Cardiotoxicity of epirubicin and doxorubicin: A double-blind randomized studv J
Lahtinen R, Kuikka J, Nousiainen T, Uusitupa M, Lansimies E. Cardiotoxicity of epirubicin and doxorubicin: A double-blind randomized study. Eur J Haematol 1991: 46: 301-305. Abstract: 24 patients with non-Hodgkin lymphoma were randomized into two muitidrug regimens including either epirubicin (N = 12) or doxorubicin (N = 12) to establish the cardiotoxicity of each treatment modality. At cumulative doses of 400-500 mg/rn2 left ventricular ejection fraction (LVEF) at rest determined by radionuclide angiocardiography decreased significantly more in the doxorubicin ( - 15 1 1 %) than in the epirubicin group (0 f. 13%, p < 0.005). During epirubicin therapy no clinically significant cardiotoxicity developed, but a decrease larger than 10% in LVEF was seen in 4 of 12 patients at a mean cumulative level of 450 mg/m2. During doxorubicin therapy 1 patient developed a heart failure at a cumulative level of 200 mg/m2 and, altogether, in 7 patients LVEF decreased more than 10%.The monitoring of cardiac toxicity is imperative in patients treated with doxorubicin and is advisable if the patient is expected to receive epirubicin at more than 450 mg/m2.
Introduction
Doxorubicin (Dx) is an effective anthracycline antibiotic in the treatment of both malignant hematopoietic and solid tumors. However, both acute and chronic, dose-related and irreversible cardiomyopathy limits the use of doxorubicin and other anthracyclines. Administration of Dx should be limited to a maximum cumulative dose of 500 mg/m2 due to a highly increased risk of congestive heart failure beyond that dose (1, 2, 3). The risk of clinically significant cardiomyopathy is even higher in patients with previous radiation of the cardiac area, in patients with a previous cardiovascular disease, and in elderly patients (4, 5, 6). Doxorubicin derivative, 4-epi-doxorubicin (epiDx) differs from Dx in the epimerization of the OH group in position 4 of the aminosugar moiety. In experimental studies, epiDx has demonstrated the same antitumor activity as Dx. Interestingly, both initial animal studies and some human studies suggest that epiDx is less cardiotoxic than Dx (7, 8, 9). Abbreviations: Dx = doxorubicin, epiDx = epirubicin, vincristine, prednisolone, COP = cyclophosphamide, CHOP = cyclophosphamide, doxorubicin, vincristine, prednisolone, CEOP = cyclophosphamide, epirubicin, vincristine, dose methotrexate, prednisolone, M-BACOD = high bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone, CR = complete remission, PR = partial remission
R. Lahtinen', J. Kuikka', T. Nousiainen', M. Uusitupa3 and E. Llnsimies'
'
Departments of Medicine, Clinical Physiology and Clinical Nutrition, Kuopio University Central Hospital, Kuopio, Finland
Key words: epirubicin - doxorubicin - anthracycline cardiotoxicity - radionuclide angiocardiography - non-Hodgkin lymphomas Correspondence: R. Lahtinen, M.D., Department of Medicine, Kuopio University Central Hospital, SF-70210 Kuopio, Finland. Accepted for publication 12 December 1990
The aim of the present study was to compare the cardiotoxicity of epiDx to that of Dx in a doubleblind, randomized clinical trial carried out in patients with non-Hodgkin lymphoma during CHOP or CEOP therapy, including the same dose of either Dx or epiDx, respectively. Patients and methods
24 patients with non-Hodgkin lymphoma in whom CHOP therapy was indicated were enrolled in the randomized, double-blind study during 4 years (Feb 1983 to March 1987) in order to compare the cardiotoxicity of 4-epi-doxorubicin (epiDx) with that or doxorubicin (Dx). All patients gave their informed consent according to the Helsinki Declaration. Before randomization, the patients were stratified according to sex and age (below and above 50 yr of age). No previous history, symptoms or signs of a heart disease were disclosed by the clinical examination, chest x-ray and resting electrocardiogram. Patients with previous hepatic or renal disease were excluded. Previous treatments for nonHodgkin lymphoma and other patient characteristics are shown in Table 1. The patients were treated with CHOP or CEOP combination therapy at 3-week intervals. CHOP-protocol was as follows : cyclophosphamide (C) 750 mg/m2 i.v. on d 1, doxorubicin (H) 50 mg/m2 on d 1 - vincristine (0) 1.4 mg/m2 on d 1 (maximum dose 2 mg per injec301
