Tao Wang and John Benitez served as roving reporters at the SOT 2013 Annual Meeting and submitted the article below.
On Sunday afternoon, March 10, at the SOT 52nd Annual Meeting, we attended the Continuing Education (CE) course PM12 entitled “Understanding Toxic Neuropathy in Drug Development: Both Clinical and Nonclinical Perspectives." Peripheral nervous system toxicity is a common complication of exposure to industrial chemicals and drugs such as chemotherapeutics. The CE course successfully integrated both nonclinical and clinical dialogues on peripheral neuropathies, with the goal that such integrated information will provide greater possibilities for successful drug development and improved patient outcomes. John Benitez from Vanderbilt University and Mary Jeanne Kallman from Covance Research Laboratories chaired the course.
Dr. Kallman opened the session with an overview of the course and Amy Chappell, an MD from Eli Lilly and Company, presented a lecture, a comprehensive summary, on the incidence of toxic neuropathy symptoms in clinical patients. Dr. Chappell emphasized the clinical situation and current treatment approaches. From the preclinical risk assessment perspective, Mark Cartwright, Merck, presented a systemic review of peripheral nervous system anatomy and recognition of neuropathies resulting from injury to the axon, neuron, myelin, or supportive tissues. After Dr. Cartwright’s presentation focusing on the histopathological evaluation of tissues to identify various neuropathies, Joseph Arezzo, Albert Einstein College of Medicine, demonstrated the usefulness of nerve functional testing in the assessment of neuropathy and its potential translation to the clinic. Dr. Arezzo emphasized that for electrophysiological testing high-frequency stimulation may be a promising technique; and specifically that testing for neurotoxicity should be done by looking at end fibers, and not proximal injury (e.g., femoral nerve).
Among many useful and critical aspects of the functional tests, one of the take-home messages for toxicologists in the drug development field is that in terms of preclincial general toxicology studies with standard histopathological examination, disappearance of an adverse finding in the nerve tissues under microscopic examination does not mean the nerve function is fully recovered. Finally, Dr. Benitez, who is a medical toxicologist, showed some examples of clinical neuropathies associated with oncolytic drugs. He emphasized that oncolytic drugs have various mechanisms behind neurotoxicity, and we should not lump them all together in an attempt to assess neuropathies. In particular, Dr. Benitez addressed the following: (1) Screening tools don’t always catch early symptoms; (2) Diagnosis is primarily by exam and nerve conduction studies; (3) Treatment options are limited for both preventative and symptomatic aspects – more research is needed; and (4) Development of chemotherapy-induced peripheral neuropathy (CIPN) causes delays in further therapy or stopping therapy altogether— which is devastating to patients!
What was unique to this CE course is that Dr. Benitez invited a patient (Linda G. Allison, MD, MPH) to the CE. Dr. Allison is a cancer survivor with severe Chemotherapy Induced Peripheral Neuropathy. (CIPN). She was a practicing clinician who loved to fill her life with fun activities including playing piano. While she was receiving the chemotherapy, she experienced horrible CIPN including excruciating pain on her hands, teeth, and face. Dr. Allison described the pain she experiences as if every one of her fingers was being hammered every minute, and that her face and teeth felt as if they were falling off. She described how she could not eat or touch anything. Her quality of life has degraded to such low level that she stated there were times when she wished that she would not have survived treatment. Even 2 years after the initial chemotherapy, Dr. Allison still could not resume her normal life’s activities, and while living in Tennessee, she still needs to wear gloves to pick up her groceries in the hot summer months.. She is still undergoing treatment, but is very picky about which drugs she will use.
In the drug development field, while we are certainly getting better and better in terms of putting much research effort on developing anti-cancer drugs that can avoid CIPN, this CE SOT course reminded everyone that saving the life of a cancer patient is indeed critical, but quality of life must be taken into account as well. Indeed the US Food and Drug Administration and the National Cancer Institute are looking at Quality of Life/adverse events in future research.