Cardioprotection for Pediatric ALL Effective at 5 Years

Nick Mulcahy

September 21, 2010

September 21, 2010 — Dexrazoxane provides long-term cardioprotection in children treated with doxorubicin for high-risk acute lymphoblastic leukemia (ALL), according to a study published online September 16 in the Lancet Oncology.

Dexrazoxane, which was approved in 1995 for the treatment of cardiomyopathy associated with doxorubicin administration in breast cancer patients, has previously been shown to reduce early myocardial injury in children with ALL (N Engl J Med.2004;351:145-153).

This new study shows that protection extends to 5 years. It also indicates that the drug works without compromising effectiveness against ALL.

"Dexrazoxane is not given routinely" to children in this setting, acknowledged the lead study author, Steven E. Lipshultz, MD, chair of the Department of Pediatrics, University of Miami Miller School of Medicine, in Florida.

Nevertheless, "the results are very encouraging," Dr. Lipshultz told Medscape Medical News. "They show that we can decrease the side effects of chemotherapy, while not diminishing its effectiveness."

The authors also recommend that dexrazoxane be studied in pediatric oncology research protocols that contain doxorubicin.

The new study is part of the Dana-Farber Cancer Institute Childhood ALL Consortium Protocol 95-01, a multicenter clinical trial for children younger than 18 years with newly diagnosed ALL.

A statistically significant protective effect of dexrazoxane, relative to doxorubicin alone, was seen at 5 years on left ventricular wall thickness (between-group difference: 0.47; 95% confidence interval [CI], 0.46 -0.48) and thickness-to-dimension ratio (0.66; 95% CI, 0.64 - 0.68), report the authors.

Also, the authors report that 5 years after completion of doxorubicin chemotherapy, mean left ventricular fractional shortening and end-systolic dimension Z scores were significantly worse than normal for children who received doxorubicin alone, but not for those who also received dexrazoxane.

The authors say that, with a median follow-up of 8.7 years (range, 1.3 - 12.1 years), event-free survival was 77% in the doxorubicin-alone group and 76% in the doxorubicin plus dexrazoxane group (P = .99).

Despite the overall positive nature of the findings, the authors have some worries.

Some subtle aspects of the data indicate that dexrazoxane is not fully protective in the long term. "Although dexrazoxane treatment seemed to result in fewer left ventricular abnormalities 5 years after therapy, some left ventricular abnormalities persisted," they note.

They also suggest that the therapy might not be effective enough to help many boys. A subgroup analysis showed dexrazoxane protection (P = .046) for the left ventricular thickness-to-dimension ratio at 5 years in girls but not in boys.

However, Crystal Mackall, MD, chief of the Pediatric Oncology Branch of the National Cancer Institute (NCI), was quoted in the NCI Cancer Bulletin as saying that this finding is not definitive. "This was not a large study and hence was not powered to detect potentially smaller differences in protective effects. Since the damage in boys was not as high to begin with, a protective effect of dexrazoxane could have been missed in this study."

Fears About Protection of Cancer Cells Too

Multidrug chemotherapy is effective for ALL, research indicates. Five-year survival rates for children with ALL treated with chemotherapy is about 80%, note the authors.

But cardiovascular health is a concern in survivors of childhood cancer, they note. For instance, cardiac morbidity and mortality are significantly higher than is expected in long-term survivors of childhood cancer.

Chemotherapy in general and doxorubicin in particular is concerning in terms of cardiovascular effects, the authors say.

Echocardiographic abnormalities, including left ventricular wall thinning and depressed left ventricular function, have been reported in cancer survivors treated with doxorubicin during childhood. The chemotherapy has been associated with both early and delayed cardiomyopathy, the authors add.

Dexrazoxane, which is an iron chelator, reduces early myocardial injury during doxorubicin treatment and has been studied mostly in adults.

But there is a fear associated with dexrazoxane — it might protect both the heart and cancer cells, say the authors.

"Other investigators have been reluctant to use dexrazoxane, because of fears that it might protect the cancer cells in addition to the cardiomyocytes," they write.

However, as the investigators point out, the comparable results in event-free survival between the doxorubicin-alone and doxorubicin plus dexrazoxane groups help dispel that concern.

Looks Good at 5 Years But What About Longer Term?

This study is the first to look at the drug's long-term effectiveness in children with ALL.

Children with newly diagnosed ALL from 9 centers in the United States, Canada, and Puerto Rico were enrolled between January 1996 and September 2000. A total of 100 children were assigned to doxorubicin alone (66 analyzed) and 105 to doxorubicin plus dexrazoxane (68 analyzed).

All patients received a cumulative doxorubicin dose of 300 mg/m2.

Patients assigned to doxorubicin plus dexrazoxane received 300 mg/m2 dexrazoxane as an intravenous bolus immediately before each dose of doxorubicin.

The primary outcomes were abnormalities in left ventricular structure (end-diastolic dimension, end-systolic dimension, and end-diastolic thickness-to-dimension ratio) and function, assessed by echocardiography. Left ventricular function was assessed from left ventricular fractional shortening, expressed as Z scores, explain the authors.

At 5 years, the good news is that the mean score for left ventricular fractional shortening for the doxorubicin plus dexrazoxane group did not differ significantly from that in healthy children, whereas the score for the doxorubicin group remained significantly reduced. The bad news, the authors suggest, is that "some left ventricular abnormalities persisted" in the doxorubicin plus dexrazoxane group.

In short, dexrazoxane appears cardioprotective at 5 years, but the longer term is unclear, especially in boys.

In the words of the authors, "whether the effects of dexrazoxane on left ventricular structure and function recorded in this study will translate into improved cardiac outcomes, such as a reduction in heart failure, is uncertain and needs longer follow-up."

This study was supported by grants from the National Institutes of Health, Children's Cardiomyopathy Foundation, University of Miami Women's Cancer Association, Lance Armstrong Foundation, Roche Diagnostics, Pfizer, and Novartis. Dr. Lipshultz reports receiving investigator-initiated grants from Pfizer, Novartis, and Roche Diagnostics to help support this study. Pfizer manufactures both doxorubicin and dexrazoxane. Novartis manufactures dexrazoxane in parts of the world outside the United States. Roche Diagnostics manufactures the immunoassay and analyzer used to measure cardiac troponin T in the patient's serum.

Lancet Oncol 2010. Published online September 16, 2010. Abstract


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