Clinical Consequences of Cancer Drug Shortage

Roxanne Nelson

December 26, 2012

For the past several years, there have been persistent shortages of critical drugs, with oncology products being particularly hard hit. A new study now clearly demonstrates just how devastating these shortages have been for cancer patients.

The shortages have now been linked to a higher rate of relapse among children, teenagers, and young adults with Hodgkin lymphoma who were enrolled in a national clinical trial, according to research published in the December 26 issue of the New England Journal of Medicine.

Treatment regimens with cyclophosphamide, which was used as a substitute for mechlorethamine, was significantly less effective in treating patients with intermediate- or high-risk Hodgkin lymphoma. The estimated 2-year event-free survival declined from 88% to 75% after the substitution was made.

The literature suggested that cyclophosphamide could safely be substituted for mechlorethamine, explained study author Monika Metzger, MD, an associate member of the Department of Oncology at St. Jude Children's Research Hospital, Memphis, Tennessee. "But we noticed that this easy substitution had an amazingly negative impact."

"It must be emphasized that when you have a regimen that works, you cannot just exchange a component and expect the same outcome," she said in an interview. "Any substitution has to be done as part of a clinical trial, to check for efficacy. We used it in good faith and assumed that it would not alter results."

Ongoing Issue

As previously reported by Medscape Medical News, patients and physicians have been dealing with an increasing number of drug shortages during the past several years, predominantly of generic injectable agents.

Drug shortages are expected to persist for the foreseeable future, despite action being taken by the US Food and Drug Administration (FDA), drug manufacturers, and other stakeholders, explained Richard Schilsky, MD, professor of medicine at the University of Chicago, Illinois, during a session held at this year's annual meeting of the American Society of Clinical Oncology (ASCO).

"The crisis has been particularly bad in cancer care," Dr. Schilsky said. "Because many of the mainstays of treatment are drugs that are decades old — generic, injectable, and irreplaceable — in many cases, there are no acceptable medical substitutes."

In many cases, patient care has been threatened as a result of drug shortages, added Dr. Schilsky, who is past president of ASCO and current chair of the ASCO Government Relations Committee.

In a survey recently released by the Community Oncology Alliance, respondents reported being faced with short supplies of a number of drugs, including doxorubicin (Adriamycin), bleomycin, carboplatin, cisplatin, cytarabine, dacarbazine, doxorubicin, dexamethasone, etoposide, 5-fluorouracil, irinotecan, leucovorin, levoleucovorin, methotrexate, oxaliplatin, paclitaxel, vincristine, and vinorelbine.

A recent critical shortage of methotrexate and doxorubicin was averted when the FDA took a number of steps to increase the supply. But the study authors note that although some of these shortages have been highlighted in the media, the shortage of mechlorethamine has not made the news.

No Direct Comparisons

As one of the first anticancer agents to become available, mechlorethamine has been used in a 12-week chemotherapy regimen that was developed at Stanford University (the Stanford V regimen) that included vinblastine, mechlorethamine, doxorubicin, vincristine, bleomycin, etoposide, and prednisone. This regimen was effective but minimized toxicity, such as allowing for preserved fertility and reduced risk for secondary leukemia as compared with the MOPP regimen for Hodgkin lymphoma (mechlorethamine, vincristine, procarbazine, and prednisone). It also lowered the risk for cardiopulmonary dysfunction compared with other treatment regimens, note the authors.

The current study was launched before the drug shortages began, and 170 patients had been treated with this regimen when the shortage of mechlorethamine emerged in 2010. The authors note that even though the COPP regimen (cyclophosphamide 600 to 650 mg per square meter, vincristine, procarbazine, and prednisone) has been widely used in both adult and pediatric trials and was believed to as effective as MOPP, no direct comparisons had ever been conducted.

"I searched the literature and could not find a single randomized trial," said Dr. Metzger.

Substitution Less Effective

Dr. Metzger and colleagues evaluated the impact of the regimen that they were forced to adopt by comparing the probability of event-free survival among 181 patients who were treated with the original Stanford V regimen, which included mechlorethamine, with the probability among 40 patients treated with the regimen that included cyclophosphamide.

In their retrospective comparison, the authors found that treatment with cyclophosphamide was significantly less effective (2-year event-free survival, 75% with cyclophosphamide [standard error (SE), 12.5%] vs 88% with mechlorethamine [SE, 2.5%; P = .01 by the log-rank test]). They acknowledge that the follow-up period is still short, with a median follow-up of 1.5 years in the cyclophosphamide group and 4.7 years in the mechlorethamine group. None of the patients in the study have died, so there is no overall survival difference to date in the 2 groups.

However, patients who relapsed received salvage therapy that included intensive cytoreduction followed by autologous stem-cell transplantation, and these treatments are associated with infertility and a higher risk for long-term toxicities.

"These complications might have been avoided if such patients had been treated with mechlorethamine," the authors say. "Moreover, it is unknown as yet whether salvage therapy has been successful in all patients who have had a relapse."

Dr. Metzger told Medscape Medical News that mechlorethamine has become available again. "According to our pharmacy at St. Jude's, it is supposedly going to stay on the market," she said. "The problems with manufacturing and regulatory issues have been resolved."

N Engl J Med. 2012;367:2461-2463. Full article