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Testing the Efficacy of Antiangiogenic Agents in Advanced Neuroendocrine Tumors

Catalan Institute of Oncology (ICO Girona), Health Services Division of Catalonia, Dr Josep Trueta University Hospital of Girona, Girona, Catalonia, Spain

To the Editor:

A number of new drugs are currently being tested in the treatment of advanced neuroendocrine tumors, a heterogeneous group of neoplasias awaiting an idoneous systemic therapy. Kulke et al¹ recently provided evidence that treatment with the antiangiogenic agent (AA) recombinant human endostatin (rhEndostatin) does not result in significant tumor regression in patients with advanced, well-differentiated long durable disease neuroendocrine tumors. The authors concluded that the absence of partial or complete responses should be assumed as clear antitumoral inefficacy for rhEndostatin and proved benefit for other AA, such as sunitinib or bevacizumab,^2,3 which have been shown to reach modest response rates in carcinoid and pancreatic endocrine tumors. We disagree with this strong statement. First, the proper and/or main end point of clinical activity for new AA still has to be recognized. However, as in many cytotoxic drug trials, this phase II study assessed rhEndostatin efficacy using objective tumor response. Second, the series of patients enrolled on the clinical trials testing the efficacy of rhEndostatin, sunitinib, and bevacizumab apparently include similar clinical characteristics (eg, age, grade, liver metastasis). However, they clearly differ in the way of tumoral response assessment. Thus, while the present study used standard WHO criteria, all the others employed the Response Evaluation Criteria in Solid Tumors criteria. In this regard, it might be of interest to evaluate, reducing the risk of error by using Response Evaluation Criteria in Solid Tumors instead of WHO criteria, whether or not some of the patients achieving stable disease as best response in Kulke et al's study (ie, 80% of the sample) would have been assessed as partial responders.⁴ Third, given the long period from diagnosis to the date of trial inclusion (median, 49.5 months), the authors reasonably argue that the high rate of tumor stabilization may actually reflect the naturally indolent nature of the disease. However, other explanations may account for this finding. Although the presence of measurable disease at baseline was required, the authors do not provide information about clearly progressing disease—either radiologic or symptomatic—at entry. Moreover, requirement of documented clinical progression as one of the inclusion criteria is not mentioned in the article. Indeed, 95% of a sample including 22 patients (ie, > 50% of the total series) was retrospectively documented to have stable disease for at least 2 months before study enrollment. Therefore, although a majority of these patients could have experienced disease progression at any time of their long durable illness, this does necessarily signify that progression occurred to the last prior therapy before inclusion. Conversely, other phase II series for bevacizumab, everolimus (Rad001; Novartis Oncology, Cambridge, MA), and gefitinib, which achieved response rates of 18%, 13%, and 4%, respectively,^3,5,6 showed baseline radiologic progression for most patients or that was mandatory for patients included in these clinical trials. While the best (and common) response in very slow growing tumors appears to closely correlate with high stabilization, other factors such as disease status at entry can strongly influence the likelihood of achieving tumor shrinkage after AA-based treatments.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Kulke MH, Bergsland EK, Ryan DP, et al: Phase II study of recombinant human endostatin in patients with advanced neuroendocrine tumors. J Clin Oncol 24:3555-3561, 2006[Abstract/Free Full Text]

2. Kulke M, Lenz H, Meropol N, et al: A phase II study to evaluate the efficacy and safety of SU11248 in patients with unresectable neuroendocrine tumors. J Clin Oncol 23:310s, 2005 (suppl; abstr 4008)

3. Yao J, Ng C, Hoff P, et al: Improved progression free survival and rapid, sustained decrease in tumor perfusion among patients with advanced carcinoid treated with bevacizumab. J Clin Oncol 23:309s, 2005 (suppl; abstr 4007)

4. Mazumdar M, Smith A, Schwartz LH: A stadistical simulation study finds discordance between WHO criteria and RECIST guideline. J Clin Epidemiol 57:358-365, 2004[CrossRef][Medline]

5. Yao JC, Phan AT, Chang DZ, et al: Phase II study of RADDO1 (everolimus) and depot otreotide (sandostatin LAR) in patients with advanced low grade neuroendocrine carcinoma (LGNET). J Clin Oncol 24:189s, 2006 (abstr 4042)

6. Hobday TJ, Holen K, Donehower R, et al: A phase II trial of gefitinib in patients with progressive metastatic neuroendocrine tumors: A phase II consortium study. J Clin Oncol 24:189s, 2006 (abstr 4043)

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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 Beltran-Fabregat, M. Articles by Menendez, J. A. Search for Related Content PubMed PubMed Citation Articles by Beltran-Fabregat, M. Articles by Menendez, J. A. Social Bookmarking                            What's this?