chemoradiotherapy and the multiple positive adjuvant chemotherapy trials (in which either a minority of patients or no patients received PORT), chemotherapy (without concurrent radiation) does represent standard adjuvant therapy.^3-6 There is phase III evidence-based medicine that this will achieve a 5% to 15% actual survival increase. Chemotherapy is usually initiated 6 to 8 weeks following surgery and usually takes 3 months to complete. Thus, PORT would have to be initiated approximately 5 months after surgery. Would PORT still confer a survival advantage, or might this result in late complications for the patient?

Finally, it is clear that local failure is not the primary cause of death in patients with stage III NSCLC. Rather, patients die from systemic disease. The recently reported US Intergroup trial evaluating chemoradiotherapy with or without surgery in this patient population, in which the addition of our best local therapy (surgery) did not improve survival, underscores this point.⁷ In both arms of the trial, 75% to 80% of patients died within 5 years. Improved local control should not be considered reason for giving patients PORT. It is difficult to determine radiographically whether someone has developed a local failure once radiation has been given. Many patients with initial local failures remain asymptomatic and eventually succumb to symptomatic distant metastases.

In conclusion, the role of PORT remains in doubt for all patients with resected NSCLC. Until one can define in a prospective manner which population of patients achieves a survival advantage with PORT, we do not believe this should be part of one's routine practice in patients with resected NSCLC, even for patients with N2 disease. We believe a more accurate conclusion to the study would be that PORT might be associated with an increase in survival in patients with N2 nodal disease, but is associated with detriment in survival for patients with N0 or N1 disease.

Authors' Disclosures of Potential Conflicts of Interest

Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Nasser H. Hanna Eli Lilly Eli Lilly; Genentech

REFERENCES

1. Lally B, Zelterman D, Colasanto J, et al: Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the Surveillance, Epidemiology, and End Results database. J Clin Oncol 24:2998-3006, 2006[Abstract/Free Full Text]

2. PORT Meta-analysis Trialist Group: Postoperative radiotherapy in non-small-cell lung cancer: Systematic review and meta-analysis of individual patient data from nine randomized controlled trials. Lancet 352:257-263, 1998[CrossRef][Medline]

3. Keller S, 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. N Engl J Med 343:1217-1222, 2000[Abstract/Free Full Text]

4. Winton T, Livingston R, Johnson D, et al: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352:2589-2597, 2005[Abstract/Free Full Text]

5. 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[Abstract/Free Full Text]

6. Douillard J, 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. J Clin Oncol 23:624s, 2005 (abstr 7013)

7. Albain K, Swann R, Rusch V, et al: Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA (N2) non-small cell lung cancer (NSCLC): Outcomes update of North American Intergroup 0139 (RTOG 9309). J Clin Oncol 23:624s, 2005 (abstr 7014)

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hanna, N. H. Articles by Einhorn, L. H. Search for Related Content PubMed PubMed Citation Articles by Hanna, N. H. Articles by Einhorn, L. H. Social Bookmarking                            What's this?