Journal of the National Cancer Institute Advance Access originally published online on June 24, 2008
JNCI Journal of the National Cancer Institute 2008 100(13):912-913; doi:10.1093/jnci/djn230
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© Oxford University Press 2008.
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Disease Progression in Some Cancers May Be Due to Low Blood Levels of Targeted Therapies
Oncologists have traditionally treated patients with drugs that are delivered intravenously and intermittently. By contrast, imatinib and many other molecularly targeted agents are taken as a pill every day.
That difference means that oncologists are facing a whole new range of challenges. Not only does patient adherence to a drug regimen come into play, but food, digestion, antacids, and drug interactions can all affect how much of a drug is absorbed. Results from several studies suggest that oncologists may improve clinical outcomes in some patients by monitoring the level of the drug in their blood.
Imatinib is broadly effective in patients with chronic myelogenous leukemia (CML) and in gastrointestinal stromal tumors (GISTs). However, data from several studies suggest that patients who have low blood concentrations of the drug are more likely to have disease progression than patients who maintain a higher concentration between doses. The low levels between doses may be due to faster drug metabolism in some patients, but some researchers think that more mundane issues associated with oral dosing, including patient adherence to the drug schedule, are probably equally relevant.
"These are nuances of drug delivery that we have never had to worry about," said Merrill J. Egorin, M.D., Ph.D., codirector of the molecular therapeutics and drug discovery program at the University of Pittsburgh Cancer Institute and professor of medicine and pharmacology at the University of Pittsburgh School of Medicine. Medical oncologists are "slowly waking up to this. I think imatinib is the incentive for this to happen because the drug works."
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Imatinib Troughs in CML
Two research groups have reported an association between a patient's trough level, or low blood concentration of imatinib between doses, and a decreased likelihood of achieving either complete cytogenetic response (CCyR) or major molecular response, which are measures of response in CML. These observations are important because long-term follow-up of patients in clinical trials shows that none of the newly diagnosed patients treated with imatinib who achieved either CCyR or major molecular response during the first 18 months had disease progression within 5 years.
For example, in a recent report published in Blood, Richard Larson, M.D., of the University of Chicago and colleagues found that among 351 patients who were enrolled in the International Randomized Interferon versus STI571 trial and treated with imatinib, the minimum drug concentration was statistically significantly higher in those who achieved a CCyR than in those who did not. Higher imatinib concentration was associated with response, independent of other clinical prognostic factors.
François-Xavier Mahon, M.D., Ph.D., of the department of clinical pharmacology and toxicology at the Centre Hospitalier Universitaire de Bordeaux in France and colleagues reported a similar association in a smaller series of patients last year. On the basis of those data, his team has started checking drug levels in patients who are not part of clinical trials and who have not had an adequate response to therapy or who have had unexpected toxicity. They reported a summary of the accumulated data at the 2008 annual meeting of the American Society of Clinical Oncology (ASCO).
Thus far, they have tested 1,072 samples and found that the mean imatinib concentration was 1,043 ng/mL, with a median of 876 ng/mL. A quarter of patients tested had a trough level of 563 ng/mL or less, and 57% were below 1,000 ng/mL, which researchers think is approximately the concentration needed to inhibit the molecular pathway that drives the disease. Of 227 patients who have been tested more than once and had an imatinib level below 1,000 ng/ml, 75 have had changes in therapy that have resulted in increased drug levels. As their trough level increased, five patients of 20 who did not have a CCyR on their first test did have one by their last test. The researchers conclude that testing drug levels can help monitor and improve responses to imatinib in some circumstances.
Troughs May Affect GIST Outcomes
Low drug concentrations also appear to affect the outcomes of GIST patients. In a retrospective analysis of a phase II trial that compared two doses of imatinib in these patients, George Demetri, M.D., associate professor of medicine at Harvard Medical School and the Dana-Farber Cancer Institute in Boston, and colleagues found that patients in the lowest quartile on the basis of drug trough levels tended to have worse clinical outcomes. Only eight (44%) of the 18 patients with the lowest drug concentration—less than 1,110 ng/mL—had an objective response, compared with 38 (69%) of the remaining 55 patients, the researchers reported at the ASCO meeting. The difference, however, was not statistically significant, so it could have occurred by chance. The difference in median time to progression between the groups was statistically significant, at 11.3 months in the patients with the lowest quartile level and more than 30 months in the other three quartiles.