Lahtinen et al. Table 1. Clinical characteristics of the patients according to treatment arm CHOP
616 Sex, M/F 49 (35-68) Age, median and range Malignancy of lymphomas (Kid histopathologic classification) Low-grade malignancy 8 High-grade malignancy 2 Histiocytosis 1 Unclassiied 1 Clinical stage (Ann Arbor classification) I 1 II 3 111 1 IV 1 Previous treatment for non-Hodgkin lymphoma Resection of tumor 0 Local radiotherapy 2' Chemotherapy with 3** cyclophosphamide or COP
CEOP
616 49 (32-65)
9 3 0 0
0 1 3 8 3 2 3
* One of these patients had received previously mediastinal radiation (18Gy). **
LVEF's of this patient at different dose levels of Dx were: 0;61,20061,300;60, 40073,45051, mean 45062. One of these patients had received one dose of doxorubicin (50 mg/m2) 16 months before this period started. EF's of this patient at different dose levels of Dx received during the study period were: 0;69, 200;60, 300;60, 400;53, 450;50, 500;40.
tion), prednisolone (P) 100 mg/m2 orally on d 1-5. In CEOP regimen, epirubicin (dose 50 mg/m2) substituted for doxorubicin. Otherwise CHOP and CEOP regimens were identical. They were given on the basis of randomization carried out by a pharmacist. CHOP or CEOP courses were continued until the cumulative dose of Dx or epiDx was 500 mg/m2. The medication with anthracyclines was discontinued before the cumulative dose reached 500 mg/m2 if symptoms or signs of cardiotoxicity were observed, or if the disease was found to be resistant to CHOP or CEOP therapy. 5 patients received anthracyclines at more than 500 mg/m2 because no clinically significant cardiotoxicity was found and only a partial remission of a responding lymphoma was seen. Their final cumulative doses were 550mg/m2 (2 patients) and 650mg/m2 (3 patients). Pretreatment evaluation of the patients included, in addition to medical history and physical examination, a complete blood cell count, serum creatinine Table 2. Response rate by treatment arm (X)
Complete remission Partial remission Primarily resistant or relapse during CHOP or CEOP
302
and liver enzymes. Evaluation of a tumor included chest x-ray, computed tomography of the abdomen, lymphography, bone marrow biopsy, and gastroscopy (3 patients) and laparotomy (4 patients). Before CHOP or CEOP therapy the patients were classified by clinical stage according to Ann Arbor classification. Kiel histopathologic classification was used (10). Tumors which were grouped as being of low-grade malignancy included lymphomas of both low- and intermediate-grade malignancy according to the Working Formulation (1 1). During CHOP or CEOP therapy the tumor was evaluated every 6th wk by clinical examination and appropriate blood tests and x-rays, and bone marrow examination if indicated. After completing the chemotherapy the patients were evaluated at intervals of 2 to 6 months. Different salvage therapies were used in the treatment of the patients who did not achieve complete remission with CHOP or CEOP (Table 3). Evaluation of resting cardiotoxicity was performed as follows : clinical examination, resting electrocardiogram and measurement of left ventricular ejection fraction (LVEF) by gated blood pool radionuclide angiography at rest. Reproducibility of the LVEF-measurements was 3.5 % with a linear correlation of 0.976 (12). LVEF was measured before anthracycline therapy was started and at the following cumulative dose levels just before the next dose: 200, 300, 400, 450 and 500 mg/m2 and at the final dose level if CHOP therapy was continued beyond the cumulative dose of 500 mg/m2 (6). LVEFs of the patients measured at baseline before Table 3. Duration of the first complete remission (months)according to the treatment arm. t;complete remission continuing Patient
CHOP
CEOP
No. 1 2 4 1 9 10 11 13 14 15 16 18 19 20 21 23
Salvage therapy
33 52t 36t 5 54t 60t 30t 66t 10 3 16
12 45t 36t
8 41t
CHOP
CEOP
* Salvage therapies leading to the first complete remission after unsuccessful treat-
7 (58) 3 (25)
4 (331 4 (33)
2 (171
4 (33)
ment with CHOP or CEOP: Ifosfamide, methotrexate, etoposide (IMVP-161, 2 patients. High-dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone (M-BACOD), 1 patient. Nitrogen mustard, vinblastine, procarbazine, prednisolone (MVPP), 1 patient. Cyclophosphamide, vincristine, methotrexate, cytarabine (COMA), 1 patient.
