Endocrine Effects of Nonsteroidal Aromatase Inhibitors and Their Clinical Impact
Authors: Emilio Bajetta, Nicoletta Zilembo, Ettore Bichisao, Per E. Lønning, Jurgen Geisler, Mitch Dowsett
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.13.3039 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12089238 Endocrine Effects of Nonsteroidal Aromatase Inhibitors and Their Clinical Impact Emilio BajettaxEmilio BajettaSearch for articles by this author , Nicoletta ZilemboxNicoletta ZilemboSearch for articles by this author , Ettore BichisaoxEttore BichisaoSearch for articles by this author Per E. LønningxPer E. LønningSearch for articles by this author , Jurgen GeislerxJurgen GeislerSearch for articles by this author , Mitch DowsettxMitch DowsettSearch for articles by this author Show More Medical Oncology B, Istituto Nazionale TumoriITMO Group, Milan, ItalyHaukeland University Hospital, Bergen, NorwayRoyal Marsden Hospital, London, United Kingdom https://doi.org/10.1200/JCO.2002.20.13.3039 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01072002In Reply:The letter by Bajetta et al raises several issues. First, Bajetta et al consider the treatment interval on each drug regimen (6 weeks) during the study period short. As they correctly stated, the aim of our study was not clinical, and we believe the design was optimal for its pharmacologic end-points. A key goal was to compare the degree of estrogen suppression and aromatase inhibition while avoiding confounding factors. To treat each patient until response evaluation would mean to extend each treatment period to at least 3 months. In addition, we have to assume that for many patients (like those achieving stable disease) a treatment period of 6 months would be required. This would increase the chance of alterations in potential confounding parameters (like body weight). Also, for patients progressing on therapy, it would be ethically questionable to cross them from one nonsteroidal aromatase inhibitor to another compound of the same class when there are no data on the efficacy of this approach.The number of patients was selected on a pragmatic basis. Studies like this are labor-intensive, and it is possible to conduct them in a limited number of patients only. It was apparent to us that if the results from our earlier separate studies with these two compounds were reproduced in this randomized study (as indeed they were) then 12 patients would be adequate. To use more than is necessary would also be ethically inappropriate. Blindness was made with respect to the laboratory analysis (the end points of this study). Each sample was coded (both for the hormone as well as aromatization analysis); the people doing the analysis were unaware of treatment arm until all data were collected.We do not perceive a need for a washout period between the treatments in this circumstance. Both drugs have a half-life of approximately 2 days, indicating there will be no drug leftover after 6 weeks on therapy. The argument that "breast cancer is neither a stable nor a chronic disease, and this condition is generally wanted by a cross-over study" is, in our opinion, irrelevant to a study of pharmacology in which the disease has no influence on the biochemical end point.We agree with their argument that "estrogen levels in postmenopausal breast cancer patients" are highly variable between patients and consider that to be a strong argument favoring our cross-over design. On the other hand, we are somewhat surprised by their argument that "no data are available demonstrating the behavior of estrogen levels when aromatase inhibitors (AI) are withdrawn". In the report of the clinical efficacy of exemestane after treatment with nonsteroidal inhibitors by Lonning et al1 (of which E. Bajetta was the second author), it was clearly stated that estrogen levels returned to normal within 4 weeks after termination of treatment with novel nonsteroidal aromatase inhibitors (anastrozole, letrozole, and vorozole). Most importantly, our statistical analysis clearly shows superiority of letrozole by each treatment sequence. We find their argument that "this approach could have biased the results in an unpredictable way" to be unsubstantiated.Bajetta et al cite their observational study, which reported that there was no difference in estrogen suppression between responders and nonresponders to aromatase inhibitors.2 Such an observational study is not appropriate to determine whether greater estrogen suppression can lead to improved efficacy. This requires randomized trials to avoid the numerous potential confounders in an observational study. In their study, Bajetta et al2 reported plasma estrogen suppression varying between 35% and 60% with exemestane. This is less than in our studies, and might be explained by limited assay sensitivity and/or cross-reactions with the steroidal drug or its metabolites.3 It is notable that in three randomized trials comparing different aromatase inhibitors (vorozole v aminoglutethimide,4 letrozole v aminoglutethimide,5 and letrozole v fadrozole6) in each case the third-generation inhibitor, which provided more complete aromatase inhibition, yielded improved outcome in at least one clinical end point. Rose et al7 will present a study comparing anastrozole to letrozole head to head as second-line treatment at this year's American Society of Clinical Oncology Annual Meeting.1. Lonning PE, Bajetta E, Murray R, et al: Activity of exemestane (Aromasin) in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: A phase II trial. J Clin Oncol 18:: 2234,2000-2244, Link, Google Scholar2. Bajetta E, Zilembo N, Bichisao E, et al: Tumor response and estrogen suppression in breast cancer patients treated with aromatase inhibitors. Ann Oncol 11:: 1017,2000-1022, Crossref, Medline, Google Scholar3. Lonning PE: Stepwise estrogen suppression manipulating the estrostat. J Steroid Biochem Molec Biol 79:: 127,2001-132, Crossref, Medline, Google Scholar4. Bergh J, Bonneterre J, Illiger HJ, et al: Vorozole (Rivizor) versus aminoglutethimide (AG) in the treatment of postmenopausal breast cancer relapsing after tamoxifen. Proc Am Soc Clin Oncol 16:: 155a,,1997 (abstr 543) Google Scholar5. Gershanovich M, Chaudri HA, Campos D, et al: Letrozole, a new oral aromatase inhibitor: Randomized trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Ann Oncol 9:: 639,1998-645, Crossref, Medline, Google Scholar6. Tominaga T, Morimoto T, Ohashi Y: A pivotal double-blind trial in Japan of an aromatase inhibitor Letrozole (third generation) vs. its predecessor fadrozole hydrochloride (second generation). Japan Letrozole Study Group. Ann Oncol 11:: 25,,2000 (suppl, O100) Crossref, Google Scholar