The Best Laid Plans

With many anti-cancer drugs taken orally, it's up to patients to comply with prescribed regimens — but what happens if they don't?

With many anti-cancer drugs taken orally, it’s up to patients to comply with prescribed regimens — but what happens if they don’t?

Technically, K. Eric Perrin takes his cancer medicine as prescribed. But, the 67-year-old retired pastor admits, he bends his daily regimen to fit “what works best for me.”

Twice a day, the Strasburg, Pa., resident takes the powerful targeted drug Nexavar (sorafenib) to keep his liver cancer at bay. But he takes the pills when it’s convenient for him — starting the day’s dosing at 3 a.m., when he’s typically sleepless, rather than an hour before breakfast, as his doctor ordered.

Perrin’s treatment illustrates a growing trend: As the number of oral anti-cancer medications grows, many cancer patients are in charge of administering their own treatments. And many don’t stick faithfully to the dosing schedules they’ve been given.

Despite his tweaks to the timing of his doses, Perrin is adhering to his treatment plan more faithfully than many others in his shoes. Some patients with cancer deviate more radically from their prescribed oral treatment regimens due to side effects, complexity or cost — and the trend is raising concern among cancer care experts.

PHOTO BY MATTHEW LESTER

K. ERIC PERRIN, pictured at home with his wife, sticks to his oral drug regimen but adjusts the timing of doses for convenience.

The World Health Organization estimates that only half of patients across all diseases adhere to prescribed medication, diets and/or lifestyle changes. In the oncology arena, oral therapies such as chemotherapies and targeted treatments comprise an estimated 25 percent of all drugs designed to control disease or prevent its recurrence, but that number is expected to climb to 50 percent or more in the future, making the issue of treatment adherence a key concern in the cancer community.

“It’s a tsunami of a problem we’re seeing come down the road,” says Ann O’Mara, head of palliative care research in the division of cancer prevention at the National Cancer Institute, “and our clinicians are not yet prepared.”

According to a national study by Harris Interactive, of the one fourth of all cancer patients who take oral drugs to manage their disease or side effects, a third admitted to not always following their doctors’ directions and half reported having forgotten to take their medicine. While adherence is strictly overseen in clinical trials, some non-adherence is built into expectations when drugs are used in real-world situations; often, adherence is defined as complying with regimens at a rate of 80 percent or better. Yet, out in the field, experts on cancer care say adherence rates can vary widely, with estimates running the gamut from 20 to 100 percent.

Unpleasant side effects are a major reason for non-compliance. Other factors, O’Mara says, may include language barriers, patient misperceptions about how well oral agents work, and a lack of available alternative treatments if a patient experiences a high burden of side effects related to initial targeted therapy.

Side Effects

Studies have shown that people who have social support, lower out-of-pocket costs and particularly those who are taking aromatase inhibitors are more likely to comply. Those who take several medications, are depressed, or are very young or very old are less likely to adhere to their prescribed regimens.While “data on adherence are scattered,” rates of adherence do seem to span “a wide range,” concedes Christine

Lombardi, an oncology nursing professional at the Hospital of the University of Pennsylvania in Philadelphia and author of “Patient Adherence to Oral Cancer Therapies: A Nursing Resource Guide.” Lombardi says patients adhere to oral drug therapies more successfully in some cancers than in others. In gastrointestinal malignancies, for example, because the targeted anticancer agents generate few side effects, patients generally do well in following clinicians’ advice. But other drugs, like Nexavar (sorafenib), which blocks kinase proteins that contribute to the growth of liver, kidney and thyroid cancers, can generate difficult side effects — nausea, vomiting and diarrhea — leading some patients to stop using them.

“Adherence can be really hard,” she says. “We’re asking them to fight all these side effects at the same time they’re fighting cancer.”

For Andrew Schorr, adhering to his regimen of the targeted drug Jakafi (ruxolitinib) as a treatment for his myelofibrosis — a bone marrow neoplasm — has been easy, because the drug has eased more discomfort than it has caused.

The twice-a-day treatment, he says, relieves the extreme fatigue, anemia, itching and enlarged liver and spleen caused by the disease.

“I’m terrified of missing a dose. Within two weeks of taking it, all my symptoms went away,” the North Carolina resident says.

Not so for Perrin, who has struggled to stick with his regimen of Nexavar because of the side effects it has brought. When the now 67-year-old first began taking the drug about 30 months ago, he started with a single daily pill, gradually upping the dosage to two pills. The severity of his early side effects filled him with dread about going to the prescribed higher dose, and although his body eventually adapted to the single pill, the increase took its expected toll.

That was when the “side effects really kicked in,” he recalls. Not only did he have diarrhea, but the exhaustion surprised him. “The fatigue was amazing,” he says. “I’m a person of boundless energy, but I could barely get through the day.”

Perrin became so exhausted, in fact, that he decided to step down as senior pastor of the Covenant Presbyterian Church in Cherry Hill, N.J., moving to Pennsylvania in mid-2014.

