Best of ASCO 2013: Off-Label Prescribing of Chemotherapy Drugs Is Common but Most Meets NCCN Compendium Criteria


Key Points

  • Off-label prescribing of drugs remains common in oncology, but about two-thirds of off-label prescribing is consistent with the NCCN compendium.
  • There is wide variation in the use of off-label drugs among cancer sites, with a low prevalence of off-label drug use for colon cancer and high prevalence of off-label use for prostate cancer and myeloma.

Off-label prescribing of drugs remains common in oncology, but about two-thirds of off-label prescribing is consistent with the National Comprehensive Cancer Network (NCCN) Drugs & Biologics Compendium, according to a study reviewed at Best of ASCO Chicago by Monika K. Krzyzanowska, MD, MPH, of Princess Margaret Cancer Centre in Toronto. “The investigators were interested in characterizing appropriate drug use, and specifically, addressing whether oncologists were choosing wisely when it came to drug therapy,” Dr. Krzyzanowska explained.

The investigators used the Surveillance, Epidemiology and End Results (SEER)-Medicare database to analyze use of intravenous chemotherapy drugs among 42,634 Medicare beneficiaries diagnosed with metastatic cancer between 1998 and 2008. Each drug was classified according to whether it had an indication approved by the Food and Drug Administration (FDA), based on NCCN compendia guidelines, or neither of these. “The NCCN compendium is recognized as an authoritative reference for insurance coverage for drug indications without FDA approval,” the investigators stated.

Overall results indicate that about 45% of patients received at least one approved drug, Dr. Krzyzanowska said. “There was certainly variation between the different sites. For example in colon cancer, the prevalence of off-label use was very low, but in a disease such as myeloma, the prevalence of off-label use was much higher.” The percentage of patients who received any unapproved drug was about 10% for colon cancer and 80% for myeloma.

As background, Dr. Krzyzanowska cited a survey of American oncologists from about 5 years ago, which suggested that the majority of American oncologists have discussed and offered off-label therapy to their patients, although a smaller proportion did so on a routine basis. She also referred to a more recent study published in the Journal of Clinical Oncology, which found that off-label use of 10 commonly prescribed intravenous chemotherapies amounted to 30%.

The Good, the Bad, and the Ugly

Dr. Krzyzanowska also reflected on what she called the good, the bad, and the ugly of off-label drug use.

“Certainly there are some good aspects about off-label therapy,” she said, citing the benefit of early access to medications that have already been shown to be efficacious. “It takes a long-time to get drug approval, so once the clinical trial is presented or published and the results look promising, if the drug is already on the market, this gives you an opportunity to get access to it early,” she said. Off-label use can also be helpful in treating rare diseases where there may not be any other treatment options.

Off-label use also presents “an opportunity in innovation in the molecular matching between drugs and molecular abnormalities,” Dr. Krzyzanowska said. “I think if we are going to use these drugs in that setting, we really need to be tracking what’s happening so that we learn from all of this.”

“In terms of the bad, there has been some work that suggests than when drug therapy that is being tested in a clinical trial is available off-label for another indication, it does have a negative impact on trial accrual,” Dr. Krzyzanowska stated. High costs can also be a negative factor. In the previously cited JCO study, total spending on off-label use of 10 commonly prescribed intravenous drugs totaled $4.5 billion in 2010.

“In terms of the ugly part of this equation, we have the issue of harm,” Dr. Krzyzanowska said, because many of the drugs prescribed off-label also have significant side effects. “The second issue is the issue of motivation,” she said. “Are we prescribing drugs off-label specifically because we think they are going to benefit patients? Or is this a way of avoiding having that difficult conversation that further treatment then would be futile and you really should be looking at supportive care and palliative care?”

Strengths and Limitations

Dr. Krzyzanowska cited the large sample size and insight into temporal trends as strengths of the study. The investigators looked at 10 years of data, and the proportion of off-label use was similar from year to year, she said.

“In terms of limitations, because this was a SEER-Medicare sample, the focus was predominantly on older patients and only on intravenous medications, so I would argue that it does underestimate off-label use, as I suspect that younger patients may be more likely to receive off-label therapy in the metastatic setting,” Dr. Krzyzanowska said. “There was also a lack of information on the motivation for off-label prescribing or the impact in terms of both efficacy as well as toxicity.”

Sit Back and Scrutinize

The current study adds to the growing literature providing evidence that off-label prescribing in common in cancer patients, but Dr. Krzyzanowska believes that more research needs to be done in this area. “I would really like to see some studies that could show us the benefit side and the toxicity side of off-label prescribing—so really the clinical outcome,” she said.

For now, however, “there is some time to sit back and scrutinize off-label use in practice,” she continued. “I think there are some areas where off-label use has less reason to be done.” As examples, she cited off-label prescribing that is not consistent with the NCCN compendium, as well as off-label prescribing of expensive drugs or “situations where the benefit is likely to be small and risk of toxicity substantial.”

Moving forward, Dr. Krzyzanowska suggested increased physician education about appropriate vs inappropriate off-label uses and decision support for physicians. Heightened patient engagement and public awareness are also very important, she said. Tracking off-label use of drugs and indications would be useful for obtaining more information about particular risk-benefit ratios for specific indications.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.