Effect of high-dose chemotherapy with subsequent transplantation of blood-forming cells on left ventricle function in patients with malignant lymphomas treated with doxorubicin in primary chemotherapy
Authors:
L. Elbl 1; I. Vášová 2; M. Krejčí 2; M. Navrátil 2; I. Tomášková 1; F. Jedlička 1; V. Chaloupka 1; J. Mayer 2; J. Vorlíček 2
Authors‘ workplace:
Oddělení funkčního vyšetřování FN Brno, pracoviště Bohunice, přednosta doc. MUDr. Václav Chaloupka, CSc.
1; Interní hematoonkologická klinika LF MU a FN Brno, pracoviště Bohunice, přednosta prof. MUDr. Jiří Vorlíček, CSc.
2
Published in:
Vnitř Lék 2006; 52(3): 221-231
Category:
Original Contributions
Overview
Purpose of study:
The authors examined whether high-dose chemotherapy with hematogenic tissue transplantation might negatively affect function of left ventricle (LV) in oncology patients with malignant lymphomas initially treated with conventional chemotherapy consisting of doxorubicin (DOX) in contrast to patients treated without the transplantation in medium- term follow up.
Patients and methodology:
The follow up group included 77 patients (39 women/38 men) at the age of 36 ± 15 (median 30, 16–67 years). All 77 patients were treated with initial chemotherapy with DOX, 22 out of that group later received high-dose chemotherapy with hematogenic tissue transplantation (HTT). 16 (73 %) patients of this subgroup underwent autologous transplantation and 5 (23 %) allogeneic transplantation. One female patient (4 %) underwent both autologous and allogeneic transplantation. The follow up period after completion of initial chemotherapy was 5–10 years (median 6 years). The patients were examined with rest echocardiography before start, after chemotherapy, and during follow-up examination. Spiroergometric test (SET) was only performed at the follow-up examination.
Results:
Both subgroups showed significant decrease of ejection fraction (EF) after chemotherapy, with further decrease in the control examination period, without mutual difference. While the HTT (HTT+) group showed no EF drop below 50 %, in the non-HTT (HTT–) group EF dropped in two (4 %) patients after chemotherapy and in four (8%) patients at the control examination. Progressing decrease of EF > 10 % was reported with 25 % of the HTT– patients (p < 0.05), but with just 13 % of the HTT+ patients (non-significant). The diastolic insufficiency (DF) was present identically in both groups with 36 % of the patients, which represents a statistically significant increase in comparison to the pre-chemotherapy condition. SET did not show any differences in burden toleration and circulation indicators between the two groups. The drop of pVO2 < 20 ml/kg/min occurred with 22 patients of both groups. Linear regression data analysis revealed existence of a significant relationship between EF change, some diastolic function indicators, pVO2 and cumulative dose of DOX (p < 0.05). The current age significantly and negatively correlated with pVO2 (p < 0.001) and DF indicators (p < 0.001). The follow up period inversely correlates with the changes of EF (p < 0.05) and pVO2 (p < 0.05), not correlating with diastolic function indicators. Multi-variant analysis did not confirm any higher risk of administration of highdose chemotherapy with HTT for significant drop of EF or its drop down to the pathological zone below 50 % (OR = 0.46; nonsignificant), for discovery of reduced cardio-pulmonary performance (pVO2 < 20 ml/kg/min) (OR = 0.35; non-significant) or for development of diastolic dysfunction (OR = 1.0; non-significant).
Conclusions:
Treatment with high-dose chemotherapy with HTT application within medium-term follow up does not result in any significant systolic or diastolic malfunction of myocardium and deterioration of cardiopulmonary performance in comparison to patients not undergoing this therapy. Treatment with cardiotoxic doxorubicin administered in the context of basic conventional chemotherapy is most likely to be responsible for occurrence of the pathological effects across the followed up group. Length of monitoring is a significant factor correlating with changed ejection fraction. This finding justifies the need for long-term prospective monitoring of ejection fraction of the left ventricle in adult patients treated with cardiotoxic chemotherapy.
