PANCREATIC ATROPHY WITH LONG TERM SORAFENIB USE

Two cases of irreversible pancreatic atrophy associated with long-term use of sorafenib (Nexavar, Bayer/Onyx) are reported in a letter published online October 9 in the New England Journal of Medicine.

Volumetric CT of the abdomen revealed a 20% reduction in the volume of the pancreas in one patient and a 35% decrease in the other patient (37 months after the initiation of sorafenib).

This may be a newly reported adverse effect of long-term treatment with the drug, suggest researchers Ségolène Hescot, MD, and colleagues from the Université Paris Descartes in France.

Sorafenib, an oral inhibitor of vascular endothelial growth factor (VEGF), as well as other tyrosine kinases, is approved for use in kidney and liver cancer, and is awaiting approval for use in thyroid cancer.

The drug has potent angiogenic activity, the researchers note. With prolonged use, the long-term effect of this potent antiangiogenesis on microvessels in normal tissues "could cause cumulative, serious, and life-threatening late toxic effects," the researchers write. "This might account for the previously reported 8% loss in skeletal muscle in patients who have received sorafenib at 12 months (P < .01), the previously reported thyroid atrophy, and the pancreatic atrophy reported here," they add.

In the 2 cases they describe, one patient had been taking sorafenib for 2.5 years and the other for 3 years, and both patients received cumulative doses of sorafenib that were higher than 1000 g.

Both patients developed diarrhea, and in both cases this was improved with pancreatic-enzyme replacement.

Acute diarrhea is an early and common adverse effect of sorafenib in up to 43% of patients, the researchers note. "We previously noted that pancreatic exocrine insufficiency could contribute to sorafenib-induced diarrhea," they write, but the 2 cases they now report suggest that pancreatic atrophy might be a consequence of prolonged treatment.

Approached for comment, Toni Choueiri, MD, director of the Kidney Cancer Center, Dana-Farber Cancer Institute/Brigham and Women's Hospital, in Boston, who has reported on other adverse effects of this class of drugs, said: "I am not completely surprised. There is a biologic rationale for this."

"The main issue is to think about such a side effect and work closely with our gastrointestinal colleagues in a multidisciplinary approach to help patients," he said.

Among the questions that need to be addressed, he said, are the following: Do other drugs that target VEGF also produce such results? Are there patients who may be particularly vulnerable to this adverse effect? And does the benefit of controlling the cancer with these drugs outweigh the risk?

The French researcher noted that one of the patients they describe as going on to develop pancreatic atrophy had a complete tumor response for a year.

N Engl J Med. Published online October 9, 2013. Abstract