Also, Demetri and Robert Maki, M.D., a medical oncologist and coleader of the adult sarcoma disease management team at Memorial Sloan-Kettering Cancer Center in New York, have data suggesting that low trough levels are associated with poorer outcomes in GIST patients taking sunitinib or sorafenib. The number of patients tested is still small, however, so the results are preliminary.
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"There is just no way a one-size-fits-all approach is going to work for optimization" of drug dosing, Maki said. He estimates that approximately 10% of GIST patients could have better responses to therapy if their blood concentration were monitored and their dose adjusted based on those results.
Behavior May Play Key Role
A key question is what causes the low trough levels. Differences in drug metabolism surely play a role, but other, modifiable factors such as drug interactions, food intake, and adherence to the regimen probably do as well.
Egorin reported at the ASCO meeting that antacids do not affect imatinib absorption, though they do affect the absorption of dasatinib, which is also used to treat CML. By contrast, Mahon’s group reported that proton pump inhibitors, diuretics, nonsteroidal anti-inflammatory drugs, beta blockers, and benzodiazepine each reduced imatinib levels by 15%–20%.
Patient adherence is one of the biggest issues. In two independent studies, researchers found that approximately 30% of patients with CML or GISTs stopped taking their imatinib prescription for 30 or more days during the first year of therapy. "That amazed me," said Francis Giles, M.D., deputy director of the Cancer Therapy and Research Center at the University of Texas Health Science Center San Antonio, who was not involved in the either study. But, he noted, that is a better adherence rate than that for women taking tamoxifen or for people on oral drugs for hypertension. "We now have a whole new problem. We have a drug that is giving a 95% freedom from CML progression at 6 or 7 years if you take it, and we have patients not taking it."
When he asks his patients why they stop taking the medication, he finds a consistent response: They feel fine; the only time they are reminded during the day that they have cancer is when they take their pill; and there is no end date at which they can look forward to stopping their medication.
"There is absolutely no doubt statistically that the overwhelming cause of so-called imatinib failure or resistance, even though it is relatively rare, is noncompliance," Giles said. "We all talk about mutations because they are sexy and a challenge, and we have to deal with them. But the truth is that if you look at reasonably large series, it would take a very long time to find 100 true chronic-phase patients who are taking their drug and who failed therapy."
Not everyone agrees that nonadherence is the main issue, but Egorin agrees that it is a key factor and emphasizes that physicians should not ignore the possibility. "Oncologists must understand that progression of disease no longer means resistance because some people could be progressing because they are no longer taking their pills," he said.
For suspected noncompliance, testing the level of drug in patients' blood is unlikely to help because they can simply take a dose the day before and mask the problem. But Mahon thinks that testing the blood level can help physicians sort out what is going on when a patient is not responding as expected or has unexpected side effects. In their patient series, 8% of the patients were tested because of compliance concerns, 8% because of concerns about imatinib interactions with other drugs, 36% because of less than ideal response, and 14% because of excessive side effects.
Testing, though, is not widely available—only one commercial laboratory in the U.S. is approved to run the test—and, more important, researchers need to show in a prospective trial that low trough levels affect clinical outcome. And they need to prospectively determine how much drug in the bloodstream is needed to induce responses rather than extrapolating from retrospective analyses.
In the meantime, though, Giles is adamant that dealing with orally dosed drugs is a "whole new world" for oncologists and that the medical community must deal with it. "What I am really afraid of is that in 3–5 years we are going to see a secondary dip in the results of imatinib therapy that is completely due to our lack of acknowledgment of this problem—and our failure to cope with it."
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J Natl Cancer Inst 2008 100: 1428-1429.
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