Epirubicin/doxorubicin cardiotoxicity group who developed a heart failure at a cumulative level of 200 mg/m2was omitted due to discontinuing of his doxorubicin therapy. Paired t-test was used to compare the changes within the groups. A p-value < 0.05 was considered statistically significant.
70.0
,-.
60.0
K
v
w L
3
50.0
Results I
\
40.0 A
0
j 100
200
300
400
500
400
500
w/m2
40’0
t t
l 0
1 100
200
300
mg/d
Fig. I. Individual LVEFs at rest before medication and at individual final or cumulative level of 400-500 mg/m2. A = CHOP group (doxorubicin) - B = CEOP group (epirubicin). Mean change in CHOP was - 15 f 11% and in CEOP 0 2 13%, CHOP vs CEOP, p < 0.005. 0 = mean.
CHOP or CEOP therapy and at final cumulative dose levels of the anthracycline are shown in Fig. 1. In 3 patients, the final cumulative dose was 100-200mg/m2. In 1 of them, belonging to the CHOP group, doxorubicin was discontinued after four CHOP courses at a cumulative level 200 mg/m2 due to a heart failure. In 2 of the remainder, belonging to the CEOP group, anthracycline therapy was discontinued after two and three courses, respectively, due to resistant, progressive lymphoma. These 2 patients from the CEOP group were dropped from all calculations. Changes in LVEF during therapy were calculated by comparing baseline LVEF to (1)final LVEF up to a cumulative dose level of 500 mg/m2 (12 cases in the CHOP group and 10 cases in the CEOP group, respectively), (2)final LVEF at a cumulative dose of 400-500 mg/m2 of anthracycline (1 1 cases in the CHOP group and 10 cases in the CEOP group, see Fig. 1) and (3) mean of LVEF’s measured at levels of 400, 450 and 500 mg/m2 of anthracycline. 1 patient in the CHOP
LVEF decreased from 61 k 8 % to 49 & 11% (mean k SD) during therapy in the CHOP group from baseline to a final dose level of up to 500 mg/m2 and the change was significant (p < 0.005), even though the patient who received one prior dose of doxorubicin and the patient who received prior mediastinal radiation were omitted. The change was smaller when basal results were compared to the mean results measured at levels of 400, 450, and 500 mg/m2, but was still statistically significant (p < 0.05). In the CEOP group the change in LVEF from 62 k 6% to 6 1 k 8 % during therapy was not significant. The difference in the LVEF changes between CHOP and CEOP groups was significant ( - 15 2 11% vs 0 k 13%, p < 0.005) when baseline values and those obtained at final dose levels from 400 to 500 mg/m2 were compared. An at least 10% decrease in LVEF was observed in half the patients (11/22) at the final cumulative level of 200-500 mg/m2- 7 of them from the CHOP group and 4 from the CEOP group. 1 patient in the CHOP group developed a severe cardiotoxicity with heart failure, at a cumulative level of 200 mg/m2 of doxorubicin, in whom the final LVEF was decreased to 19%. A chest x-ray of his heart revealed dilated left ventricle (heart size 740 cm2/m2). 6 wk later he experienced severe shortness of breath and was admitted to the district hospital where digitalis and diuretics were started. In addition, 1 patient in the CHOP group developed moderate cardiotoxicity with a LVEF decline from 69% to 40%. During follow-up, this patient did not develop a clinical heart failure. Mild cardiotoxicity (a decline of 10% or more in LVEF) was seen in 5 patients in the CHOP group and in 4 patients in the CEOP group. However, in 1 of the 4 CEOP patients LVEF decreased only after this patient had received doxorubicin in the M-BACOD regimen, given for neurorelapse developing during CEOP therapy. In 2 of CHOP patients with mild cardiotoxicity (LVEF decrease > 10%) doxorubicin was discontinued because of increased dyspnea in strain at cumulative levels of 400 and 450 mg/m2. In the CEOP group, no patient developed clinically manifest cardiotoxicity. In 5 patients, the final cumulative dose of anthracyclines was more than 500 mg/m2. In 2 of these, a 303
Lahtinen et al.