Additional Obstacles

“Anybody who doesn’t have a strong will would have trouble adhering to these drugs,” he suggests. In his case, Perrin found that his strong religious faith helped him “tough it out.”In addition to harsh side effects, high cost may be a deterrent to adherence, as many newer targeted agents are extremely expensive, sometimes costing as much as $8,000 to $12,000 a month, O’Mara says.

Schorr recognizes that his treatment, Jakafi, is expensive at $8,000 each month. He considers himself lucky that his insurer, Blue Cross, covers that cost, but knows that some other patients face high co-payments or deductibles.

In fact, a recent study showed that higher out-of-pocket costs for one particular cancer medication increased the chances that patients would skip doses or stop taking the drug altogether. According to the findings, patients in employer- sponsored health plans who had higher co-payments for Gleevec (imatinib), an oral drug for chronic myeloid leukemia, were 70 percent more likely to stop taking it and 42 percent more likely to skip doses. Co-payments ranged from nothing to more than $4,500 for a one-month supply.

While prices for Gleevec could drop this year after the drug goes off patent, the cost of many other cancer treatments may actually go up as regimens become more advanced. Given cancer’s Darwinian nature, some regimens, such as those used to treat melanoma and breast cancer, now include two or three targeted therapies given together, each honing in on a different pathway a tumor might use, and more combination therapies are expected to emerge.

“You can’t discount cost,” stresses Helen Chew, a professor of medicine in the Division of Hematology/Oncology at the University of California, Davis. “These drugs are relatively new and lack generics, making them more expensive.”

Medicare patients, in particular, might get into financial trouble when they fall into the “doughnut hole” each year and federal insurance coverage runs out, Chew adds, leaving these seniors to absorb the remaining cost.

Still another level of complexity involves specialty pharmacies, according to Pamela Ginex, a nurse researcher at Memorial Sloan Kettering Cancer Center in New York. Most of these newer targeted agents are unavailable at chain-store or local pharmacies, or even at the hospital, she says, so patients often receive their pills through the mail. That means they have to remember to order their prescriptions on time to prevent gaps in treatment.

And then there are the problems posed by complicated regimens.

“One of our biggest concerns is unintentional non-adherence,” says Ginex. “In most cases, patients want to take their drugs as prescribed.” But some may forget to take their pills, or else forget to stop when they should — particularly because some oral medicines are not taken every day, or are taken for a week or two with a break and then restarted. For instance, Xeloda (capecitabine), approved for Dukes’ stage C colon cancer, is given twice a day for 14 days, but then stopped for seven days; Ibrance (palbociclib), recently approved for breast cancer, is given daily for 21 days out of every 28 day cycle, while the hormonal therapy that accompanies it is given daily for all 28 days. Furthermore, some patients with cancer may need to remember to take different medication doses in the morning and at night, or to take drugs with or without food.

Chew also distinguishes between anti-cancer pills that patients take for a few months and those that must be taken for many years. “It’s far harder, in terms of compliance,” to stick with longterm therapy, she says.

That’s the situation in which Perrin finds himself. As with many targeted therapies under development today, Perrin’s Nexavar pills work by controlling active disease, and must be taken indefinitely.

Non-Adherence Can Affect Outcomes

“I asked my oncologist how long that might be,” he says, “and she said, ‘As long as they are effective.’ I understood that to mean I would outgrow it (the medicine) or it would outgrow me.”Typically, the most aggressive cancers require a combination of intravenous chemotherapy and oral medicines, Lombardi and other experts say. As long as patients show up for their infusions, they’ll get their chemotherapy. But when it comes to oral regimens, patients are on their own. And if they stop complying, researchers aren’t sure what will happen.

“What is the demarcation between having enough drug (for benefit and tolerability), and what leads to a bad outcome?” O’Mara asks. “It’s a fuzzy area, still, and we should be researching it.”

Intuitively, it makes sense that severe complications can result when patients fail to take their oral drugs as directed in more aggressive cancers. Lombardi says the data are scant, but that some exist in specific cancers, showing that when patients take only half of what’s prescribed, progression and worsening disease can be anticipated. Without proper doses, she says, oral therapies can’t fully succeed in their mission: to precisely target the molecules involved in cancer cell growth and survival while sparing normal cells.

Most of the available data on treatment adherence, Chew says, exist on the prevention side, around drugs like aromatase inhibitors in breast cancer, which doctors prescribe after breast cancer surgery to prevent recurrences or further spread of disease.

One 2013 study of adherence to such hormonal therapies — in which patients took five years of either tamoxifen or aromatase inhibitors, or combinations of both — found that those with low rates of adherence (less than 80 percent of all prescribed doses taken) faced a nearly 20 percent higher risk of death. The study also showed that adhering well for the whole five years, compared with less than three years, decreased the risk of death.

