New Targeted Therapies: Recognizing and Managing Toxicities

As new targeted cancertherapies come into use, side-effectprofiles are also emerging: infusionreactions to monoclonal antibodyproducts such as trastuzumab(Herceptin) and rituximab (Rituxan);skin rashes and edema for imatinibmesylate (Gleevec); rash and diarrheain patients treated with gefitinib (ZD1839, Iressa) and erlotinib (OSI-774, Tarceva); and hypersensitivity topaclitaxel (Taxol) and docetaxel(Taxotere). Four leading investigatorsreported these toxicities and suggestedsupportive care at the 14th InternationalMeeting of the MultinationalAssociation for Supportive Care inCancer (MASCC). Although someside effects require interruptions intreatment, the researchers said thatpatients usually are able to completethe new regimens.Cancer treatments based on monoclonalantibodies have produced infusionreactions ranging from flu-likesymptoms to rare but life-threatening hypotension, bronchospasm, and hypoxia,according to Robert O. Dillman,MD, medical director, Hoag CancerCenter, Newport Beach, California.He cited the following products,all approved since 1997: rituximab(Rituxan) and yttrium-90 ibritumomabtiuxetan (Zevalin) for B-celllymphoma, trastuzumab (Herceptin)for breast cancer, gemtuzumabozogamicin (Mylotarg) for acute myelogenousleukemia, andalemtuzumab(Campath 1-H) for chronic lymphocyticleukemia.Reactions With Antigens"With monoclonal antibodies, thekey to the toxicity reflects the locationof the antigen-that is, the moleculethe monoclonal antibody reacts with,"Dr. Dillman told ONI. "It is not aninherent toxicity within the productitself. It is not an allergic reaction."For example, reactions with antigenson epithelial cells in the gastrointestinaltract can produce abdominal pain,nausea, vomiting, and diarrhea. If theantigens are expressed on neuralsheaths, neuropathy can result.He advised caution when treatingpatients with high numbers of antigen-expressing cells circulating in thebloodstream, especially if the patienthas underlying cardiovascular or respiratorydisease. When the white bloodcell count is high, a rapid infusion cancause respiratory distress, he said,warning that tumor lysis syndrome isa risk in patients with large numbersof antigen-dense cells that have a highmitotic index.In a recent rituximab study, he said,77% of patients had reactions duringthe first infusion. Typically, slowingthe infusion provided relief. "In patientswho 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 amajor problem," clinicians have notfocused on identifying the optimalsupportive care, Dr. Dillman said. Headvised hydrating the patient and saidthat reactions have been treated witha variety of anti-inflammatory agents,including acetaminophen, H1blockers, H2 blockers, nonsteroidalanti-inflammatory drugs (NSAIDs),and corticosteroids. "In some situations,the reactivity of the normal tissuesis almost nonexistent," he said."In others, there's a very predictablereaction, some of which you can atleast prevent, decrease, or anticipate."ImatinibThe beneficial effects of imatinibhave been "amazing and better thanwe would have predicted," said GeorgeD. Demetri, MD, director of the Centerfor Sarcoma and Bone Oncology,Dana-Farber Cancer Institute. Imatinibis benefiting about 85% of thepatients taking it for gastrointestinalstromal tumor, he said, but virtuallyall had adverse events.Dr. Demetri said the most seriousadverse event was an abdominal tumorrupture that contributed to a patientdeath. He said that mild edema is common, occurring in 72% of patients,and that ruptures on the skinsurface have led to unusual bleedingand "minor to more severe" rashes.Some adverse events are puzzling.For example, one patient on imatinibnoted a varicose vein disappear fromthe left leg while another remainedstable on the right leg. Occasionally,patients have had asymmetrical swellingsthat go away after a day or so.Some patients were afraid theywould be removed from clinical trials if they reported side effects to theironcologists, Dr. Demetri said. Thesepatients formed a support organization,called The Life Raft Group(www.liferaftgroup.org), and establisheda limited-access mailing listto exchange information amongthemselves."Patients were expressing concernthat if they openly discussed symptoms,we would take them off study.They didn't want that," he said. "Theydid a survey where they tracked sideeffects of the drug, and what we sawon the Internet was somewhat morehonestly reported."Imanitib is so new, investigatorsstill have much to learn about adverseevents, he added, expressing surprisethat hematologic toxicities have notbeen more of a problemin patients."We would have predicted greater toxicity-but there are remarkablyfew sequelae," he said.EGFR InhibitorsThe HER1/epidermal growth factorreceptor (HER1/EGFR) inhibitorsgefitinib and erlotinib have so farcaused minimal toxicity in patientsparticipating in clinical trials, said RomanPerez-Soler, MD, chair of oncologyat Montefiore Medical Center andchief of the Division of Medical Oncologyat Albert Einstein College ofMedicine, both in New York.About two-thirds of patients onIressa have some kind of rash, he said,but 48% are grade 1 and 13% aregrade 2. Slightly more than half (57%)develop diarrhea. Typically, treatmentis interrupted for a few days whilethey take an over-the-counter remedy,Dr. Perez-Soler said. Side effectswith Tarceva are also mild. Three offour patients have a rash, mostly grade1 or 2, and 61% have diarrhea.At this point, learning to select patientswho will benefit from EGFRinhibitors is more of a problem thantoxicity, Dr. Perez-Soler said.TaxanesPaclitaxel and docetaxel haveunique side-effect profiles that go beyondthe toxicities they share withother cytotoxic agents, said MaurieMarkman, MD, director of the ClevelandClinic Taussig Cancer Center.High risk of hypersensitivity reactionsis common for both taxanes, he said.Peripheral neuropathies are more ofa concern with paclitaxel, as are thefeverless, flu-like symptoms that comewith arthralgias and myalgias. Significantfluid retention, pleural effusion,ascites, and peripheral edema have occurredwith high cumulative doses of docetaxel. These are in addition tomore common reactions such as bonemarrow suppression, alopecia, andstomatitis."Complete alopecia is absolutelythe rule," Dr. Markman said. "Anyonesuggesting a patient won't losehair hasn't used the agent."Despite these toxicities, the taxanesare highly effective agents that can besafely administered. "Careful monitoringfor immediate side effects anddelayed toxicities is important," hesaid.While hypersensitivity reactionsare a major concern, they are rarelyfatal. The key to managing them, hesaid, is recognizing that they are instantaneous."I've treated a thousandpatients with Taxol," he said. "I'venever seen a reaction that wasn't immediate."A nurse should sit with apatient when taxanes are started andbe prepared to respond, he said. "Thenurse should not walk out of theroom," he said. If the patient has areaction, Dr. Markman advised waiting30 to 60 minutes and then startingthe infusion again with diphenhydramine.Classic desensitizationregimens can also be used to preparepatients, he said.Although NSAIDs can reduce theseverity of flu-like systems occurringin 10% to 20% of patients onpaclitaxel, he advised that some patientsmay require a narcotic analgesia.He said that he has used low-doseprednisone with some success. Oraldexamethasone can significantly reducethe incidence of fluid retentionin patients receiving docetaxel, Dr.Markman said. He cautioned, however,that steroids should be reducedif patients are put on weekly taxaneregimens.