Effective Drug Is 'Tainted,' Unused in Pediatric Cancer

Nick Mulcahy

September 12, 2016

In 1990, after Steven Lipshultz, MD, published the first-ever study on late cardiotoxicity in a group of long-term survivors of childhood cancer who had received heart-damaging chemotherapy for cancer, in the New England Journal of Medicine, he was invited to give grand rounds by David Nathan, MD, the head of pediatrics at Harvard Medical School and Boston Children's Hospital.

Dr Nathan, whose career spanned back to dire times when 90% of all pediatric patients with cancer died soon after diagnosis and treatment, told him in front of the assembly, "Well, Steve, at least the patients are alive for you to study this and try to make it better."

Dr Lipshultz, who moved on from Boston and is now at Children's Hospital of Michigan in Detroit, has never forgotten the well-intended rebuke from Dr Nathan and its underlying message: The efficacy of cancer treatments is of paramount importance.

But things have since changed in pediatric cancer, Dr Lipshultz respectfully says. "We have shifted the paradigm," he told Medscape Medical News.

The shift is from the "last generation's" credo of "we have to keep them alive" to currently having an estimated half million long-term survivors of pediatric cancer in the United States. Patient outcomes are now not just a matter of living and dying but a matter of "level of function," he said. Case in point: Current survivors are a high-risk population for late treatment effects, with cardiotoxicity being one of the most prominent and debilitating.

Notably, survivors with a history of anthracycline treatment are at greater risk for cardiotoxicity because of the drugs' inherent adverse effects against cardiomyocytes.

"When anthracyclines kill heart cells early in childhood development, patients don't have enough heart muscle left for an adequate-sized heart over time," Dr Lipshultz explained, adding that the average age of treatment for childhood leukemia is 4 years old. About 5% anthracycline-treated pediatric patients will have heart failure or other serious cardiovascular complications at 15 to 20 years and 10% to 12% will have the same at 20 to 30 years, he said.

For these and other reasons, Dr Lipshultz and colleagues have published a new review paper on the cardioprotective benefits of dexrazoxane (Zinecard, Pfizer and generic) in pediatric patients with cancer treated with anthracyclines, published online September 5 in the British Journal of Clinical Pharmacology.

What's Going On?

In the United States, dexrazoxane, a chelating agent believed to interfere with treatment-induced, iron-based oxidative stress on the heart, is indicated for use in adults with breast cancer undergoing treatment with doxorubicin, an anthracycline.

But for children and adolescents, dexrazoxane has an orphan designation for prevention of anthracycline-induced cardiomyopathy.

The drug has repeatedly been shown, in clinical trials funded by the National Institutes of Health, to improve cardiovascular markers in children and not decrease the effectiveness of chemotherapy.

The trials include Dana-Farber Cancer Institute Childhood ALL Consortium Protocol 95-01, which found that dexrazoxane provides long-term (5-year) cardioprotection in children treated with doxorubicin for high-risk acute lymphoblastic leukemia (ALL), as reported by Medscape Medical News in 2010.

Furthermore, the American Heart Association and American Academy of Pediatrics endorse dexrazoxane's use as a cardioprotectant among children and adolescents undergoing anthracycline chemotherapy.

And in 2015, the Children's Oncology Group, the largest pediatric clinical trials organization in the North America, put into policy that all protocols involving anthracyclines include dexrazoxane (except in select circumstances).

So, why did a 2012 analysis from researchers at the Children's Hospital of Philadelphia (CHOP) find that only 2% of eligible pediatric patients with ALL and myeloid leukemia who underwent anthracycline treatment during a 10-year study period received dexrazoxane (Pediatr Blood Cancer. 2013;60:616-620)?

In short, why has dexrazoxane been neglected?

The CHOP authors said that "dexrazoxane use in children is not universally accepted due to concerns about toxicity, impact on the antitumor effect of anthracyclines, and risk of secondary malignant neoplasms." The latter issue, they said, needed further investigation to "define its true effect."

However, in their new review article, Dr Lipshultz and colleagues counter that the risk for secondary malignant neoplasms has not, in fact, been borne out in studies with the longest follow-up.

Three large, consecutive, multicenter randomized controlled trials studied the incidence of secondary malignant neoplasms among patients with high-risk ALL treated with dexrazoxane and doxorubicin. After a median follow-up of 3.8 years, only 1 secondary malignant neoplasms was observed among the total 553 patients (Eur J Cancer. 2011;47:1373-1379).

