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Since Chemotherapy Is Now the Standard in Node-Positive Lung Cancer, What Is the Role of Postoperative Radiotherapy?

Department of Radiation Oncology, Wayne State University School of Medicine, Karmanos Cancer Hospital, Detroit Medical Center, Detroit, MI

Steven Keller

Department of Surgery, Albert Einstein/Montefiore, School of Medicine, Bronx, NY

To the Editor:

The recent publication of the article by Lally et al¹ and the accompanying editorial² stimulate the discussion about the appropriate use of postoperative radiotherapy (PORT) for patients undergoing resections for non–small-cell lung cancer (NSCLC). The PORT Meta-Analysis Group article³ has irritated many radiation oncologists because the meta-analysis seems to enshrine the mistakes of the individual trials. As a result, many oncologists have criticized this trial, resulting in many carping, minor complaints. Drs Bonner and Spencer² begin a new round of criticism with their assault on PORT's defects, but their only new argument is a phase II trial published by the Radiation Therapy Oncology Group in May of 2005.⁴ As a phase II study, one can report the response and caution about toxicity, but overemphasizing the promise of survival is fraught with error. By superimposing the results of their rather small, selected patient postoperative phase II pilot on the Eastern Cooperative Oncology Group 3590 survival plot⁵—a large prospective phase III trial that compared the results of chemoradiotherapy to radiotherapy alone—the phase II results overextend their bounds and the optimistic glow of survival is wrongly overemphasized. Comparing phase II results with a published phase III study gives preliminary results the promise of authenticity, and may undermine the results of scientifically valid studies like the PORT meta-analysis, and even the Lally et al article, which, while retrospective, is based on a large Surveillance, Epidemiology, and End Results (SEER) database.

Curiously, Lally et al is quite sober in their revelation about PORT results. Overall, PORT had a negative impact on survival of the entire data set of more than 5,600 patients. The N2 subset seems to have a significant survival benefit that appears most prominently after 3 years. However, there appeared to be a negative effect of PORT to the N0 and N1 subsets. The Lally et al article provides some very interesting univariate prognostic factors, which are too numerous to highlight here.¹ Furthermore, SEER does not report whether chemotherapy is used or not, and the radiotherapy details that were analyzed in the PORT meta-analysis are not recorded in SEER. What we do not know will not allow similar criticism, but it does not allow us to inductively reason that the techniques, equipment, and doses were better (despite the obvious facts that three-dimensional conformal therapy was not widely used until 1995 or later, and positron emission tomography was not prevalent until after 2000). Indeed, we do not know even today what the appropriate target or dose might be.

Evidence now strongly supports the use of systemic therapy, for those patients who can tolerate it, in patients with stage N1 and N2 NSCLC completely resected for cure. This evidence is based on cisplatin therapy, and strongest for cisplatin combined with vinorelbine.^6,7 Neither the Lally et al article nor the Bonner and Spencer editorial emphasize that outside of the United States virtually no one uses carboplatin plus paclitaxel, which has never demonstrated superiority of the combination over older two-drug platinum-based combinations or newer ones with vinorelbine^7,8 in prospective trials with comparative arms. Instead, championing the use of PORT based on uncontrolled retrospective studies not using the current standard, Bonner and Spencer, and the Lally et al article by inference, justify the use of a marginally effective modality (PORT) without mentioning the new standard (postoperative chemotherapy). Also, pattern of failure cannot be assessed from the SEER data, nor can any of the radiotherapy variables that were so heavily criticized in the PORT meta-analysis. There is a prospective trial of postoperative therapy, which permits neoadjuvant or adjuvant chemotherapy, developing in Europe, but none emerging in the United States.

As in the Adjuvant Navelbine International Trialist Association and International Adjuvant Lung Cancer trials,^7,8 we may need international cooperation to complete a trial for N1 and N2 patients. We would propose that a PORT trial should give at least two cycles of cisplatin-based therapy (preferably with vinorelbine), exclude ERCC1-positive patients, and randomly assign patients to either PORT or two additional cycles of chemotherapy. The PORT group could sequence cycle 3 and 4 chemotherapy after the radiotherapy as an option. The end point should be primarily survival, with local control as a secondary end point.

We all hope for gene profiles to identify prognostic groups, or factors that predict response to therapy. ERCC1 may predict survival (with ERCC1-negative tumors associated with poorer prognosis). However, cisplatin-based chemotherapy was detrimental in the ERCC1-positive group.⁸

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.

Employment: N/A Leadership: N/A Consultant: Andrew Turrisi, Pharmacyclics, GSM Biologics Stock: N/A Honoraria: N/A Research Funds: N/A Testimony: Andrew Turrisi, Trop, McLeod, McKnight, Brittain, Todara Other: N/A

REFERENCES

1. Lally BE, Zelterman D, Colasanto JM, et al: Postoperative radiotherapy for stage II and 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. Bonner JA, Spencer SA: Post-operative radiotherapy in non–small-cell lung cancer warrants further exploration in the era of adjuvant chemotherapy and conformal radiotherapy. J Clin Oncol 24:2978-2980, 2006[Free Full Text]

3. PORT Meta-Analysis Trialists Group: Effects of postoperative radiotherapy in non-small-cell lung cancer: Systematic review and meta-analysis of individual patient data from nine randomized controlled trials. Lancet 353:257-263, 1998

4. Bradley JD, Paulus R, Graham MV, et al: Phase II trial of postoperative adjuvant paclitaxel/carboplatin and thoracic radiotherapy in resected stage II and IIIa non-small-cell lung cancer: Promising long-term results of the radiation Therapy Oncology Group –RTOG 9705. J Clin Oncol 23:3480-3487, 2005[Abstract/Free Full Text]

5. Keller SM, Adak S, Wagner H, et al: A randomized trial of post-operative adjuvant therapy in patients with completely resected stage II or III-A non-small cell lung cancer: Eastern Cooperative Oncology Group. N Engl J Med 343:1217-1222, 2000[Abstract/Free Full Text]

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 353:2589-2597, 2005[Free Full Text]

7. Drouillard J-Y, Rossell 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 months median follow up: On behalf of the Adjuvant Navelbine International Trialist Association. J Clin Oncol 23:624s, 2005 (abstr 7013)

8. Olaussen KA, Dunant A, Fouret P, et al: DNA repair by ERCC1 in non-small cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 355:983-991, 2006[Abstract/Free Full Text]

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