further decrease of LVEF was detected after 500 mg/m2. LVEF's of these 2 patients at a cumulative level of 500mg/m2 were 56 and 53% and at 650 mg/m2 were 50 and 46%, respectively. Both of these patients received doxorubicin. Epirubicin did not reduce LVEF when the cumulative dose increased from 500 to 650 mg/m2 (1 patient) and from 500 to 550 mg/m2 (2 patients). The 1st of these 3 patients belonged to the CHOP group initially and the LVEF of this patient at a level of 500mg/m2 doxorubicin was 47%. In relapse, this patient received M-BACOD courses with epirubicin and, at a cumulative level of 650 mg/m2 anthracyclines (Dx + epiDx), LVEF was still 68%. The numbers of patients who responded are shown according to treatment arm in Table 2 and durations of the complete remissions (CR) achieved with different therapies are shown in Table 3. The overall response rate in the CHOP group was 83% (10/12)andintheCEOPgroup66% (8/12). 16ofthe 24 patients achieved CR (67%) (7/12 with CHOP, 4/12 with CEOP and 5 patients with different salvage regimens). In December 1989, 11/24 (46%) patients were in complete remission. 9 of them were in the first CR, 4 achieved with CHOP, 2 with CEOP and 3 with salvage therapies. The duration of the first CR in December 1989 in the whole series, calculated after completion of CHOP or CEOP therapy, varied from 3 to 66 + months. 7 of 16 patients with CR have had a relapse of the disease. All except 1 patient relapsed within 16 months after completion of the induction therapy. The survival, calculated from the start of CHOP or CEOP therapy, varied from 5 to 78 months. There was no significant difference in the duration of CR or survival between CHOP and CEOP groups. In the whole series there were no significant correlations between response or survival and the clinical stage or the histopathologic classification determined before treatment. 10 patients have died so far during follow-up - 8 due to resistant lymphoma, 1due to a septic infection during agranulocytosis after a salvage cytostatic course, and 1 patient died suddenly of unknown causes. No fatal complications were observed that were attributable to CHOP or CEOP therapy. Discussion
Our double-blind, prospective randomized trial consisting of 24 patients with non-Hodgkin lymphoma treated with CHOP or CEOP regimens confirmed previous findings of lower cardiotoxicity of epirubicin as compared to its parent compound doxorubicin (13, 14, 15). The mean LVEF decreased significantly more in the CHOP group than in the 304
CEOP group at the cumulative level of 450 mg/m2 as compared with baseline values measured before these therapies. In addition, in the CHOP group 1 patient developed a heart failure at the cumulative dose level of 200 mg/m2 of doxorubicin. Changes in LVEF's were significantly different between the treatment groups, even after the patient with overt congestive heart failure was omitted from comparisons. LVEF decreased more than 10% in half the patients at cumulative levels up to 500 mg/m2 - 7 in the CHOP group and 4 in the CEOP group. However, in l patient in the CEOP group a decrease in LVEF was not detected before the patient had received doxorubicin in a salvage regimen given for a relapse. None of the patients in this series had a previous heart disease according to clinical examination, ECG and chest x-ray. 1 patient had previously received mediastinal irridation, but LVEF did not change during therapy in this case. In