Furthermore, a recent report from the Children's Oncology Group concluded that dexrazoxane had no adverse effect on overall long-term survival among patients with T-cell ALL, T-cell acute lymphoblastic lymphoma, or low-, intermediate- or high-risk Hodgkin lymphoma after a median follow-up of 12.6 years (J Clin Oncol. 2015;33:2639-2645).

But these data do not seem to matter much.

Daniel Lenihan, MD, a cardiologist at Vanderbilt University Medical Center in Nashville, Tennessee, said that a single study, published nearly 10 years ago, appears to have had a large and lasting effect on the reputation of dexrazoxane.

Dr Lenihan, who was asked for comment, said that a 2007 study indicated "dexrazoxane may slightly increase the risk of secondary leukemia."

Specifically, the study found that in patients with low- and high-risk Hodgkin lymphoma, dexrazoxane might increase the incidence of secondary malignant neoplasms when added to standard treatment of doxorubicin, bleomycin, vincristine, and etoposide (ABVE) or dose-intensified ABVE with prednisone and cyclophosphamide followed by low-dose radiation (J Clin Oncol. 2007;25:493-500).

This conclusion was based on the results of Pediatric Oncology Group trials 9426 and 9425, in which 10 secondary malignant neoplasms occurred among 478 patients randomly assigned to treatment with or without dexrazoxane.

At the time, Dr Lipshultz and two colleagues, writing a letter to the editor, in response to the published study, called the secondary cancers finding "a claim without compelling evidence."

Nevertheless, on the basis of these data, the European Medicines Agency's (EMA's) Committee for Medicinal Products for Human Use reported in 2011 that dexrazoxane may be associated with secondary malignant neoplasms in children.

Dr Lenihan explained how this has played out.

The EMA, which is the European version of the US Food and Drug Administration, had dexrazoxane placed in a "black box" warning status, which meant it is not recommended at all, he said. Even though the black box was removed about 2 years ago, the damage had been done.

"The implications that have led to these warnings historically have forever tainted the drug," Dr Lenihan told Medscape Medical News in an email.  "It will be hard to get clinicians to reconsider at this point although the data actually shows it to be effective."

The implications that have led to these warnings historically have forever tainted the drug. Dr Daniel Lenihan

Dr Lipshultz also described additional circumstances that have kept dexrazoxane on the sidelines of pediatric cancer treatment.

First, the drug, as a generic, does not have Big Pharma promoting it, he said. In a related matter, the drug suffers from "a limited supply chain," which means drug shortages.

Also, the head of the hospital formulary at a major center in Canada has told Dr Lipshultz that dexrazoxane competes with heart failure medications for drug budget allowances.

The same problem exists among insurers in the United States, but in a different way. Insurers are willing to pay for drugs to treat heart failure among children receiving anthracyclines (which is a rare occurrence) but protest at paying for its use as a protective agent for events that may or may not occur years later.

Last but not least, oncologists are still learning to incorporate the contributions of the emerging field of cardio-oncology, Dr Lipshultz suggested.

Oncologists treat cancer; this drug doesn't treat cancer. However, oncologists are the ones who must prescribe this. Dr Steven Lipshultz

"Oncologists treat cancer; this drug doesn't treat cancer. However, oncologists are the ones must prescribe this," he said, explaining that this bind results in low use.

"This is one of the reasons why we have created the field of cardio-oncology," he added. The field has been a long time coming, he explained. In the 1980s, "nobody knew" that chemotherapies spawned cardiac late effects. But now, various organizations have begun to issue guidelines to help oncologists manage the often-seen cardiovascular adverse events that follow cancer treatments.

"Dexrazoxane should therefor be a concomitant treatment among children, adolescents, and young adults treated with anthracyclines now and in the foreseeable future," conclude the review authors.

The review paper was supported in part by grants from National Institutes of Health, Chiron, Pfizer Pharmaceuticals Inc, Lance Armstrong Foundation, Women's Cancer Association, Roche Diagnostics Corp, the Scott Howard Fund, the Michael Garil Fund, the Parker Family Foundation, Sofia's Hope, and the American Heart Association. Dr Lipshultz has served as an advisor to Clinigen Group, which has a dexrazoxane product. Dr Lenihan has disclosed no relevant financial relationships.

Br J Clin Pharmacol. Published online September 5, 2016. Abstract

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