Originally published as JCO Early Release 10.1200/JCO.2009.23.2447 on July 27 2009

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Reply to S.S. Agarwala et al

2nd Department of Internal Medicine-Propaedeutic, Oncology Section, University General Hospital Attikon, Athens, Greece

Urania Dafni

Laboratory of Biostatistics, University of Athens School of Nursing, Athens, Greece

Helen Gogas

1st Department of Medicine, University of Athens Medical School, Laiko Hospital, Athens, Greece

In the letter by Agarwala et al, two main concerns are raised regarding the design of the noninferiority study by Pectasides et al.¹ They refer to the noninferiority margin used and the interferon alfa-2b dose used. These points according to Agarwala et al are mentioned in the article but not given the appropriate weight. In our opinion they are.

The noninferiority margin as clearly stated in the article is based "on the hypothesis that the 1-month induction regimen (arm A) would be considered as efficacious as the conventional regimen (arm B) if the relapse rate at 3 years from study entry was no more than 15% higher in arm A compared with arm B." This margin was chosen in 1997 by the protocol team as the maximum difference that would allow us to consider arm A noninferior to arm B. The final interpretation of noninferiority obviously depends on the size of the noninferiority margin, the observed 3-year relapse rates that are virtually identical in the two groups and the estimated 95% CI upper limit of the difference on this basis of 9% to 10%. In the final conclusion of the article, it is emphasized that "this study does not rule out the possibility of smaller differences between arms A and B." In short, we have presented the results with caveats regarding all of the points repeated here by Agarwala et al.

On the second point, the result of European Organisation for the Research and Treatment of Cancer trial 18952,² published in 2005, that the 10 x 10⁶ U administered subcutaneously for 1 year as maintenance therapy is no different from observation, is consistent with this noninferiority study. No claim of comparison of either of the two regimens in Pectasides et al to the Eastern Cooperative Oncology Group (ECOG) standard dosages is made. As we mention in our concluding statement the ECOG 1697 trial is posed to answer the question of efficacy for the high-dose interferon portion of the standard ECOG high-dose interferon regimen.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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 or Leadership Position: None Consultant or Advisory Role: Helen Gogas, Schering-Plough (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None

REFERENCES

1. Pectasides D, Dafni U, Bafaloukos D, et al: Randomized phase III study of 1 month versus 1 year of adjuvant high-dose interferon alfa-2b in patients with resected high-risk melanoma. J Clin Oncol 27:939–944, 2009.[Abstract/Free Full Text]

2. Eggermont AM, Suciu S, MacKie R, et al: Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): Randomized controlled trial. Lancet 366:1189–1196, 2005.[CrossRef][Medline]

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