Jelić Svetislav B.

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177www.onk.ns.ac.yu/Archive   October 1, 2004Management of hematological complications of malignancyand chemotherapy: The role of hematopoietic growth factorsSvetislav Jeli￿ABSTRACTKEY WORDS: Neoplasms; Antineoplastic Agents; Hematologic Diseases; Anemia; Thrombocytopenia;Neutropenia; Hematopoietic Cell Growth FactorsIinstitute of Oncology and Radiology of Serbia, Belgrade,Serbia & Montenegro; Address correspondence to:Svetislav Jeli￿, Institute of Oncology and Radiology ofSerbia, Department of Medical Oncology, Pasterova 14,11000 Belgrade, Serbia & Montenegro, The manuscriptwas received: 15.08.2004, Accepted for publication:15.09.2004© 2004, Institute of Oncology  Sremska Kamenica, Serbia andMontenegroArch Oncol 2004;12(3):177-8.CONFERENCE ARTICLEUDC: 616-006:616.15:615-085Cancer related syndromes involving haematopoesis and the process of hemostasis arenot exceptional.The hematopoietic disturbances related to cancer include erythrocytosis, cancer relatedanemia, and either thrombocytosis or thrombocytopenia.Pancytopenia with erythroblastosis in peripheral blood is usually the consequence of bonemarrow invasion and might be a terminal phenomenon. Treatment is supportive andincludes transfusions of packed red blood cells, eventually platelets when needed. It issometimes associated with disseminated intravascular coagulation when appropriatemeasures are required. Nevertheless this syndrome is usually a sign of generalized malig-nancy, not any more candidates for cytotoxic treatment.Erithrocytosis has been traditionally associated with erythropoietin producing tumors suchas renal cell carcinoma, hepatocelular carcinoma and cerebelar hemangioblastoma. In theclinical practice this syndrome is extremely rare. Erytrocytosis secondary to tumors is usu-ally not high enough to require treatment.Thrombocytosis is quite common in cancer patients and is usually associated withadvanced disease. Thrombosis and hemorrhage are rarely associated with cancer throm-bocytosis and if not associated with hypercoagulability syndrome does not require treat-ment. Anemia in cancer patients most commonly affects the form of the normocytic andnormochromic anemia of chronic disease. It is supposedly caused by a number of factorsincluding iron metabolism and storage disturbance and deficient erythropoietin production.Recombinant erythropoietin has been avocated in low-grade cancer anemia but the issueremains controversial.The most important hematological disturbances in cancer patients are migrating throm-bophlebitis and disseminated intravascular coagulation.Migrating thrombophlebitis is most often seen in patients with adenocarcinoma, especiallyin mucin producing adenocarcinomas of the gastrointestinal tract. It can also occur inbreast, ovarian, prostate, and especially pancreatic cancer. The treatment of this disorderincludes treatment of the underlying malignancy as the most effective measure when pos-sible. Treatment should also include heparin application but it is frequently ineffective; bet-ter results are obtained with low molecular weight heparins, enoxaparin sodium being pos-sibly the most effective drug at the moment available.Disseminated intravascular coagulation in cancer patients may occur in several prognosti-cally different settings:- As a terminal event in disseminated malignant disease; in this situation the specific treat-ment is usually ineffective and very often only symptomatic treatment is required.- As a component of the tumor lysis syndrome; in this situation we are dealing with achemotherapy responsive tumor and every effort of treatment with antithrombin III prepara-tions, platelets transfusions and low molecular weight heparins is required.- As a potentially transitory event during febrile neutropenia caused by gram-negative bac-teria; this potentially fatal complication should be dealt with most seriously in order to savethe patient. Treatment includes all measures as in the disseminated intravascular coagula-tion related to tumor lysis syndrome.The synthesis of recombinant hematopoietic growth factors has opened a new era in treat-ing cytopenic complications of both malignancy and chemotherapy.The thrombopoietins for treatment of cytotoxic drug induced thrombocytopenia are still invery early investigational clinical phases. Thrombocytopenia related to cancer or to cyto-toxic chemotherapy is best treated by platelet transfusions.Treatment of cancer or chemotherapy related anemia by different recombinant erythropoi-etins has been and still remains a topic of controversy. Erythropoietins have been claimedto have beneficial effects in low-grade cancer and chemotherapy related anemia especiallythe anemia during chemotherapy with platinum derivatives.The beneficial effects claimed for erythropoietins include better chemotherapy efficacy,relief of the so-called fatigue syndrome and improvement of quality of life. Several trialshave assessed the impact of erythropoietin administration in low-grade anemia patientsreceiving chemotherapy. The results were not equivocal. There are data suggesting that ery-thropoietin administration positively affects quality of life; these data apparently need moredetailed evaluation. It has been stated that although some of the results indicate that epo-etin has positive effects on quality of life, methological limitations inherent in most of thestudies hamper interpretation of data. More robust designs are required to show any sig-nificant quality of life and fatigue relieving benefits for cancer patients undergoing erythro-poietin treatment.On the other