SPECIAL DEPARTMENTS
Authors: Kurt Hellmann, Martee L. Hensley, Lynn M. Schuchter, Eric P. Winer, Neal J. Meropol, David Pfister
Journal: Journal of Clinical Oncology (2000)

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.2000.18.9.2004 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 10784645 Kurt HellmannxKurt HellmannSearch for articles by this author Martee L. HensleyxMartee L. HensleySearch for articles by this author , Lynn M. SchuchterxLynn M. SchuchterSearch for articles by this author , Eric P. WinerxEric P. WinerSearch for articles by this author , Neal J. MeropolxNeal J. MeropolSearch for articles by this author , David PfisterxDavid PfisterSearch for articles by this author Show More WithyhamEast Sussex, United KingdomChemotherapy and Radiotherapy Protectants Expert Panel Co-ChairMemorial Sloan-Kettering Cancer Center New YorkNYChemotherapy and Radiotherapy Protectants Expert Panel Co-ChairUniversity of Pennsylvania Cancer Center PhiladelphiaPAChemotherapy and Radiotherapy Protectants Expert Panel MemberDana-Farber Cancer Institute BostonMAChemotherapy and Radiotherapy Protectants Expert Panel MemberFox Chase Cancer Center PhiladelphiaPAChairAmerican Society of Clinical Oncology Health Services Research CommitteeMemorial Sloan-Kettering Cancer Center New York, NY https://doi.org/10.1200/JCO.2000.18.9.2004 First Page Full Text PDF Figures and Tables © 2000 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse09052000In Reply:We are pleased that the publication of the American Society of Clinical Oncology Clinical Practice Guidelines for the Use of Chemotherapy and Radiotherapy Protectants1 has generated such interest. Dr Hellmann raises certain issues regarding the dexrazoxane (DZR) section of the guidelines that merit further clarification.He expresses concern that the Guideline Panel may have erroneously overstated the degree of granulocytopenia associated with the use of DZR in combination with doxorubicin. We wish to provide the following direct quote from Swain et al2: “With regard to hematologic toxicity, WBC was significantly lower at nadir (days 1 to 18) on the DZR arms (P = .12) and was characterized for the majority of patients as grades 3 and 4 toxicity. Granulocyte counts were significantly lower at nadir for the patients on the DZR arms (P = .009). This was largely due to grade 4 granulocytopenia, which occurred in 75% of patients on the DZR arms and 64% of those on the (PLA) placebo arms.” These are the exact percentages that are quoted in the guideline. We hope that by providing the reader with the full paragraph addressing granulocytopenia from the Swain study that the issue of hematologic toxicity from DZR use is clarified.Hellmann notes that the Panel may have been overly concerned about the significantly lower response rate observed in metastatic breast cancer patients receiving fluorouracil, doxorubicin, and cyclophosphamide (FAC) plus DZR (n = 168) compared with patients receiving FAC plus placebo (n = 181) in trial 088001 (overall response, 47% v 61%, respectively; P = .019). The Panel considered the fact that other smaller studies, which were reviewed for the guidelines,1 have not shown significantly lower response rates among patients receiving DZR. However, in the Panel’s deliberations, the larger study by Swain (n = 349) was felt to be the only randomized trial large enough to detect a small to moderately sized difference in response rates.Another issue is that the Panel underemphasized the overall survival results among women with metastatic breast cancer. It is important to recognize that the observed survival benefit is not from a randomized trial. A subgroup of women in the Swain study who were initially randomized to receive FAC plus placebo (n = 99) in the original study served as historical controls for comparison with women who received FAC plus placebo for six cycles and then continued on FAC plus DZR for all subsequent cycles (n = 102).3 Only women who were responding to FAC plus placebo went on to receive FAC plus DZR. This selected population was likely to have a favorable overall survival because only responding women continued on therapy. Those women who continued on FAC with DZR added after six cycles lived twice as long as women who continued on FAC plus placebo (P < .001). This finding is discussed in a full paragraph of the guideline and is used as supportive evidence for the Panel’s recommendation that “the use of dexrazoxane be considered for patients with metastatic breast cancer who have received ≥ 300 mg/m2 of doxorubicin in the metastatic setting and who may benefit from continued doxorubicin-containing therapy.” We note that this recommendation is in accordance with the following statement from Swain’s recent review: “Therefore, recommendations are to administer dexrazoxane after 300 mg/m2 of doxorubicin in patients with advanced breast cancer in whom continued therapy is indicated,”4 and that the Panel’s recommendation is in accordance with the United States Food and Drug Administration recommendations for use of dexrazoxane.Hellmann suggests that the Panel has neglected to highlight for the reader that DZR is a “potent inhibitor of topoisomerase II,” and that “in addition, it prevents the emergence of resistance to doxorubicin and potentiates a number of anticancer drugs,” referencing his review article published in a supplement to the Seminars in Oncology.5 He provides supporting data from an L1210 mouse leukemia system. Our literature review similarly identified information largely derived from cellular and animal models, and some of these investigators have expressed caution with regard to the integration of chemotherapy with DZR.6,7 The Panel appreciates the insights provided by these data and looks forward to their evolution and development, but published information from human trials was emphasized in developing the guidelines for use of chemotherapy and radiotherapy protectants in patients.Regarding nausea and vomiting, we agree that the text of the Swain article states that nausea and vomiting were significantly more severe on the placebo arm than on the DZR arm (all grades, P = .024 and P = .003, respectively; grade 3/4, P = .062 and P = .52, respectively). The Panel regrets this error, appreciates its identification, and will correct it during the next update of the guideline planned for later this year. However, considering all factors collectively, this does not impact the Panel’s recommendations regarding DZR use.The development of clinical practice guidelines is an iterative process. As new data become available, guidelines require review and revision. The chemotherapy and radiotherapy protectant guidelines were reviewed before publication by all members of the Panel, by a series of independent outside reviewers, and by members of the American Society of Clinical Oncology Board of Directors. After careful consideration of the issues raised in Hellmann’s letter, the Panel feels that the current guidelines for use of DZR do not require revision. However, as outlined in the Methods section of the document, a formal mechanism exists to review the guidelines, including an updated literature search on a regular basis, to address evolving and new concerns and issues.4. Hensley ML, Schuchter LM, Lindley C, et al: American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. J Clin Oncol 17::3333,1999-3355, Link, Google Scholar4. Swain SM, Whaley FS, Gerber MC, et al: Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 15::1318,1997-1332, Link, Google Scholar4. Swain SM, Whaley FS, Gerver MC, et al: Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy. J Clin Oncol 15::1333,1997-1340, Link, Google Scholar4. Swain SM: Adult multicenter trials using dexrazoxane to protect against cardiac toxicity. Semin Oncol 25::43,1998-47, (suppl 10) Google Scholar4. Hellman K: Overview and historical development of dexrazoxane. Semin Oncol 25::48,1998-54, (suppl 10) Google Scholar4. Sehested M, Jensen PB, Sorensen BS, et al: Antagonistic effect of the cardioprotector (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl) propane (ICRF-187) on DNA breaks and cytotoxicity induced by the topoisomerase II directed drugs daunorubicin and etoposide (VP-16). Biochem Pharm 46::389,1993-93, Crossref, Medline, Google Scholar4. Hasinoff BB, Chee GL, Thampatty P, et al: The cardioprotective and DNA topoisomerase II inhibitory agent dexrazoxane (ICRF-187) antagonizes camptothecin-mediated growth inhibition of Chinese hamster ovary cells by inhibition of DNA synthesis. Anticancer Drugs 10::47,1999-54, Crossref, Medline, Google Scholar