what is virtualization technology: Shortage of Drug for Children's Cancer May Have Upped Relapse ...

Thursday, December 27, 2012

Shortage of Drug for Children's Cancer May Have Upped Relapse ...

WEDNESDAY Dec. 26, 2012 -- When a national shortage of a cancer drug that had helped treat children with Hodgkin's lymphoma for decades forced doctors to find a substitute, they thought they had settled on a drug that would work just as well for these young cancer patients.

But a new analysis suggests they were mistaken.

Mechlorethamine, also known as nitrogen mustard, had been part of a common chemotherapy regimen for Hodgkin's since the 1960s, but experts believed the drug cyclophosphamide would perform equally well. The statistics in the analysis tell another story, however, with two-year remission rates dropping from 88 percent to 75 percent after the switch was made.

"We thought this would be an easy substitution. Cyclophosphamide has been used forever for Hodgkin's lymphoma," said analysis co-author Dr. Monica Metzger, an associate member of the department of oncology at St. Jude Children's Research Hospital in Memphis, Tenn. "We thought the equivalent dose would work just as well, but it doesn't work the same in this chemotherapy regimen. More patients relapsed."

"There are many treatments that work very well. Both mechlorethamine and cyclophosphamide are efficacious, but once you begin a regimen of medications, you have to follow the whole regimen," Metzger said. "It's like a recipe. Like any other recipe, it calls for certain ingredients, and if you make a substitution, you get different results."

The original chemotherapy regimen for Hodgkin's lymphoma, dubbed MOPP, included mechlorethamine, vincristine, procarbazine and prednisone. This combination of drugs was effective, but it also was linked to secondary leukemia and infertility.

Since then, other chemotherapy combinations have been developed to help lessen the side effects. In an effort to further improve outcomes for those with Hodgkin's lymphoma, a newer regimen called Stanford V was developed at Stanford University. This regimen included a shorter course of treatment and lower doses of some of the drugs, including a lower cumulative dose of mechlorethamine.

The Pediatric Hodgkin Lymphoma Consortium, a group of medical centers (including St. Jude's) that conducts clinical trials for pediatric Hodgkin's lymphoma, began using the Stanford V regimen along with low-dose radiation therapy in 2002 for high-risk patients, and in 2006 for patients with an intermediate-risk cancer.

The shortage of mechlorethamine began in 2009. Just one company manufactured the drug, and a manufacturing issue caused the company to abruptly stop making the drug. This caused a worldwide shortage of the drug, Metzger said. Mechlorethamine has only recently become available again, she added.

To see what impact the substitution had on relapses, the researchers turned to the consortium's clinical trial, and compared nearly 200 patients who were treated with the original regimen to 40 patients who were treated with the substituted regimen.

They found that the treatment regimen including cyclophosphamide was significantly less effective.

The analysis is published in the Dec. 27 issue of the New England Journal of Medicine.

Fortunately, there are additional treatment options for people who relapse, although they likely will be exposed to more radiation and have additional side effects that they might have been spared on the original regimen.

Metzger said the U.S. Food and Drug Administration has started to put some programs in place that will help prevent shortages of vital generic medications, such as having the manufacturers let the agency know early if they're planning on exiting the market, or if they're anticipating any manufacturing problems.

Dr. Arlene Redner, associate chief of oncology at Cohen Children's Medical Center in New Hyde Park, N.Y., suggested, "The FDA should ensure that the orphan drugs that are vital in pediatric oncology are manufactured and [that there are] companies known to have excellent manufacturing facilities without production problems to produce them."

"The decision to manufacture these orphan drugs or to stop the manufacture of them should not be a decision of the drug company alone," Redner added. "These drugs should be produced at more than one facility."

Redner also sought to reassure concerned parents, and said it's important to know that "there are other excellent therapies for pediatric Hodgkin's lymphoma that have not required the use of mechlorethamine."

More information

Learn more about how the U.S. Food and Drug Administration handles drug shortages.