Antifungal drug delays need for chemo in advanced prostate cancer, study suggests

ScienceDaily (June 2, 2011) — The oral antifungal drug itraconazole, most commonly used to treat nail fungus, may keep prostate cancer from worsening and delay the need for chemotherapy in men with advanced disease. Details of the finding, from a clinical trial led by Johns Hopkins experts, are scheduled for presentation on June 4 at the 2011 American Society of Clinical Oncology (ASCO) annual meeting.

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Currently, the drug is approved to treat fungal infections in nails and other organs. Serious side effects can include heart failure, and Johns Hopkins experts caution that itraconazole needs further study before it can be considered for prostate cancer treatment.

Identified as a potential anticancer drug after Hopkins scientists scoured a database of more than 3,000 FDA-approved drugs, itraconazole appears to block tumor blood vessel growth -- the only drug in its class to do so -- much like the anticancer drug bevacizumab (Avastin). The antifungal also disrupts a key cancer-initiating biological pathway called Hedgehog. Laboratory testing by Johns Hopkins scientist Jun Liu, Ph.D., has shown that human prostate tumors implanted in mice shrink when treated with itraconazole.

"The most effective therapy we have right now for metastatic prostate cancer is hormone therapy, and when it doesn't work, the next step is usually chemotherapy," says Emmanuel Antonarakis, M.D., assistant professor of oncology at the Johns Hopkins Kimmel Cancer Center. In a search for compounds that could put off chemotherapy, the Johns Hopkins team turned to itraconazole.

For the study, patients with prostate cancer that had spread to other organs and did not respond to hormone therapy were randomly assigned to receive low or high doses of itraconazole.

Over 24 weeks of daily treatment with oral itraconazole, the investigators tracked the length of time for each patient's prostate cancer to worsen (called progression-free survival). Evidence of worsening disease was measured by a 25 percent increase in their blood level of prostate specific antigen (PSA), a marker for prostate cancer.

Early in the trial, preliminary analysis of 17 men receiving low doses of itraconazole showed that only two of them (11.8 percent) had stable or declining PSA. Because of the limited response, no further men were given low doses of the drug.

However, 11 of 24 (48.4 percent) men taking high doses of itraconazole had stable or declining PSA levels lasting at least 24 weeks. In addition, nearly a third of men taking the high dose had PSA reductions of 30 percent or more. Metastatic prostate cancer patients receiving no treatment typically would worsen in eight to 12 weeks, according to Antonarakis.

The investigators also found that 12 of 14 men taking high doses of itraconazole had lower levels of circulating tumor cells present in their blood after therapy, compared with their baseline levels.

Seven patients experienced side effects, including low potassium, hypertension and fluid retention, but the problems were resolved with potassium replacement pills, anti-hypertension drugs, and diuretics.

"We also tested whether itraconazole acted as hormone therapy by tracking levels of testosterone and DHEA (a testosterone derivative) in the blood, and we found no reductions of either testosterone or DHEA," says Antonarakis. "This finding shows that itraconazole is not just another hormone therapy, and has a unique mechanism of action."

Antonarakis and colleagues next plan to examine blood and skin samples taken from study participants specifically to look for levels of proteins linked to tumor blood vessel formation and the Hedgehog pathway.

"With these results, we believe that high-dose itraconazole is worth studying in a larger group of men with advanced prostate cancer," adds Antonarakis.

The clinical trial was funded by the Department of Defense (DoD) Prostate Cancer Research Program, the Commonwealth Foundation for Cancer Research, the David H. Koch Charitable Foundation, a 2009 American Society of Clinical Oncology (ASCO) Young Investigator Award granted to Antonarakis, and the National Institutes of Health/National Cancer Institute.

In addition to Antonarakis, other investigators participating in the research on behalf of the Prostate Cancer Clinical Trials Consortium included Amanda Blackford, Serina King, Anja Frost, Seun Ajiboye, Sushant Kachhap, Michelle Rudek, and Michael Carducci from Johns Hopkins; Elisabeth Heath from the Karmanos Cancer Institute; David Smith from University of Michigan, Ann Arbor; and Dana Rathkopf and Daniel Danila from Memorial Sloan Kettering Cancer Center.

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Many patients fail to properly take oral chemo, leading to complications

ScienceDaily (May 25, 2011) — As the use of oral chemotherapy continues to rise, researchers from Michigan State University have discovered many patients fail to properly take the cancer-fighting medication, a significant clinical problem that can result in complications and premature death.

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That lack of adherence needs to be addressed by the health care community, said College of Nursing researcher Barbara Given, who led the study that is published in the May edition of Seminars in Oncology Nursing.

"Given the increasing use of oral chemotherapy in treating cancer, patient adherence is critical to successful outcomes," said Given, associate dean for research for the college. "Health care providers need to monitor and facilitate adherence by identifying barriers and implementing strategies to overcome them."

During the past decade, the use of oral cancer-fighting medication is transforming how oncology care is delivered, Given said: About 10 percent of cancer chemotherapy is provided to patients orally, and the National Comprehensive Cancer Network predicts that by 2013, the rate will increase to 25 percent.

"This phenomenon shifts the care from a safe, controlled process in hospitals or clinics to patients' homes where adherence becomes the patient's and family's responsibility," she said.

While patients benefit by avoiding trips to clinics and hospitals, complex dosing regimens and side effects are challenging to manage -- and poor adherence may lead to disease progression and premature death.

As part of the study, Given and her team identified the barriers that prevent optimal adherence, looking at factors ranging from age, race and gender to health literacy, social support, cost and how much communication there exists between health providers and patients.

Part of the overall problem, Given added, is that measuring and studying adherence to oral medications is difficult because patients are aware of being observed, and patients may adhere more than the average patient who is receiving the same therapy.

"Future research needs to develop better methods for measurement and intervention," she said. "We need to better understand what factors determine patients' adherence. Nurses play a crucial role in promoting adherence and will be key in adopting new treatment plans to help patients."

Given's research was funded by two grants from the Oncology Nursing Society Foundation.

The May edition of Seminars in Oncology Nursing, of which Given was a guest editor, focuses entirely on oral medications in treating cancer. Other MSU researchers with articles in the journal include Sandra Spoelstra, an assistant professor with the College of Nursing and a 2010 Ph.D. graduate, and Bill Given, a professor in the College of Human Medicine.

Spoelstra, also a co-author on Barbara Given's article on the challenges of taking oral chemotherapy, worked with Bill Given on papers focusing on how to best measure adherence to oral medications as well as the policy implications of such drugs.

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