addition, 1 patient had previously received one dose of doxorubicin, but in his case LVEF had decreased significantly already at the cumulative level of 200 mg/m2. Previously, Torti and coworkers, by studying endomyocardial biopsies, observed that cardiac lesions induced by epirubicin and doxorubicin were identical, but that approximately 180 mg/m2 more epirubicin that doxorubicin had to be administered to achieve the same degree of anthracycline injury (14). Dardir et al. (16), when studying cardiac toxicity with biopsies in patients receiving epirubicin as a single chemotherapeutic agent, demonstrated an increased myocardial damage at cumulative doses beyond 450 mg/m2 of epirubicin, but when the dose was less than 450mg/m2 only minimal hemodynamic disturbances were observed (16). Also recent clinical studies on patients with breast cancer have shown that cardiotoxicity of epirubicin only becomes manifest by clearly larger cumulative doses than those of doxorubicin (13, 15, 17). In our series, the overall response rate ot CHOP therapy was in accordance with previous results of CHOP regimens (18). There were no significant differences in the response rate or survival between the treatment arms. However, some tendency to get more response with CHOP than with CEOP was observed (83 vs 66%). Previous pilot studies have shown the efficacy of epirubicin in the treatment of non-Hodgkin lymphomas (7, 9, 19). In a recent study, the response rate of high-grade lymphomas for CEOP compared favorably to the response rate for CHOP (84vs 7 1%) (20). The dose of epiDx per course was 60 mg/m2 in that study. It might be that the optimal dose of epirubicin in the CEOP regimen is higher than the 50 mg/m2 used in our study. However, the number of patients and the follow-up were too small and too
Epirubicin/doxorubicin cardiotoxicity short to allow any definite conclusions to be drawn with regard to the clinical effects of these two anthracyclines. In conclusion, a lower cardiotoxicity of epirubicin as compared with doxorubicin was demonstrated in a double-blind, randomized clinical trial involving 24 patients with non-Hodgkin lymphoma treated with CHOP or CEOP regimens. Although no clinically significant cardiotoxicity was seen in patients treated with epirubicin, 4 of 12 patients in the CEOP group showed a decrease of 10% or more in LVEF at a mean cumulative level of 450 mg/m2. It is suggested, therefore, that patients expected to receive epirubicin at more than 450 mg/m2 should be monitored for latent cardiotoxicity. References 1. LEFRAKEA, PITHAJ, ROSENHEIM S, GOTTLIEBJA. A
2. 3.
4. 5.
6. 7.
clinicopathologic analysis of Adriamycin cardiotoxicity. Cancer 1973: 32: 302-314. S, et al. Adriamycin LEFRAKEA, PITHAJ, ROSENHEIM (NSC-123 127) cardiomyopathy. Cancer Chemother Rep Part 3 1975: 6: 203-208. MINOWRA, BENJAMINRS, GOTTLIEBJA. Adriamycin (NSC- 123127) cardiomyopathy an overview with determination of risk factors. Cancer Chemother Rep Part 3 1975: 6: 195-201. MINOWRA, BENJAMIN RS, LEEET, GOTTLIEB GA. Adriarisk factors. Cancer 1977: 39: mycin cardiomyopathy 1397-1402. BRISTOWMR, MASONJW, BILLINGHAM ME, DANIELS JR. Doxorubicin cardiomyopathy: Evaluation by phonocardiography, endomyocardial biopsy, and cardiac catheterization. Ann Intern Med 1978: 88: 168-175. E. NonLAHTINEN R, UUSITUPA M, KUIKKA J, LANSIMIES invasive evaluation of anthracycline-induced cardiotoxicity in man. Acta Med Scand 1982: 212: 201-206. G. Toxic and theraBONFANTE V, VILLANI F, BONADONNA peutic activity of 4'-epi-doxorubicin. Tumori 1982: 68:
-
-
8. GANZINA F. 4'-epi-doxorubicin, a new analogue of doxorubicin: a preliminary overview of preclinical and clinical data. Cancer Treat Rev 1983: 10: 1-22. 9. CERSOIMO RJ, HONG WK. Epirubicin: a review of the pharmacology, clinical activity, and adversed effects of an Adriamycin analogue. J Clin Oncol 1986: 4: 425-439. 10. LENNERTK. Principles of the classification. In: Histopathology of Non-Hodgkin's Lymphomas (based on the Kiel classification). New York: Springer-Verlag, 1981: 7-1 I . 11. The Non-Hodgkin's Lymphoma Pathologic Classification Project. National Cancer Institute Sponsored Study of Classification of Non-Hodgkin's Lymphomas. Summary and Description of a Working Formulation for Clinical Usage. Cancer 1982: 49: 2112-2135. 12. MUSTONENJ. Left ventricular function in middle-aged diabetic patients without clinically evident cardiovascular disease. Thesis. Kuopio, Finland: University of Kuopio, 1988. 13. JAINKK, CASPERES, GELLERNL, et al. A prospective randomized comparison of epirubicin and doxorubicin in patients with advanced breast cancer. J Clin Oncol 1985: 3: 818-826. 14. TORTIFM, BRISTOW MM, LUMBL, et al. Cardiotoxicity of epirubicin and doxorubicin: assessment by endomyocardial biopsy. Cancer Res 1986: 46: 3722-3727. 15. The French Epirubicin Study Group. A prospective randomized phase 111 trial comparing combination chemotherapy with cyclophosphamide, fluorouracil, and either doxorubicin or epirubicin. J Clin Oncol 1988: 6: 679-688. VJ, MIKHAEL YS, et a]. Cardiac 16. DARDIRMD, FERRANS morphologic and functional changes induced by Epirubicin chemotherapy. J Clin Oncol 1989: 7: 947-948. 17. The Italian multicentre breast cancer study with epirubicin. J Clin Oncol 1988: 6: 976-982. 18. JONESSE, GROZEAPN, METZ EN, et al. Superiority of Adriamycin-containing combination chemotherapy in the treatment of diffuse lymphoma. Cancer 1979: 43: 417-425. 19. LOPEZM, DILAUROL, CANZINA F, PERNOC-F, PAPALDO P, DIPIETRON. Epirubicin in non-Hodgkin's lymphomas. Am J Clin Oncol 1985: 8: 151-153. 20. AL-ISMAILSAD, WHITTAKER JA, COUGHJ. Combination chemotherapy including epirubicin for the management of non-Hodgkin's lymphoma. Eur J Cancer Clin Oncol 1987: 23: 1379-1384.
105-1 11.
305
Lahtinen R, Kuikka J, Nousiainen T, Uusitupa M, Lansimies E. Cardiotoxicity of epirubicin and doxorubicin: A double-blind randomized study. Eur J Haematol 1991: 46: 301-305. Abstract: 24 patients with non-Hodgkin lymphoma were randomized into two muitidrug regimens including either epirubicin (N = 12) or doxorubicin (N = 12) to establish the cardiotoxicity of each treatment modality. At cumulative doses of 400-500 mg/rn2 left ventricular ejection fraction (LVEF) at rest determined by radionuclide angiocardiography decreased significantly more in the doxorubicin ( - 15 1 1 %) than in the epirubicin group (0 f. 13%, p < 0.005). During epirubicin therapy no clinically significant cardiotoxicity developed, but a decrease larger than 10% in LVEF was seen in 4 of 12 patients at a mean cumulative level of 450 mg/m2. During doxorubicin therapy 1 patient developed a heart failure at a cumulative level of 200 mg/m2 and, altogether, in 7 patients LVEF decreased more than 10%.The monitoring of cardiac toxicity is imperative in patients treated with doxorubicin and is advisable if the patient is expected to receive epirubicin at more than 450 mg/m2.