Key words:
cardiotoxicity – high-dose chemotherapy – hematogenic tissue transplantation
Sources
1. Limat S, Demesmay K, Voillat L et al. Early cardiotoxicity of the CHOP regimen in aggresive non-Hodgkin’s lymphoma. Annal Oncol 2003; 14: 277-281.
2. Brice P, Tredaniel J, Monsuez JJ et al. Cardiopulmonary toxicity after three courses of ABVD and mediastinal irradiation in favorable Hodgkin’s disease. Annals Oncol 1991; 2: 73-76.
3. Reena N, Ramakrishnan G, Nair NN et al. A randomized comparison of the efficacy and toxicity of epirubicin and doxorubicin in the treatment of patients with non-Hodgkin’s lymphoma. Cancer 1998; 82: 2282-2288.
4. Nousianen T, Jantunen E, Vanninen E et al. Early decline in left ventricular ejection fraction predicts doxorubicin cardiotoxicity in lymphoma patients. Br J Cancer 2002; 86: 1697-1700.
5. Nousianen T, Vanninen E, Jantunen E at al. Neuroendocrine changes during the evolution of doxorubicin-induced left ventricular dysfunction in adult lymphoma patients. Clin Science 2001; 101: 601-607.
6. Hequet O, Le QH, Moullet I et al. Subclinical late cardiomyopathy after doxorubicin therapy for lymphoma in adults. J Clin Oncol 2004; 22: 1864-1871.
7. Blume KG, Forman SJ, Appelbaum FR. Hematopoietic Cell Transplantation. 3rd ed. Boston: Blackwell Science 2004.
8. Morandi P, Ruffini PA, Benvenuto GM et al. Cardiac toxicity of high-dose chemotherapy. Bone Marrow Transplant 2005; 35: 323-334.
9. Diehl V, Thomas RT, Re D. Hodgkin’s lymphoma-diagnosis and treatment. Lancet 2004; 5: 19-26.
10. Messori A, Vaiani M, Trippoli S. Survival in patients with intermediate or high-grade non-Hodgkin’s lymphoma: meta-analysis of randomized studies comparing third generation regimens with CHOP. Br J Cancer 2001; 84: 303-307.
11. Slavin S, Nagler A, Naprstek E et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998; 91: 756-763.
12. Otto CM. Echocardiographic evaluation of left and right ventricular systolic function. In: Otto CM Textbook of clinical echocardiography. 2nd ed. Philadelphia: WB Saunders 2000: 100-131.
13. Beck KC, Weisman IM. Methods for cardiopulmonary exercise testing. In: Weisman IM, Zeballos RJ. Clinical exercise testing. Prog Respir Res. Basel: Karger 2002: 43-5914.
14. Quigg RJ. Clinical utility of cardiopulmonary exercise testing data in heart failure. In: Balady GJ, Pina IL Exercise and heart failure. 1st ed. New York: Futura Publishing Company Armonk 1997: 221-243.
15. Mayer J. Will transplantation of peripheral blood stem haematopoietic cells definitively replace bone marrow transplantation? Vnitř Lék 2000; 46: 785-793.
16. Kmonicek M, Jebavy L, Lanska M et al. The treatment of multiple myeloma with an allogeneic peripheral blood stem cell transplantation using a non-myeloablative conditioning regimen. Vnitř Lék 2000; 46: 377-383.
17. Vambera M, Jabali Y, Pesl L et al. Cardiac damage in a young woman with Hodgkin’s disease and long term survival after combination therapy and bone marrow transplantation. Vnitř Lék 2003; 49: 77-81.
18. Hertenstein B, Stefanic M, Schmeiser T et al. Cardiac toxicity of bone marrow transplantation: predictive value of cardiologic evaluation before transplant. J Clin Oncol 1994; 12: 998-1004.
19. Simbre VC, Duffy SA, Dadlani GH et al. Cardiotoxicity of cancer chemotherapy. Pediatr Drugs 2005; 7: 187-202.
20. Chanan-Khan A, Srinivasan S, Czuczmen S. Prevention and management of cardiotoxicity from antineoplastic therapy. J Support Oncol 2004; 2: 251-266.