“The best data I know are in breast cancer,” Chew says, “but we don’t always have data on how much of an oral drug you have to take in order for it to be effective. For instance, prior studies of chemotherapy after early breast cancer show that, if a patient took at least 85 percent of the intended dose, she got the intended benefit. But these results don’t necessarily translate to oral agents. If a patient takes a (targeted oral anti-cancer) drug 90 percent of the time, studies aren’t clear on the benefit.”

Solutions Ahead

Some clarity was provided by a small, phase 3 study published in 2007, which demonstrated that an interruption in treatment with Gleevec for advanced gastrointestinal stromal tumors resulted in rapid disease progression for most patients. In the interrupted group, 26 of 32 patients experienced disease progression, compared with eight of 26 patients in the continuous therapy group.“There’s not one solution” when it comes to medication adherence, Ginex concludes. The patient with breast cancer on (maintenance) tamoxifen, she points out, has a different experience, and different concerns, than someone taking oral treatment for metastatic pancreatic cancer.

Still, Ginex is working on the problem.

With Laura Fennimore, director of clinical programs at the University of Pittsburgh Medical Center Health Plan, Ginex presented a report at an Oncology Nursing Society meeting in 2014 on lessons learned from HIV about treatment adherence that can be applied to cancer patients.

There are many studies addressing the issue of medication adherence in patients who have HIV, she says, and there are marked similarities between treating AIDS and cancer, including a grave diagnosis and complicated treatment regimens that patients are asked to follow. Not surprisingly, Ginex says, researchers have highlighted a need for “good communication, not only for patients, but to help support the medical team.”

Indeed, for health care providers, the shift to oral medications has created a new treatment paradigm. “We need to rethink how to follow patients, and we’re in the process of doing so now,” she says. “Although nurses tend to ask patients about adherence, getting back a ‘yes’ or ‘no’ answer is insufficient. Nurses need to say to the patient, ‘Tell me what you’re taking every day, and when.’ That way we can identify patients who might be having difficulties.”

Some supports for patients that have demonstrated success include medication reminders sent by text and the use of electronic pill dispensers that can monitor whether drugs have been taken and signal patients that they are due for a scheduled dose.

A Personal Decision

Meanwhile, a variety of new options designed to encourage adherence are sprouting up within the health care system. They include hospital-based medication adherence support programs, as well as ideas for minimizing the side effects of medications.For Danette Kienstra, forgetting had nothing to do with her decision to cut back on one of her breast cancer drugs, despite a busy life as a mother of three and a longtime piano teacher.

“I had a huge weight gain,” she says, on two hormonal therapies, tamoxifen and Arimidex (anastrozole), adding that the regimen “took away all of my estrogen, making me very tired.”

Diagnosed with invasive breast cancer in 2004, Kienstra, then age 45 and a resident of Indian Harbour Beach, Fla., underwent three surgeries in the midst of back-to-back hurricanes barreling down the state’s east coast near her home.

Once she had completed four months of chemotherapy and six weeks of radiation, Kienstra went on tamoxifen for three years, then was prescribed Arimidex for two more years — all as adjuvant, or preventive, therapy. Although she took tamoxifen religiously, she says, when doctors put her on the aromatase inhibitor, she grew more lax. She never experienced the severe joint pain commonly associated with these drugs, but she was depressed by her weight gain, and therefore did not regularly take her Arimidex.

PHOTO BY MARY MARTINDALE

DANETTE KIENSTRA, pictured with her husband and sons, stopped taking hormonal therapy prescribed after initial breast cancer treatment because of side effects.

“I wasn’t worried” about harmful consequences, she says.

“But several times I missed a week or so, and that’s when I started bleeding,” raising doctors’ concerns. However, tests showed no signs of cancer, and Kienstra has been cancer-free ever since. Also, she lost all the extra weight, which she attributes not to diet, but to her excitement about being in a local musical.

Looking back, Kienstra says, given the chance, she would have been non-adherent even to her intravenous chemotherapy.

“After all the surgery I went through, I felt I was done,” she says. “I felt I was cured.”

On the website of the Dr. Susan Love Research Foundation, Love, a breast cancer specialist, writes that it’s not uncommon for women to stop their long-term maintenance hormone therapy before they’ve reached the five-year treatment mark, due to side effects. And for some women, that might be OK based on their specific situations.

“I think one of the most important pieces of information that may get lost…is that the additional five years of therapy only offers a ‘modest’ benefit in survival,” so women should talk to their doctors about whether they need an entire five-year maintenance course, Love writes.

She recommends that patients work with their doctors to determine their risk of dying from breast cancer at the time of diagnosis, and how much surgery and chemotherapy are expected to reduce that risk — possibly getting those numbers by using a special online calculator. “If your chance of dying was 5 percent and it goes to 2.5 percent, that is different than if your risk of dying or recurrence (was) 30 percent and it goes to 15 percent,” she writes.

Based on that risk assessment and other information, Love concludes, “a woman will…have to decide whether staying on treatment longer is the best option for her.”