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University of Washington High-Dose Cyclophosphamide, Mitoxantrone, and Etoposide Experience in Metastatic Breast Cancer: Unexpected Cardiac Toxicity

University of Washington, School of Medicine, Seattle, WA

To the Editor:The positive results for high-dose therapy reported by Bezwoda in two randomized breast cancer chemotherapy trials conducted in South Africa^1,2 influenced the breast cancer community worldwide. The results of the metastatic trial by Bezwoda et al,¹ published in the Journal of Clinical Oncology in 1995, stimulated our institution to undertake a clinical trial designed to replicate and build on the Bezwoda high-dose regimen. We encountered unexpected, fatal cardiac toxicity leading to two deaths and early study closure. We were unable to explain the degree of cardiac toxicity seen in our study, which was not reported in a similar patient population with identical drug doses in the Bezwoda trial. The recently published audits of the Bezwoda trials by Weiss et al^3,4 revealed fabricated data and a severe breach of medical ethics that has led to a retraction by the Journal of Clinical Oncology of the 1995 publication on which we based our study. The audit findings, particularly the lack of follow-up on patients who received high-dose therapy, offer some explanation as to the discrepancy between the toxicity seen with the high-dose regimen in South Africa and in Seattle, WA.

Between 1998 and 1999, the University of Washington initiated a phase II trial of high-dose up-front induction chemotherapy followed by standard dose consolidation in stage IV breast cancer. The high-dose regimen consisted of two cycles of cyclophosphamide, mitoxantrone, and etoposide (CNV), with doses and schedule identical to that described by Bezwoda et al.¹ Each cycle included 45 mg/m² mitoxantrone given over 1 hour, which was reduced to 35 mg/m² per cycle for patients with previous left-sided chest radiation. Each cycle was supported by peripheral-blood stem-cell infusion. The CNV regimen was chosen because of impressive response and survival rates (95% overall response rate, 51% complete response rate, and 90-week median survival) reported by Bezwoda et al¹ in metastatic breast cancer patients. In addition, significant toxicity of this regimen was reportedly minor. The primary objective of our study was to attempt replication of Bezwoda et al’s previously reported response and survival rates. Eligibility was restricted to women with previously untreated stage IV disease at least 1 year from completion of adjuvant therapy, age < 50 years, with left ventricular ejection fraction (LVEF) > 50%. This study was closed in the fall of 1999 because of toxicity, with only six patients enrolled. Four patients received two full cycles of CNV, one received one cycle and declined further therapy, and one progressed after stem-cell mobilization and was taken off protocol. Four patients experienced severe symptomatic (grade 4) cardiac toxicity. Two died as a result of cardiomyopathy, one suffered significant cardiac compromise until her death caused by progressive disease, and one is alive with cardiac compromise despite intensive medical management.

All patients who developed cardiac toxicity were in their thirties and had LVEFs of > 60% on study entry. Patient no. 1 presented with stage IV disease de novo, therefore having received no prior therapy. This patient’s cardiac symptoms were evident 4 months after her second cycle of CNV. She is currently alive without evidence of disease, with an LVEF of 15% on last evaluation. Patient no. 2 died of progressive disease without symptomatic cardiac toxicity, although she did experience a decrease in LVEF from 71% before the study to 50% after the study. Patient no. 3 had prior adjuvant doxorubicin and cyclophosphamide chemotherapy. This patient received only one cycle of CNV. Her cardiac symptoms manifested with 3 months of treatment. She died of congestive heart failure 7 months after CNV. Patient no. 4 received a nonanthracycline adjuvant chemotherapy regimen and right-sided radiation therapy. This patient’s cardiomyopathy did not become clinically apparent until 1 year after her high-dose CNV treatment, when she began trastuzumab for disease progression. She had persistent cardiomyopathy (LVEF 15% 14 months after CNV) and thrombocytopenia 1 year after therapy when she died of progressive disease. Patient no. 5 progressed during peripheral-blood stem-cell collection and was taken off study before receiving high-dose therapy. Patient no. 6 had prior adjuvant doxorubicin and left-sided chest wall radiation. Her mitoxantrone dose was reduced to 25 mg/m² in each cycle. This patient’s cardiac symptoms began 1 month after her second cycle of CNV, despite a normal LVEF after the first CNV cycle. She died of congestive heart failure 6 months after CNV therapy.

In the Bezwoda et al¹ metastatic high-dose study, a 7% incidence of delayed cardiac toxicity was reported in the high-dose CNV arm, all in patients who had received left-chest or mediastinal radiation. The rare cardiac toxicity in that study was reportedly well-controlled with medical therapy, with no deaths caused by congestive heart failure. These data are now known to be invalid and fraudulent. We have reviewed our protocol and the medical literature in attempting to find an explanation for the profound cardiomyopathy seen in our study. In a study by Shpall et al⁵ using intensive single-agent mitoxantrone for metastatic breast cancer, 10 out of 27 patients developed evidence of cardiac toxicity at a mean cumulative dose of 83 mg/m². Seven of the 10 had not been previously exposed to doxorubicin. However, only two of the patients reported by Shpall et al⁵ were symptomatic, and although one patient died of congestive heart failure, these cardiotoxicity rates, with similar cumulative mitoxantrone doses, are much lower than those seen in our study. The cardiac toxicity seen in our trial is likely a combination of the high bolus and cumulative doses of mitoxantrone as given in association with other high-dose chemotherapy agents.

In the treatment of metastatic breast cancer, an almost invariably fatal disease, patients and their physicians are often willing to accept some risk of toxicity and even death from treatment with the hope of gaining an unknown possible increase in survival and advancing therapies for future generations. The women who enrolled onto our study gave their consent based in large part on misreported and falsified response and toxicity data for the regimen we were offering them. It is unknown how many women worldwide may have been harmed by treatment that resulted from the fraudulent studies conducted and reported by Bezwoda et al. Our experience emphasizes the need for caution and confirmation of single-institution clinical trial results, even those conducted with the highest standards by respected investigators and institutions, before widespread acceptance and adoption into clinical practice occurs. This shocking episode of scientific fraudulence stresses the need for review and development of guidelines and procedures that will safeguard the integrity of clinical trials research and protect our patients from unnecessary harm.

REFERENCES

1. Bezwoda WR, Seymour L, Dansey RD: High-dose chemotherapy with hematopoietic rescue as primary treatment for metastatic breast cancer: A randomized trial. J Clin Oncol 13: 2483-2489, 1995[Abstract]

2. Bezwoda WR: Randomised, controlled trial of high dose chemotherapy (HD-CNVp) versus standard dose (CAF) chemotherapy for high risk, surgically treated, primary breast cancer. Proc Am Soc Clin Oncol 18: 2a, 1999 (abstr 4)

3. Weiss RB, Rifkin RM, Stewart FM, et al: High-dose chemotherapy for high-risk primary breast cancer: An on-site review of the Bezwoda study. Lancet 18: 999-1003, 2000

4. Weiss RB, Gill GG, Hudis CA: An on-site audit of the South African trial of high-dose chemotherapy for metastatic breast cancer and associated publications. J Clin Oncol 19: 2771-2777, 2001[Abstract/Free Full Text]

5. Shpall EJ, Jones RB, Holland JF, et al: Intensive single-agent mitoxantrone fo metastatic breast cancer. J Natl Cancer Inst 80: 204-208, 1988[Abstract/Free Full Text]

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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 Gralow, J. R. Articles by Livingston, R. B. Search for Related Content PubMed PubMed Citation Articles by Gralow, J. R. Articles by Livingston, R. B. Social Bookmarking                            What's this?