hand several recent data point to extreme caution in prescribing erythropoietin.It has been shown that several pediatric tumors express a functional erythropoietin recep-tor that promotes angiogenesis and tumor cell survival. Also erythropoietin receptorappears frequently expressed in papillary thyroid carcinoma. Experimental data suggest thaterythropoietin/erythropoietin receptor system is a significant angiogenic factor in chemical-ly induced murine hepatic tumors. More data are needed in a variety of other human tumorsin order to determine or eliminate the possibility that erythropoietin might as tumor facili-tating agent.The recombinant factors that induce granulocytopoiesis i.e., GC-SF and GM-CSF have beensynthesized and subject to extensive studies. ESMO has provided (11) minimal clinical rec-ommendations for the applications of these factors outside controlled clinical trials.It that been stated that rates of febrile neutropenia and related mortality rates are relativelylow for most standard chemotherapies. These low rates do not justify routine use of G-CSFor GM-CSF in primary prevention of febrile neutropenia in routine chemotherapy regimens.Indications for primary prophylaxis of febrile neutropenia include the probability of febrileneutropenia over 40% for a given chemotherapy regimen or situations where dose reduc-tion is deemed to be detrimental to outcome.The special situations for use of G-CSF or GM-CSF during chemotherapy include specialsituations for primary prophylaxis, secondary prophylaxis, and therapy of high-risk febrileneutropenia.Primary prophylaxis is indicated when bone marrow reserve is a reduced due to:- Prior extensive chemotherapy resulting in a stable neutrophil count below 1.5x109/L.- Prior radiotherapy involving over 20% of hematopoietic bone marrow.- Patients affected with human immunodeficiency virus, especially if under retroviralchemotherapy.Secondary prophylaxis is indicated in the following situations:- Further infections in the next treatment cycle considered life threatening.- Need for chemotherapy dose reduction below threshold of efficacy.- Need for delay of next treatment cycles if considered detrimental for response achieve-ment and/or compromising cure rate or disease free and overall survival.The granulocyte colonies promoting factors are indicated in the treatment of febrile neu-tropenia only in the category of high-risk febrile neutropenia i.e. febrile neutropenia lastingfor more than 7 days, or associated with hypotension or sepsis, or associated with pneu-monia or fungal infection.The application of these factors is not indicated in the general therapy of febrile neutrope-nia and even less in the therapy of afebrile neutropenia. Their use is contraindicated duringradiotherapy to the chest due to increased rate of complications and death. If they are givenimmediately prior or simultaneously with chemotherapy there is a risk for severe thrombo-cytopenia. They should not be applied in patients with chemotherapy induced bone marrowaplasia and severe thrombocytopenia. The use of hematopoietic growth factors in autolo-gous or allogenic stem cell transplantation or for mobilization of peripheral blood stem cellsis outside the scope of this presentation.SUGGESTED LITERATURE1. Bettomley A, Thomas R, van Steen K, Flechtner H, Djulbegovic B. Human recombinant erythro-poietin and quality of life:  wonder drug or something to wonder about? Lancet Oncol2002;3(3):145-53.2. Yasud Y, Fujita Y, Matsuo T, Koinuma S, Hara S, Tazaki A et al. Erythropoietin regulates tumourgrowth of human malignancies. Carcinogenesis 2003;24(6):1021-9.3. Rizzo JD, Lichtin AE, Woolf SH, Seidenfeld J, Bennett CL, Cella D et al. Use of epoetin in patientswith cancer: evidence-based clinical practice guidelines of the American Society of ClinicalOncology and the American Society of Hematology. Blood 2002;100(7):2303-20.4. Nakamatsu K, Nishimura Y, Suzuki M, Kanamori S, Maenishi O, Yasuda Y. Erythropoietin/ery-thropoietin-receptor system as an angiogenic factor in chemically induced murine hepatictumors. Int J Clin Oncol 2004;9(3):184-8.5. Eccles TG, Patel A, Verma A, Nicholson D, Lukes Y, Tuttle RM et al. Erythropoietin and the ery-thropoietin receptor are expressed by papillary thyroid carcinoma from children and adolescents.Expression of erythropoietin receptor might be a favorable prognostic indicator. Ann Clin Lab Sci2003;33(4):411-22.6. Batra S, Perelman N, Luck LR, Shimada H, Malik P. Pediatric tumor cells express erythropoietinand a functional erythropoietin receptor that promotes angiogenesis and tumor cell survival. LabInvest 2003;83(10):1477-87.7. Zhou M, Liao QK, Li FY, Gao J, Fu RY, Luo CH et al Erythropoietin increases transferrin receptorexpression and the impact of erythropoietin on K562 leukemic cell cycle. Zhonghua Er Ke Za Zhi2003;41(7):528-30.8. ESMO Minimum Clinical Recommendations for the application of hematopoietic growth factors(hGFs), European Society for Medical Oncology, Lugano, 20049. John V, Foon KA, Patchell RA. Paraneoplastic syndromes. In: De Vita V, Hellman S, RosenbergS, editors. Cancer-Priciples and Practice of Oncology, 5th ed. Philadelphia: Lippincot-Raven;1997. p. 2397-422.10. Griffin JD. Haematopoietic growth factors. In: De Vita V, Hellman S, Rosenberg S, editors.Cancer-Priciples and Practice of Oncology, 5th ed. Philadelphia: Lippincot-Raven; 1997. p.2639-57.11. Available from www.esmo.orgJeli￿ S.178www.onk.ns.ac.yu/Archive   October 1, 2004

Management of hematological complications of malignancy and chemotherapy: The role of hematopoietic growth factors

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