38 ONCOLOGY DECEMBER 2009 • INTERNAL MEDICINE NEWS Diarrhea Increased With Targeted Cancer Agents

BY CAROLINE HELWICK With the epidermal growth factor receptor inhibitor Cholestyramine can be tried for diarrhea that is as- erlotinib (Tarceva), the incidence—but not the severity— sociated with sorafenib, sunitinib (Sutent), and C HICAGO — The incidence of the oldest side effect of diarrhea is dose related. Sorafenib (Nexavar), a mul- flavopiridol. of anticancer treatment—diarrhea—is rising in paral- titargeted vascular inhibitor, causes diarrhea in 30%-43% The usual management strategies also apply, added lel with the use of targeted agents, and clinicians need of patients. This is thought to be related to small-vessel Dr. Brell. Clinicians should monitor stool output close- to manage this proactively in order to keep patients on ischemia or ischemic colitis with mucosal changes, and ly; stop supportive medications for constipation; use treatment, said Dr. Joanna M. Brell of the Division of to direct damage to mucosal cells. With bortezomib (Vel- oral loperamide (Imodium) up to 16 mg/day, or diphe- Cancer Prevention at the National Cancer Institute. cade), an NF kappaB inhibitor, diarrhea can have a rela- noxylate plus atropine (Lomotil) 5 mg two to four times “Diarrhea occurs in about 80% of chemotherapy pa- tively quick onset (with associated postural hypotension, per day; give intravenous fluids; rule out C. difficile; pre- tients, and about 30% is grade syncope, or near-syncope) and can scribe empiric antibiotics; and give octreotide (Sando- 3/4 toxicity. It is common, it is as- There is little to be dose limiting. Flavopiridol, statin LAR Depot) 100 mcg three times daily, or at high- sociated with newer targeted no evidence to which inhibits multiple cyclin-de- er doses). therapies, it is additive with com- guide the pendent kinases, enhances the ef- Clinicians should check for the use of medications bination treatment, and patients management of ficacy of other chemotherapies. that might increase diarrhea, such as CYP3A4 inhibitors are receiving treatment for longer diarrhea due to Cholestyramine can bind to that can affect drug metabolism such that levels of the periods. We’d better be good at targeted flavopiridol and therefore protect anticancer therapy are increased and therefore toxicity managing it,” she told attendees therapies. against diarrhea, but how this may is enhanced. at the annual Chicago Supportive affect anticancer treatment is un- For prophylaxis, data are even more limited. Dr. Brell Oncology Conference. DR. BRELL known, Dr. Brell said. suggested trying cholestyramine prior to dosing so- Diarrhea is a class effect of rafenib and sunitinib, giving octreotide LAR monthly, many older drugs and of the small-molecule agents that Management of Diarrhea Due to Targeted Agents and giving octreotide and loperamide prior to chemora- are approved in treating at least 10 malignancies, with There is little to no evidence to guide the management diation to the pelvis. many more compounds in the pipeline. (See box.) The of diarrhea that is specifically associated with targeted The meeting was sponsored by Elsevier Oncology, a fact that more targeted agents will be used in mainte- therapies, Dr. Brell said. Unlike conventional sister company to this news organization. ■ nance therapy means that more patients will experience chemotherapy, the goal with diarrhea for longer periods of time, Dr. Brell warned. these agents is not to increase The physical consequences include dehydration, elec- response, and they are not Selected Drugs Associated With Treatment-Induced Diarrhea trolyte imbalance, acute renal failure, renal insuffi- dosed according to body sur- Older Agents Targeted Biologics New Compounds* ciency, weight loss, malnutrition, and risk of infection. face area. The actual effective It causes generalized malaise, diminishes activities of dose of the drugs, therefore, is 5-FU-based Lapatinib Histone deacetylase daily living, enhances treatment noncompliance, and re- generally unknown. regimens (plus capecitabine) inhibitors (chidamide) duces quality of life. Importantly, an abnormal GI tract Given these considerations, Capecitabine Erlotinib Heat shock protein 90 may affect absorption of oral chemotherapy, and dose the major management strate- inhibitor (AUY922) reductions of anticancer drugs or discontinuations of gy with these agents is dose Irinotecan Cetuximab, panitumumab Raf kinase inhibitor treatment are sometimes required. delay, she said. Brief dose in- (XL281) “Treatment delays have uncertain effects on the tu- terruptions are usually ade- Taxanes Sorafenib, sunitinib Proteasome inhibitor EWS mor, and this is distressing to the patient, who wants quate, and the dose can usual- (carfilzomib) N full treatment,” she said. ly be maintained in spite of Cisplatin Bortezomib the toxicity, “which we don’t EDICAL Why Diarrhea Occurs With Targeted Agents do with [5-fluorouracil] or Methotrexate Imatinib M Raltitrexed

