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Drug Shortage Has Adverse Effect on Young Hodgkin Lymphoma Patients

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Elevated rates of relapse associated with mechlorethamine shortage

A national drug shortage of mechlorethamine has been linked to a higher rate of relapse among children, teenagers, and young adults with Hodgkin lymphoma enrolled in a national clinical trial, according to a report issued by researchers involved in a multi-institutional study.

For patients enrolled in the study, the estimated 2-year cancer-free survival decreased from 88% to 75% after the drug cyclophosphamide was substituted for mechlorethamine. The study, involving the treatment of patients with intermediate- or high-risk Hodgkin lymphoma, was launched before the drug shortages began. The drug substitution occurred following a mechlorethamine shortage that started in 2009.

An analysis of the study, and the first evidence of a drug shortage adversely impacting treatment outcomes in specific patients, appears in the December 27, 2012, edition of the New England Journal of Medicine.

Widely used in treatment of both adults and children with Hodgkin lymphoma, cyclophosphamide was considered a safe and effective alternative to mechlorethamine.

“This is a devastating example of how drug shortages affect patients and why these shortages must be prevented,” said Monika Metzger, MD, an associate member of the St. Jude Department of Oncology and the study’s principal investigator. “Our results demonstrate that, for many chemotherapy drugs, there are no adequate substitute drugs available.”

“This puts a face on the problem of drug shortages and shows that the problem is real, not theoretical. This is about a curative therapy that we were unable to administer because the drug we needed was not available,” said Michael Link, MD, a professor of pediatrics in hematology-oncology at Stanford and a member of the pediatric hematology-oncology service at Packard Children’s Hospital. Link is the senior author of the new report. “Despite heroic efforts by the drug shortage office of the Food and Drug Administration to solve the shortages of a number of medically necessary drugs, it is clear that patients are still suffering from the unavailability of life-saving drugs.”

Working as the Pediatric Hodgkin Consortium, in 2002 the 5 institutions involved in this study (St. Jude Children’s Research Hospital, Dana-Farber/Children’s Hospital Cancer Center, Stanford University School of Medicine and Lucile Packard Children’s Hospital at Stanford, Massachusetts General Hospital, and Maine Medical Center) adopted a 7-drug chemotherapy regimen that included mechlorethamine for the treatment of high-risk pediatric patients. The goal was to reduce the risk of second cancers, infertility, and other problems associated with the earlier treatments while preserving high cure rates.

Patients involved in the study ranged in age from 3 to 21. Half of the participants were age 14 or younger. The trial consisted of 12 weeks of the 7-drug chemotherapy regimen. Based on their response to chemotherapy, patients received radiotherapy along with the dose. The protocol was revised when mechlorethamine became unavailable, and cyclophosphamide was used as a substitution.

When assessing the effect of the substitution, researchers learned that estimated disease-free survival was 88% for the 181 patients whose treatment included mechlorethamine, while for the 40 patients who received cyclophosphamide, it was 75%. Therefore, researchers stopped enrolling new patients in the trials.

“We can think of no credible explanation for this dramatic difference in event-free survival other than the drug substitution,” the researchers noted.

No study patients have died. Those who relapsed received additional intensive therapy that is associated with higher odds for infertility and other health problems later. According to researchers, it is too soon to know if these patients will have the same long-term survival rates as those who did not relapse.

Source: Dana-Farber Cancer Institute.