Introduction
Doxorubicin (Dx) is an effective anthracycline antibiotic in the treatment of both malignant hematopoietic and solid tumors. However, both acute and chronic, dose-related and irreversible cardiomyopathy limits the use of doxorubicin and other anthracyclines. Administration of Dx should be limited to a maximum cumulative dose of 500 mg/m2 due to a highly increased risk of congestive heart failure beyond that dose (1, 2, 3). The risk of clinically significant cardiomyopathy is even higher in patients with previous radiation of the cardiac area, in patients with a previous cardiovascular disease, and in elderly patients (4, 5, 6). Doxorubicin derivative, 4-epi-doxorubicin (epiDx) differs from Dx in the epimerization of the OH group in position 4 of the aminosugar moiety. In experimental studies, epiDx has demonstrated the same antitumor activity as Dx. Interestingly, both initial animal studies and some human studies suggest that epiDx is less cardiotoxic than Dx (7, 8, 9). Abbreviations: Dx = doxorubicin, epiDx = epirubicin, vincristine, prednisolone, COP = cyclophosphamide, CHOP = cyclophosphamide, doxorubicin, vincristine, prednisolone, CEOP = cyclophosphamide, epirubicin, vincristine, dose methotrexate, prednisolone, M-BACOD = high bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone, CR = complete remission, PR = partial remission
R. Lahtinen', J. Kuikka', T. Nousiainen', M. Uusitupa3 and E. Llnsimies'
'
Departments of Medicine, Clinical Physiology and Clinical Nutrition, Kuopio University Central Hospital, Kuopio, Finland
Key words: epirubicin - doxorubicin - anthracycline cardiotoxicity - radionuclide angiocardiography - non-Hodgkin lymphomas Correspondence: R. Lahtinen, M.D., Department of Medicine, Kuopio University Central Hospital, SF-70210 Kuopio, Finland. Accepted for publication 12 December 1990
The aim of the present study was to compare the cardiotoxicity of epiDx to that of Dx in a doubleblind, randomized clinical trial carried out in patients with non-Hodgkin lymphoma during CHOP or CEOP therapy, including the same dose of either Dx or epiDx, respectively. Patients and methods
24 patients with non-Hodgkin lymphoma in whom CHOP therapy was indicated were enrolled in the randomized, double-blind study during 4 years (Feb 1983 to March 1987) in order to compare the cardiotoxicity of 4-epi-doxorubicin (epiDx) with that or doxorubicin (Dx). All patients gave their informed consent according to the Helsinki Declaration. Before randomization, the patients were stratified according to sex and age (below and above 50 yr of age). No previous history, symptoms or signs of a heart disease were disclosed by the clinical examination, chest x-ray and resting electrocardiogram. Patients with previous hepatic or renal disease were excluded. Previous treatments for nonHodgkin lymphoma and other patient characteristics are shown in Table 1. The patients were treated with CHOP or CEOP combination therapy at 3-week intervals. CHOP-protocol was as follows : cyclophosphamide (C) 750 mg/m2 i.v. on d 1, doxorubicin (H) 50 mg/m2 on d 1 - vincristine (0) 1.4 mg/m2 on d 1 (maximum dose 2 mg per injec301
Lahtinen et al. Table 1. Clinical characteristics of the patients according to treatment arm CHOP
616 Sex, M/F 49 (35-68) Age, median and range Malignancy of lymphomas (Kid histopathologic classification) Low-grade malignancy 8 High-grade malignancy 2 Histiocytosis 1 Unclassiied 1 Clinical stage (Ann Arbor classification) I 1 II 3 111 1 IV 1 Previous treatment for non-Hodgkin lymphoma Resection of tumor 0 Local radiotherapy 2' Chemotherapy with 3** cyclophosphamide or COP
CEOP
616 49 (32-65)
9 3 0 0
0 1 3 8 3 2 3
* One of these patients had received previously mediastinal radiation (18Gy). **
LVEF's of this patient at different dose levels of Dx were: 0;61,20061,300;60, 40073,45051, mean 45062. One of these patients had received one dose of doxorubicin (50 mg/m2) 16 months before this period started. EF's of this patient at different dose levels of Dx received during the study period were: 0;69, 200;60, 300;60, 400;53, 450;50, 500;40.
