Access to and Appropriate Use of Oncology Drugs Called Into Question by ASCO Studies 


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Studies presented at this year’s ASCO Annual Meeting suggest that despite the wealth of amazing oncolytics on the market, drug shortages persist, drug substitutions are common, off-label use of drugs occurs frequently, and patients find their costs burdensome.

Drug Shortage Persists

The shortage of oncology drugs has not eased substantially over the past year. Rather, oncologists are adapting their practices to cope with it, often without guidance, according to surveys presented at the Annual Meeting.

Richard L. Schilsky, MD, Chief Medical Officer of ASCO, relayed the results of an ASCO survey that sought to determine whether recent legislative and regulatory efforts had ameliorated shortages.1 A subset of ASCO members from the United States were queried in October 2012 (n = 390) and again in April 2013 (n = 462). Results of the second survey suggested the situation has improved somewhat, but oncologists still need to substitute drugs and make other adaptations.

While 59% of respondents reported being aware of ongoing drug shortages in their community, this number was slightly higher—70%—last fall, according to Dr. Schilsky. Forty percent felt the drug shortage has not been resolved: 17% believed the shortage is worse now, 16% considered it unchanged, and 9% noticed improvements for some drugs but worsening for others.

Furthermore, oncologists expressed growing concern over the shortage of drugs used in supportive care, such as antiemetics, pain medications, and basic intravenous fluids and electrolytes.

Most Physicians Still Feel the Pinch

In a separate survey of 250 oncologists/hematologists, 83% reported encountering shortages of curative and palliative chemotherapy agents in recent months, and these shortages frequently affected the quality and cost of patient care.2

“Drug shortages are affecting the treatment of curable malignancies. We don’t know the extent to which adaptations forced by these shortages led to adverse clinical outcomes for patients,” said Keerthi Gogineni, MD, of the University of Pennsylvania, Philadelphia, at a press briefing.

“We were surprised by the large number of oncologists who had to make changes in how they care for patients due to drug shortages,” she added.

The survey was distributed to 454 randomly selected ASCO members, and 214 responses from March 2012 to March 2013 were analyzed.

Shortages were most commonly reported for leucovorin, liposomal doxorubicin, fluorouracil (5-FU), bleomycin, and cytarabine, and these and other shortages compromised the delivery of standard chemotherapy in 83% of patients, according to the respondents.

To adapt, physicians changed the treatment regimen (78%), substituted drugs part way through therapy (77%), delayed treatment (43%), “rationed” treatment (37%), omitted doses (29%), reduced doses (20%), and referred patients to other practices (17%). Most providers (70%) indicated they lacked institutional recommendations on these measures.

Nearly 60% of physicians substituted more expensive agents when cheaper generics were not available. This included levoleucovorin (Fusilev) for leucovorin; capecitabine (Xeloda) for 5-FU; and nab-paclitaxel (Abraxane) for paclitaxel. For one cycle of chemotherapy for colorectal cancer, levoleucovorin costs about 30 times that of leucovorin and capecitabine is 140 times more expensive than 5-FU, Dr. Gogineni pointed out.

In addition, clinical trial enrollment is suffering, according to both speakers. In Dr. Gogineni’s survey, 13% of respondents said shortages prevented enrollment or completion of clinical trials. According to Dr. Schilsky, 23 protocols of the Cancer and Leukemia Group B (CALGB) clinical trials group have been affected by drug shortages. The CALGB has recommended delaying registration of new patients, borrowing drugs from neighboring institutions, substituting alternative drugs, and omitting drugs in short supply as possible actions that an institution could take if faced with a drug shortage for patients on protocol. 

While the U.S. Food and Drug Administration (FDA) has stopgap measures in place to ease the situation, Dr. Schilsky indicated that “permanent solutions will require enhancing the business model of generic drug manufacturing.”

Drug Costs for Unapproved Compounds

A significant proportion of cancer patients receive treatments that are neither FDA-approved nor endorsed by the compendia of the National Comprehensive Cancer Network (NCCN). The Surveillance, Epidemiology, and End Results (SEER)-Medicare database from 1998 to 2008 also indicated that 18% of drug costs go toward unapproved drugs.3

“We found a lot of off-label use,” said Dawn L. Hershman, MD, MS, of Columbia University, New York.

The study of 42,634 patients with metastatic breast, ovarian, lung, colon, and prostate cancer and multiple myeloma found the following number of unapproved drugs being used (ie, neither FDA-approved nor NCCN-endorsed): 20 in breast cancer, 8 in colon cancer, 8 in lung cancer, 18 in multiple myeloma, 28 in ovarian cancer, 33 in prostate cancer, and 13 in uterine cancer.

The percentage of patients receiving only an approved drug was just 55%, meaning that 45% of patients received a drug that was not FDA-approved. Variability was high by tumor type, with multiple myeloma patients the most likely to receive an unapproved drug (80%) and colon cancer patients the least likely (10%). The pattern was consistent across the 10-year time period, Dr. Hershman reported.

