The hypothesis made sense, and the drug was promising.
The hypothesis was that reducing depression could also reduce fatigue in cancer patients, based on the widespread observation that the two often coexist. The drug was paroxetine (Paxil®), and there was a feasible biologic model showing how serotonin might play a role in cancer-related fatigue.
"It all made perfect sense," said Gary Morrow, Ph.D., of the University of Rochester, N.Y., who led a large, randomized trial to test the hypothesis. "It seemed to fit a lot of what we had observed and a lot of what we know. It just happened not to be accurate."
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More in Pipeline
The surprising and disappointing outcome of the Paxil trial leaves clinicians about where they were beforewith little to offer patients for this common and debilitating aspect of cancer treatment. Other drugs are in the pipeline, however, and more trials are planned as oncologists increasingly recognize the impact of fatigue on patients.
Fatigue affects the majority of cancer patients in treatment, according to various estimates. For example, one recent survey of more than 300 chemotherapy patients by Greg Curt, M.D., at the National Cancer Institute found that 76% of cancer patients reported fatigue during chemotherapy, and 30% reported that they experienced that fatigue daily. Among patients who worked, 75% had to change their employment status because of fatigue.
Despite its widespread occurrence, fatigue is seldom addressed in clinical practice. And for those who do try to address the problem, the field of potential treatments is still very limited. "Its where we were with nausea and emesis 15 years ago," said Morrow.
Of the current candidates for managing fatigue, the most studied is methylphenidate (Ritalin®), the same psychostimulant used widely for attention deficit disorder. A phase III trial by the Eastern Cooperative Oncology Group is now comparing methylphenidate to a placebo in patients taking interferon. Originally designed to test the drug in patients with melanoma who were taking high-dose interferon, this trial has recently been modified to include any cancer patient taking interferon at any dose, said principal investigator Paul Hutson, Pharm.D., University of Wisconsin, Madison.
So far, accrual to the trial has been "slower than we hoped," Hutson said. One reason may be that Ritalin is a controlled substance, and in a few states oncologists must obtain permission from state officials to use it in the trial.
Another large, randomized methylphenidate trial, still under review, will test the psychostimulant in chemotherapynot interferonpatients, said Morrow, who will also lead this second CCOP trial. This study will compare the drug to a placebo in more than 700 patients and could open by early fall, Morrow said.
Steroids
The other frequently mentioned approach for managing fatigue is the use of low-dose steroids, such as dexamethasone and prednisone. Russell K. Portenoy, M.D., chairman of the Department of Pain Medicine and Palliative Care at Beth Israel Medical Center, New York, said that there is a large clinical experience with these drugs in cancer fatigue and that, among oncologists who do address fatigue, their use "could be called conventional medical practice."
However, they have never been evaluated in a clinical trial in which fatigue was the primary end point. Portenoy said that the necessity of investing in a randomized controlled trial of steroids is now recognized and that investigators are exploring the possibility. David Cella, Ph.D., chair of ECOGs quality of life committee, said that at its June meeting, the cooperative group would consider a trial with dexamethasone (Decadron®), among other candidates, for managing fatigue. He added that the group plans to begin enrolling patients in at least one trial that has fatigue reduction as its end point by the end of the year.
Other Psychostimulants
While methylphenidate and low-dose steroids are the two drugs most frequently mentioned, others could be on the way. A new psychostimulant called modafinil (Provigil®) has been approved for narcolepsy and, anecdotally, seems to have an effect on cancer fatigue. "Its getting a lot of favorable reviews," Portenoy said.
Cephalon Inc., West Chester, Pa., the company that makes the drug, has no plans to evaluate its effect on fatigue in a trial, according to a spokesperson. However, ECOG will consider a trial with modafinil at its June meeting, Cella said.
Erythropoietin is also being considered outside of its standard use in patients with anemia. At Beth Israel and several other institutions, a trial in patients who have had brain irradiation is about to begin, Portenoy said, to see whether erythropoietin can alleviate the fatigue associated with this treatment.
The hypothesis is based on animal studies showing that erythropoietin reduces injury from ischemia, concussion, and other types of brain injury. In support of this idea, a study reported in the September issue of the Proceedings of the National Academy of Sciences demonstrated that rat brain capillaries have receptors for erythropoietin, enabling the drug to cross the blood-brain barrier.
Erythropoietin to treat fatigue in patients with slightly lowered hemoglobin levels, i.e., lower than 12 g/dL but not lower than 10 g/dL, is also a possibility for a trial. It is one of the concepts that ECOG will consider, Cella said.
Another very new approach to fatigue, based on preliminary data, is the use of antihistamines. In a poster session at the ASCO annual meeting, Eddie Reed, M.D., West Virginia University, Morgantown, reported that the tricyclic antihistamine loratidine (Claritin®) appeared to reduce fatigue among ovarian cancer patients being treated with irofulven. The finding suggests, he said, that some treatment regimens may induce fatigue through cytokine release mediated by the H-1 histamine receptor. Reed said that a trial with loratidine, in which fatigue would be an end point, is under consideration.
Nonpharmacologic Approaches
Nonpharmacologic approaches to cancer fatigue are also under study. Exercise has been shown to help in small studies among selected patients. Other investigators are interested in nutrition and alternative therapies, but little evidence of their effectiveness has been published to date. Cella said that in addition to pharmacologic treatments, the ECOG meeting will consider exercise and lifestyle interventions.
All symptomspain, nausea, fatigue, and othershave psychological as well as physiologic components, Morrow said, and one of the frontiers in fatigue research is the examination of how behavioral and biological factors may interact. "The crossroads of psyche and soma is a very worthwhile place to be doing research," he said.
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