'Drug holidays' might help melanoma, but probably not all cancers

January 10, 2013 | by Shawn Le

Cancer cells can build up a resistance to the drugs commonly used to combat the disease – it’s one of cancer’s many defensive survival mechanisms. In a research letter published Jan. 9 in the journal Nature, however, researchers report that intermittent treatment appears to have helped overcome drug-resistant melanoma in the lab.

The results are promising, but they’re hardly ready for prime-time.

Researchers might overcome drug resistant-melanoma by using intermittent treatment instead of standard treatment. Researchers might overcome drug resistant-melanoma by using intermittent treatment instead of standard treatment.

Cy Stein, M.D., Ph.D., City of Hope's Arthur and Rosalie Kaplan Chair and Professor of the Department of Medical Oncology & Therapeutics Research, is cautious about whether the results — found in mice — will translate into human benefit.

Scientists in the study used mice with a common type of melanoma linked to a mutation in the BRAF gene. More than half of all melanoma patients have a BRAF-mutated cancer. The drug vemurafenib inhibits BRAF proteins, which leads to apoptosis – or natural cell death – of the melanoma. However, the melanoma can develop a resistance to vemurafenib.

Not only do the cancer cells find different ways to survive the lack of BRAF proteins, they also learn to thrive on the drug treatment itself, feeding off of the vemurafenib to continue growing.

The researchers found that starting and stopping treatment on an irregular schedule overcame the survival mechanism. The cancer cells that became resistant to vemurafenib and needed the drug in order to survive died off without it; the resulting surviving melanoma cells became vulnerable to the drug once treatment started again.

But all cancers are different. And humans are hardly mice. Stein’s experience with treating human patients with prostate cancer offers an example of how much more more complicated the picture can be.

“In prostate and breast cancer, however, we not infrequently see that a drug can be given that produces a response, then the disease recurs, and when we remove that drug, we see another response,” he said. “On occasion, these withdrawal responses can be quite durable. The reason that happens is probably quite different than what the Nature paper describes, though.”

Results from one 17-year long clinical trial presented at the 2012 annual meeting of the American Society for Clinical Oncology outline the potential risks of intermittent therapy. The study looked at 3,040 men diagnosed with metastatic, hormone-sensitive prostate cancer between 1995 and 2008. The men either received the standard continuous androgen-deprivation therapy or intermittent therapy. Treatment resistance was not a factor in the study.

In this prostate study, researchers found that the median overall survival time for men who received continuous therapy was 5.8 years, with 29 percent of these men surviving at least 10 years. Men on intermittent therapy had a median overall survival time of 5.1 years, with 23 percent surviving at least 10 years.

The results of the mouse study in melanoma may be promising if they can be reproduced in humans, but Stein says the general benefit of “drug holidays” will be in managing the side effects of treatment, not necessarily in managing the cancer itself.

“Drug holidays are something we usually think of as given for toxicity, so patients can recover before restarting therapy,” he said. “I suspect that given what we know of cancer biology, drug holidays – except for toxicity – will not be common.”

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