"Prednisone Use in Lymphoma" TUMOR TIDBITS, AN EMAIL NEWSLETTER FROM GULF COAST VETERINARY ONCOLOGY Number 109; November 14, 2003. ======================================================================= Are you currently managing a dog with cancer that is anemic? If so, it may be eligible for one of our clinical trials and the next 4 months of cancer therapy (radiation therapy, surgery, chemotherapy, and appropriate diagostic evaluations) could be a no charge to the family? For further information, call us in Houston (713-693-1166) or in San Antonio (210-822-1913). ======================================================================= THIS WEEK'S TUMOR TIDBIT: Prednisone Use in Lymphoma. ======================================================================= There is a general belief among veterinary oncologists that dogs receiving prednisone prior to chemotherapy experience shorter remissions, possibly as a result of prednisone- induced MDR. But did you know that prednisone does NOT induce multidrug resistance in lymphoma cells? This tidbit reviews the history of prednisone use in lymphoma and supports the use of prednisone in managing dogs with lymphoma. What is multidrug resistance? Multidrug resistance (MDR) is the reason for chemotherapeutic failure in all canine lymphoma patients. Classic MDR involves P-glycoprotein, a transmembrane protein which serves as an efflux pump for certain chemotherapeutic agents. Expression of P- glycoprotein by tumor cells renders them resistant to a variety of structurally and functionally different agents including the Vinca alkaloids, anthracyclines, taxanes, and epipodophyllotoxins. With the discovery of numerous other mechanisms of resistance to chemotherapeutic agents, MDR now refers to a phenotype of simultaneous resistance to multiple agents that differ in structure. Many, if not most, oncologists advise against using glucocorticoids for treating dogs suspected of having lymphoma. The reason is that unless lymph node aspirates or biopsy samples have already been procured, the rapid lymphocytolytic effects of glucocorticoids may obscure the diagnosis. Unfortunately, many veterinary oncologists and veterinarians also recommend avoidance of prednisone prior to beginning additional chemotherapy, possibly as a result of prednisone-induced MDR. Does this really happen? Unfortunately, evidence-based answers to these questions are not currently available. Only one study has documented an effect of glucocorticoid pretreatment on the outcome of lymphoma in dogs (Price et al, 1991). The objective of this study was to evaluate the efficacy and toxicity of doxorubicin/cyclophosphamide as maintenance therapy in dogs with multicentric lymphoma. Eleven of 28 dogs enrolled in this study had received glucocorticoids before initiation of combination chemotherapy. The median duration of remission for these 11 dogs receiving glucocorticoids prior to chemotherapy was significantly (P < 0.01) shorter than that of the 17 dogs that did not (134 versus 267 days). According to this study, the duration of glucocorticoid therapy (more than 2 weeks compared to less than 2 weeks) did not affect outcome. While the data from this particular study appears convincing, there are important factors that were not evaluated (Hahn, et al, 1992). In particular, the immunophenotype, which has a strong inverse correlation with prognosis, was not compared between groups. Because the number of dogs in each group was small, a slightly higher percentage of dogs with T-cell lymphoma in the prednisone-treated group could skew the results. Furthermore, similar effects have not been documented in dogs with lymphoma that were treated with other chemotherapy protocols. One might argue that it is inappropriate to apply results from this study of 11 dogs to all other dogs treated with other chemotherapy protocols. Yet, results from this study have led to the general recommendation that glucocorticoids should be avoided in canine lymphoma patients if future chemotherapy is planned. Did you know that prednisone does not induce the MDR phenotype in lymphocytes? Though many chemotherapeutic drugs induce expression of P-glycoprotein and/or MDR, the ability of glucocorticoids to induce P-glycoprotein or MDR expression in human or canine tumors has not been demonstrated. The ability of steroids to upregulate P-glycoprotein expression is tissue- and species-dependent. Don’t forget that several decades ago, glucocorticoids were used as single-drug therapy for certain types of leukemias and lymphomas in human patients. Similar to what has been described in canine lymphoma patients, glucocorticoids were initially effective in producing remission in these patients. In fact, a low glucocorticoid receptor content correlated with a poorer prognosis in general for lymphomas (B-cell lymphoma, Burkitt’s lymphoma) and some leukemias (AML; ALL) in people. When is withholding glucocorticoids is inappropriate? While there is some suggestive evidence that pretreatment with glucocorticoids may adversely affect patient outcome, the evidence is by no means compelling. Furthermore, there are several situations in which withholding glucocorticoid therapy may adversely affect patient outcome or quality of life. For example, withholding glucocorticoids in a hypercalcemic patient with a suspected, but not confirmed, diagnosis of lymphoma may increase the risk of irreversible nephrotoxicity. In some situations, it may take 2-3 weeks or more before an oncologist can examine a patient diagnosed with lymphoma. Since advanced WHO stage and substage are negative prognostic indicators for canine lymphoma, advancement of disease associated with the delay in receiving chemotherapy may adversely affect prognosis in some patients. Finally, withholding glucocorticoid therapy while waiting for combination chemotherapy treatment adversely affects the quality of life for patients in WHO substage b. What’s the answer on prednisone for lymphoma? Actually, the question is this - do those beneficial effects outweigh the possible harmful effects. Our opinion is that once a needle aspiration sample has been obtained and reviewed in-house as suspect for lymphoma and core biopsy specimens have been submitted for pathology confirmation then it is paramount that glucocorticoid support begin; especially if hypercalcemia or depressed behavior is present. Obviously more research is needed to adequately address this question and prospective clinical trials. For further reading, consider: Hahn KA, Richardson RC, MA Cline, Teclaw RF, Carlton WW, DeNicola DB, Bonney PL. Is maintenance chemotherapy appropriate for the management of canine malignant lymphoma? J Vet Int Med 1992;6:3-10. Mealey KL. Do glucorticoids induce drug resistance. Proceedings American College Veterinary Internal Medicine, 2003. Price G, Page R, Fischer B, et al. Efficacy and toxicity of doxorubicin/cyclophosphamide maintenance therapy in dogs with multicentric lymphosarcoma. J Vet Int Med 5:259-262, 1991. ======================================================================= As always, we hope this info helps and don't hesitate to call or email us Gulf Coast Veterinary Oncology! Kevin A. Hahn, DVM, PhD, Diplomate ACVIM (Oncology), drhahn@gcvs.com Janet K. Carreras, VMD, Diplomate ACVIM (Oncology), drcarreras@gcvs.com Glen K. King, DVM, MS, Diplomate ACVR (Radiology & Radiation Therapy), drking@gcvs.com Gulf Coast Veterinary Diagnostic Imaging & Oncology 1111 West Loop South, Suite 150, Houston, TX 77027 P: 713.693.1166 F: 713.693.1167 W: www.gcvs.com ======================================================================= Copyright © 2003, Gulf Coast Veterinary Oncology