Analysis Highlights Impact of Drug Shortages

Clinicians have long been aware that cancer drug shortages create anxiety and wreak havoc on dosing schedules. Now a retrospective comparison study published in the New England Journal of Medicine shows that substituting one drug for another that's in short supply can have a measurable and negative impact on treatment outcomes.

Led by St. Jude Children's Research Hospital in Memphis, TN, the researchers compared the effect of substituting cyclophosphamide for mechlorethamine in children undergoing treatment with a multidrug regimen for Hodgkin lymphoma. The analysis showed that cyclophosphamide use was associated with a 75% chance of 2-year event-free survival, compared with 88% in children treated with mechlorethamine.

Mechlorethamine fell into short supply in 2010 after its sole producer, Lundbeck, of Deerfield, IL, changed manufacturing sites, and has only recently become available again.

In response to the shortage, investigators from the Pediatric Hodgkin Lymphoma Consortium switched to cyclophosphamide in ongoing treatments employing the long-standing Stanford V regimen, which combines vinblastine, mechlorethamine, doxorubicin, vincristine, bleomycin, etoposide, and prednisone.

A review of the literature had suggested that this substitution could be made safely. However, after the investigators noticed unanticipated relapses, they initiated the retrospective analysis.

The analysis was based on studying all patients treated with the Stanford V regimen in trials conducted by the consortium. Data included in the analysis represent results from 181 patients treated with the original regimen for a median of 4.7 years and 40 patients treated with a modified regimen that replaced mechlorethamine with cyclophosphamide for a median of 1.5 years.

Michael Link, MD, from Stanford University University School of Medicine in Palo Alto, CA, and the Lucile Packard Children's Hospital at Stanford, who was the study's senior author, says the statistically significant difference was unexpected, given that the 2 drugs—both of which are alkylating agents—are often used interchangeably. “This was a best-case substitution that we thought would be least likely to produce a negative outcome,” he says. “And yet here was this measurable effect.”

Link notes that the analysis provides direct evidence that cancer drug shortages can have a direct impact on patient health and that drug substitutions can affect treatment efficacy. “So regardless of the motivation—be it a lack of availability or a desire to save on cost—it's important to test the consequences of the substitution before implementing it broadly,” he says.

Erin Fox, PharmD, director of drug information services at the University of Utah Hospitals and Clinics in Salt Lake City, says the work provides welcome data showing that cancer drug shortages have consequences. “We've had lots of reports of deaths and patient-care impacts, but they haven't been as well defined as they are in this paper,” she says. “And unfortunately, this problem won't be resolved until we have a more stable drug supply chain. As it stands now, there aren't many opportunities to make up the difference when supplies get disrupted.”