New Targeted Therapies: Recognizing and Managing Toxicities

As new targeted cancer therapies come into use, side-effect profiles are also emerging: infusion reactions to monoclonal antibody products such as trastuzumab(Drug information on trastuzumab) (Herceptin) and rituximab(Drug information on rituximab) (Rituxan); skin rashes and edema for imatinib mesylate (Gleevec); rash and diarrhea in patients treated with gefitinib(Drug information on gefitinib) (ZD1839, Iressa) and erlotinib (OSI- 774, Tarceva); and hypersensitivity to paclitaxel(Drug information on paclitaxel) (Taxol) and docetaxel(Drug information on docetaxel) (Taxotere). Four leading investigators reported these toxicities and suggested supportive care at the 14th International Meeting of the Multinational Association for Supportive Care in Cancer (MASCC). Although some side effects require interruptions in treatment, the researchers said that patients usually are able to complete the new regimens. Cancer treatments based on monoclonal antibodies have produced infusion reactions ranging from flu-like symptoms to rare but life-threatening hypotension, bronchospasm, and hypoxia, according to Robert O. Dillman, MD, medical director, Hoag Cancer Center, Newport Beach, California. He cited the following products, all approved since 1997: rituximab (Rituxan) and yttrium-90 ibritumomab tiuxetan (Zevalin) for B-cell lymphoma, trastuzumab (Herceptin) for breast cancer, gemtuzumab ozogamicin (Mylotarg) for acute myelogenous leukemia, andalemtuzumab (Campath 1-H) for chronic lymphocytic leukemia. Reactions With Antigens "With monoclonal antibodies, the key to the toxicity reflects the location of the antigen-that is, the molecule the monoclonal antibody reacts with," Dr. Dillman told ONI. "It is not an inherent toxicity within the product itself. It is not an allergic reaction." For example, reactions with antigens on epithelial cells in the gastrointestinal tract can produce abdominal pain, nausea, vomiting, and diarrhea. If the antigens are expressed on neural sheaths, neuropathy can result. He advised caution when treating patients with high numbers of antigen- expressing cells circulating in the bloodstream, especially if the patient has underlying cardiovascular or respiratory disease. When the white blood cell count is high, a rapid infusion can cause respiratory distress, he said, warning that tumor lysis syndrome is a risk in patients with large numbers of antigen-dense cells that have a high mitotic index. In a recent rituximab study, he said, 77% of patients had reactions during the first infusion. Typically, slowing the infusion provided relief. "In patients who have an infusion reaction, once circulating cells have cleared, there is no reaction when rechallenged," he said. Because most infusion reactions have been "more of a nuisance than a major problem," clinicians have not focused on identifying the optimal supportive care, Dr. Dillman said. He advised hydrating the patient and said that reactions have been treated with a variety of anti-inflammatory agents, including acetaminophen, H1 blockers, H2 blockers, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids. "In some situations, the reactivity of the normal tissues is almost nonexistent," he said. "In others, there's a very predictable reaction, some of which you can at least prevent, decrease, or anticipate." Imatinib The beneficial effects of imatinib(Drug information on imatinib) have been "amazing and better than we would have predicted," said George D. Demetri, MD, director of the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute. Imatinib is benefiting about 85% of the patients taking it for gastrointestinal stromal tumor, he said, but virtually all had adverse events. Dr. Demetri said the most serious adverse event was an abdominal tumor rupture that contributed to a patient death. He said that mild edema is common, occurring in 72% of patients, and that ruptures on the skin surface have led to unusual bleeding and "minor to more severe" rashes. Some adverse events are puzzling. For example, one patient on imatinib noted a varicose vein disappear from the left leg while another remained stable on the right leg. Occasionally, patients have had asymmetrical swellings that go away after a day or so. Some patients were afraid they would be removed from clinical trials if they reported side effects to their oncologists, Dr. Demetri said. These patients formed a support organization, called The Life Raft Group (www.liferaftgroup.org), and established a limited-access mailing list to exchange information among themselves. "Patients were expressing concern that if they openly discussed symptoms, we would take them off study. They didn't want that," he said. "They did a survey where they tracked side effects of the drug, and what we saw on the Internet was somewhat more honestly reported." Imanitib is so new, investigators still have much to learn about adverse events, he added, expressing surprise that hematologic toxicities have not been more of a problemin patients. "We would have predicted greater toxicity-but there are remarkably few sequelae," he said. EGFR Inhibitors The HER1/epidermal growth factor receptor (HER1/EGFR) inhibitors gefitinib and erlotinib have so far caused minimal toxicity in patients participating in clinical trials, said Roman Perez-Soler, MD, chair of oncology at Montefiore Medical Center and chief of the Division of Medical Oncology at Albert Einstein College of Medicine, both in New York. About two-thirds of patients on Iressa have some kind of rash, he said, but 48% are grade 1 and 13% are grade 2. Slightly more than half (57%) develop diarrhea. Typically, treatment is interrupted for a few days while they take an over-the-counter remedy, Dr. Perez-Soler said. Side effects with Tarceva are also mild. Three of four patients have a rash, mostly grade 1 or 2, and 61% have diarrhea. At this point, learning to select patients who will benefit from EGFR inhibitors is more of a problem than toxicity, Dr. Perez-Soler said. Taxanes Paclitaxel and docetaxel have unique side-effect profiles that go beyond the toxicities they share with other cytotoxic agents, said Maurie Markman, MD, director of the Cleveland Clinic Taussig Cancer Center. High risk of hypersensitivity reactions is common for both taxanes, he said. Peripheral neuropathies are more of a concern with paclitaxel, as are the feverless, flu-like symptoms that come with arthralgias and myalgias. Significant fluid retention, pleural effusion, ascites, and peripheral edema have occurred with high cumulative doses of docetaxel. These are in addition to more common reactions such as bone marrow suppression, alopecia, and stomatitis. "Complete alopecia is absolutely the rule," Dr. Markman said. "Anyone suggesting a patient won't lose hair hasn't used the agent." Despite these toxicities, the taxanes are highly effective agents that can be safely administered. "Careful monitoring for immediate side effects and delayed toxicities is important," he said. While hypersensitivity reactions are a major concern, they are rarely fatal. The key to managing them, he said, is recognizing that they are instantaneous. "I've treated a thousand patients with Taxol," he said. "I've never seen a reaction that wasn't immediate." A nurse should sit with a patient when taxanes are started and be prepared to respond, he said. "The nurse should not walk out of the room," he said. If the patient has a reaction, Dr. Markman advised waiting 30 to 60 minutes and then starting the infusion again with diphenhydramine(Drug information on diphenhydramine). Classic desensitization regimens can also be used to prepare patients, he said. Although NSAIDs can reduce the severity of flu-like systems occurring in 10% to 20% of patients on paclitaxel, he advised that some patients may require a narcotic analgesia. He said that he has used low-dose prednisone(Drug information on prednisone) with some success. Oral dexamethasone(Drug information on dexamethasone) can significantly reduce the incidence of fluid retention in patients receiving docetaxel, Dr. Markman said. He cautioned, however, that steroids should be reduced if patients are put on weekly taxane regimens.