21. Youssef G, Links M. The prevention and management of cardiovascular complications of chemotherapy in patients with cancer. Am J Cardiovasc Drugs 2005; 5: 233-243.
22. Tjeerdsma G, Meinardi MT, van der Graaf WT et al. Early detection of anthracycline induced cardiotoxicity in asymptomatic patients with normal left ventricular systolic function: autonomic versus echocardiographic variables. Heart 1999; 81: 419-423.
23. Fujimaki K, Maruta A, Yoshida M et al. Severe cardiac toxicity in hematological stem cell transplantation: predictive value of reduced left ventricular ejection fraction. Bone Marrow Transplant 2001; 27: 307-310.
24. Lehman S, Isberg B, Ljungman P et al. Cardiac systolic function before and after hematopoietic stem cell transplantation. Bone Marrow Transplant 2000; 26: 187-192.
25. Steinherz LJ, Steinherz PG, Mangiacasale D et al. Cardiac changes with cyclophosphamide. Med Pediatr Oncol 1981; 9: 417-422.
26. Brockstein BE, Smiley C, Al-Sadir J et al. Cardiac and pulmonary toxicity in patients undergoing high-dose chemotherapy for lymphoma and breast cancer: prognostic factors. Bone Marrow Transplant 2000; 25: 885-894.
27. Kubešová H, Elbl L. Problematika kardiálních komplikací v souvislosti s transplantací krvetvorných buněk. In: Elbl et al. Poškození srdce protinádorovou léčbou. Praha: Grada Publishing 2002: 118-130.
28. Auner HW, Tinchon C, Brezinschek RI et al. Monitoring of cardiac function by serum cardiac troponin T levels, ventricular repolarisation indices, and echocardiography after conditioning with fractional total body irradiation and high-dose cyclophosphamide. Eur J Hematol 2002; 69: 1-6.
29. Cardinale D, Sandri MT, Martinoni A et al. Left ventricular dysfunction predicted by early troponin T release after high-dose chemotherapy. J Am Coll Cardiol 2000; 36: 517-522.
30. Murdych T, Wiesdorf DJ. Serious cardiac complications during bone marrow transplantation at the University of Minesota, 1977 - 1997. Bone Marrow Transplant 2001; 28: 283-287.
31. Elbl L, Chaloupka V, Vášová I et al. Poškození funkce levé komory srdeční po léčbě doxorubicinem u nemocných s maligními lymfomy. Vnitř Lék 2000; 46: 768-775.
32. Bejnamin EJ, Levy D, Keaven M et al. Determinants of Doppler indexes of left ventricular diastolic function in normal subjects (the Framingham Heart Study). Am J Cardiol 1992; 70: 508-515.
33. Steinherz LJ, Graham T, Hurwitz R et al. Guidelines for cardiac monitoring of children during and after anthracycline therapy: Report of the Cardiology Committee of the Childrens Cancer Study Group. Pediatrics 1992; 89: 942-949.
34. Schwartz RG, McKenzie WB, Alexander J et al. Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy: sever-year experience using serial radionuclide angiocardiography. Am J Med 1987; 82: 1109-1118.
35. Henein M, Lindqvist P, Francis D et al. Tissue Doppler analysis of age-dependency in diastolic ventricular behaviour and filling. Eur Heart J 2002; 23: 162-171.
36. Irvine DM, Vincent L, Graydon J et al. The prevalence and correlates of fatigue in patients receiving treatment with chemotherapy and radiotherapy. A comparison with fatigue experienced by healthy individuals. Cancer Nurs 1994; 17: 367-378.
37. Mock V. Fatigue management. Cancer 2001; 92: 1699-1707.
38. Carlson K, Smedmyr B, Backlund L et al. Subclinical disturbances in cardiac function at rest and in gas exchange during exercise are common findings after autologous bone marrow transplantation. Bone Marrow Transplant 1994; 14: 949-954.
39. Dimeo FC, Timan MHM, Bertz H et al. Aerobic exercise in the rehabilitation of cancer patients after high dose chemotherapy and autologous peripheral stem cell transplantation. Cancer 1997; 79: 1717-1722.
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