The mechanisms by which diarrhea occurs with tar- irinotecan,” she noted. Dose LOBAL geted agents were recently described (Nat. Clin. Pract. reductions are done, if re- *Reported at ASCO 2009 to have dose-limiting toxicity. G Oncol. 2008;5:268-78). They vary according to the class quired, to maintain quality of Source: Dr. Brell LSEVIER of agent. life. E Young Adults With Cancer Fare Better at Pediatric Centers

BY BRUCE JANCIN they’re treating a different population of atric cancers such as acute lymphoblastic childhood leukemia, and acute leukemia young people than is encountered in leukemia (ALL) are typically mesodermal is the most common cause of cancer C OLORADO S PRINGS — Older ado- children’s hospitals: that is, emancipated in origin, whereas adult malignancies are death before age 35. Outcomes in young lescents and young adults with certain youths who are less likely to be treat- generally epithelial. Mendelian genetics adults with ALL have historically been cancers have markedly better outcomes ment compliant than are young patients and lifestyle risk factors play only a lim- worse than in younger patients with the when treated in pediatric centers than in who are still living with their parents. ited role in most childhood tumors, so malignancy. However, a recent Spanish adult oncology centers, based on multi- Pediatric oncologists counter that their routine screening and risk reduction ef- study showed that outcomes in ALL pa- ple studies conducted in the United forts aren’t emphasized. Pediatric cancers tients (aged 19-30 years) who received States and Western European countries. are often microscopically disseminated— the standard pediatric ALL regimen were “The cancers that are more pediatric in ‘Treatment in rather than localized—at the time of di- equal to those in patients aged 15-18 nature—acute lymphoblastic leukemia, pediatric settings agnosis, so systemic therapy is almost al- years (J. Clin. Oncol. 2008;26:1843-9). acute myeloid leukemia, bone and soft yields better ways required. A retrospective study of 321 ALL pa- tissue sarcomas—all have evidence that results’ in young Pediatric cancers are more treatment tients (aged 16-20 years) who participat- treatment in pediatric settings yields bet- adults with responsive than most adult cancers, and ed in clinical trials conducted by the ter results,” said Dr. Stephen P. Hunger, certain cancers. children tolerate intensive systemic ther- Children’s Cancer Group vs. the adult professor of pediatrics, director of the apy far better than adults. Also, cancer oncology Cancer and Leukemia Group center for cancer and blood disorders, DR. HUNGER patients at a children’s hospital are rou- B showed a 63% event-free survival rate and chief of pediatric hematology/on- tinely enrolled in a clinical trial under the at 7 years for those treated in pediatric cology/bone marrow transplantation at superior outcomes result from their auspices of the National Cancer Insti- centers, compared with just 34% in those the University of Colorado at Denver. treatment teams’ far greater experience tute–sponsored Children’s Oncology treated in adult settings (Blood 2008; Even when adult oncologists employ with these types of cancers—and a cor- Group, with all that implies in terms of 112:1646-54). treatment protocols similar to those used respondingly greater willingness to treat state-of-the-art treatment, whereas old- Similarly, a series of retrospective Eu- in children’s hospitals, the outcomes aggressively, Dr. Hunger explained at er adolescents and young adults treated ropean studies has shown ALL cure rates seem to be better in the pediatric setting. the annual conference of the Colorado in adult oncology centers are not typi- to be an absolute 20%-30% higher in old- The explanation for the difference in the Academy of Family Physicians. cally part of a clinical trial, Dr. Hunger er adolescents and young adults treated results remains unclear. There are key biologic differences be- continued. in pediatric versus adult clinical trials Some adult oncologists argue that tween pediatric and adult cancers. Pedi- ALL accounts for 80% of all cases of (Hematology January 2006;128-32). ■