Altogether, 70% of unapproved drugs were NCCN endorsed. The mean number of unapproved drugs was 1.5 per patient.

“The bulk of unapproved drugs are, however, compendia-approved, and this is reassuring because we think the compendia are appropriate,” she said. About half the compendia-supported drugs were eventually FDA-approved, but those that did not become FDA-approved were not deleted from the compendia and continued to be used.

A breakdown of the cost according to appropriate use revealed that nearly $150 million was reimbursed for drugs that were neither FDA-approved nor compendia-supported, primarily for the treatment of multiple myeloma and prostate cancer.

“We didn’t think we would find any unapproved use of drugs. We thought regulations were in place to stop that,” she commented.

Monika K. Krzyzanowska, MD, MPH, of the Princess Margaret Cancer Center, Toronto, discussed the study and noted that some off-label use is not completely “inappropriate”—for example, in rare cases where there is little evidence to guide practice or prior to approval of a drug for which evidence of benefit has just emerged. In some cases, however, drugs are used in a disease for which they have not been well studied.

But clearly, oncologists are not “choosing wisely” in all circumstances, she said. “Greater scrutiny of off-label use is needed, especially for diseases or drugs where there is a high prevalence of inappropriate prescribing, for expensive drugs, and for situations where the benefit is likely small and the risk of toxicity substantial, such as in patients with advanced cancer and poor performance status.”

Financial Distress Felt by Patients

In a Duke University survey, 17% of insured cancer patients reported “high” or “overwhelming” financial distress, but only 25% of this group brought this to the attention of their oncologist.4

“Even insured cancer patients may experience considerable financial distress, but little has been known about whether patients want to include cost discussions in treatment decision-making,” said S. Yousuf Zafar, MD, of Duke Cancer Institute. “We found a disconnect between a desire to talk about cost and actually having this discussion,” he observed.

The analysis by Duke University researchers was a cross-sectional study of 300 insured adults with solid tumors treated for at least 1 month. Participants were surveyed in person and were asked about financial distress, out-of-pocket costs, discussion about costs with their physician, and aspects of decision-making.

The average patient was a married 60-year-old with at least a high school education and household income of $60,000. Fifty-five percent had private insurance and 36% had Medicare. Colorectal cancer was the most common diagnosis, and three-quarters of patients had advanced disease.

Patients responded to eight questions on a 10-point scale, such as “Do you have stress related to your financial situation?” “Are you living paycheck to paycheck?” and “Could you handle an $8,000 financial emergency?”

High or overwhelming financial distress was reported by 17% of patients. About half of all respondents expressed a desire to talk about cost with their oncologist, but only 19% actually engaged in a cost discussion. Of those who did, 57% said this resulted in decreased expenses.

Interestingly, approximately one-third of patients believed they might receive inferior care should they express a concern over costs. “The fact that many patients said they wanted the best care regardless of cost carries the implication that patients link cost to quality, and if they broach the topic of cost they might receive lesser quality care,” he suggested.

Twenty percent believed financial issues were “not my doctor’s job” or matters where “my doctor can’t help,” while 10% were “embarrassed” to bring up the topic. However, 21% said cost should “always be taken into account.” In an exploratory analysis, white race and high level of distress were significantly associated with likelihood of discussing costs.

The fact that the majority of patients who actually have cost discussions find them helpful indicates there are “false barriers” to these discussions, Dr. Zafar maintained. “We need to at least identify patients at greatest risk for financial distress. We might not have all the answers, but broaching the topic can go a long way.” ■

Disclosure: Drs. Schilsky, Hershman, and Zafar reported no potential conflicts of interest. Dr. Gogineni has received research funding from Pfizer. Dr. Krzyzanowska has an uncompensated consultant or advisory role with Bayer/Onyx, has received honoraria from AstraZeneca, Novartis, and Sanofi, and has received research funding from AstraZeneca and Exelixis.

References

1. Schilsky RL: Improvising when standard therapy is not available. 2013 ASCO Annual Meeting. Abstract CRA6510. Presented June 4, 2013.

2. Emanuel EJ, Shuman D, Chinn D, et al: Impact of oncology drug shortages. 2013 ASCO Annual Meeting. Abstract CRA6510. Presented June 4, 2013.

3. Hershman DL, Neugut AI, Buono D, et al: Off-label and compendia use of chemotherapy in patients with metastatic cancer. 2013 ASCO Annual Meeting. Abstract 6509. Presented June 4, 2013.

4. Zafar Y, Abernethy AP, Tulsky FA, et al: Financial distress, communication, and cancer treatment decision-making: Does cost matter? 2013 ASCO Annual Meeting. Abstract 6506. Presented June 3, 2013.



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