tion), prednisolone (P) 100 mg/m2 orally on d 1-5. In CEOP regimen, epirubicin (dose 50 mg/m2) substituted for doxorubicin. Otherwise CHOP and CEOP regimens were identical. They were given on the basis of randomization carried out by a pharmacist. CHOP or CEOP courses were continued until the cumulative dose of Dx or epiDx was 500 mg/m2. The medication with anthracyclines was discontinued before the cumulative dose reached 500 mg/m2 if symptoms or signs of cardiotoxicity were observed, or if the disease was found to be resistant to CHOP or CEOP therapy. 5 patients received anthracyclines at more than 500 mg/m2 because no clinically significant cardiotoxicity was found and only a partial remission of a responding lymphoma was seen. Their final cumulative doses were 550mg/m2 (2 patients) and 650mg/m2 (3 patients). Pretreatment evaluation of the patients included, in addition to medical history and physical examination, a complete blood cell count, serum creatinine Table 2. Response rate by treatment arm (X)
Complete remission Partial remission Primarily resistant or relapse during CHOP or CEOP
302
and liver enzymes. Evaluation of a tumor included chest x-ray, computed tomography of the abdomen, lymphography, bone marrow biopsy, and gastroscopy (3 patients) and laparotomy (4 patients). Before CHOP or CEOP therapy the patients were classified by clinical stage according to Ann Arbor classification. Kiel histopathologic classification was used (10). Tumors which were grouped as being of low-grade malignancy included lymphomas of both low- and intermediate-grade malignancy according to the Working Formulation (1 1). During CHOP or CEOP therapy the tumor was evaluated every 6th wk by clinical examination and appropriate blood tests and x-rays, and bone marrow examination if indicated. After completing the chemotherapy the patients were evaluated at intervals of 2 to 6 months. Different salvage therapies were used in the treatment of the patients who did not achieve complete remission with CHOP or CEOP (Table 3). Evaluation of resting cardiotoxicity was performed as follows : clinical examination, resting electrocardiogram and measurement of left ventricular ejection fraction (LVEF) by gated blood pool radionuclide angiography at rest. Reproducibility of the LVEF-measurements was 3.5 % with a linear correlation of 0.976 (12). LVEF was measured before anthracycline therapy was started and at the following cumulative dose levels just before the next dose: 200, 300, 400, 450 and 500 mg/m2 and at the final dose level if CHOP therapy was continued beyond the cumulative dose of 500 mg/m2 (6). LVEFs of the patients measured at baseline before Table 3. Duration of the first complete remission (months)according to the treatment arm. t;complete remission continuing Patient
CHOP
CEOP
No. 1 2 4 1 9 10 11 13 14 15 16 18 19 20 21 23
Salvage therapy
33 52t 36t 5 54t 60t 30t 66t 10 3 16
12 45t 36t
8 41t
CHOP
CEOP
* Salvage therapies leading to the first complete remission after unsuccessful treat-
7 (58) 3 (25)
4 (331 4 (33)
2 (171
4 (33)
ment with CHOP or CEOP: Ifosfamide, methotrexate, etoposide (IMVP-161, 2 patients. High-dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone (M-BACOD), 1 patient. Nitrogen mustard, vinblastine, procarbazine, prednisolone (MVPP), 1 patient. Cyclophosphamide, vincristine, methotrexate, cytarabine (COMA), 1 patient.
Epirubicin/doxorubicin cardiotoxicity group who developed a heart failure at a cumulative level of 200 mg/m2was omitted due to discontinuing of his doxorubicin therapy. Paired t-test was used to compare the changes within the groups. A p-value < 0.05 was considered statistically significant.
70.0
,-.
60.0
K
v
w L
3
50.0
Results I
\
40.0 A
0
j 100
200
300
400
500
400
500
w/m2
40’0
t t
l 0
1 100
200
300
mg/d
Fig. I. Individual LVEFs at rest before medication and at individual final or cumulative level of 400-500 mg/m2. A = CHOP group (doxorubicin) - B = CEOP group (epirubicin). Mean change in CHOP was - 15 f 11% and in CEOP 0 2 13%, CHOP vs CEOP, p < 0.005. 0 = mean.
CHOP or CEOP therapy and at final cumulative dose levels of the anthracycline are shown in Fig. 1. In 3 patients, the final cumulative dose was 100-200mg/m2. In 1 of them, belonging to the CHOP group, doxorubicin was discontinued after four CHOP courses at a cumulative level 200 mg/m2 due to a heart failure. In 2 of the remainder, belonging to the CEOP group, anthracycline therapy was discontinued after two and three courses, respectively, due to resistant, progressive lymphoma. These 2 patients from the CEOP group were dropped from all calculations. Changes in LVEF during therapy were calculated by comparing baseline LVEF to (1)final LVEF up to a cumulative dose level of 500 mg/m2 (12 cases in the CHOP group and 10 cases in the CEOP group, respectively), (2)final LVEF at a cumulative dose of 400-500 mg/m2 of anthracycline (1 1 cases in the CHOP group and 10 cases in the CEOP group, see Fig. 1) and (3) mean of LVEF’s measured at levels of 400, 450 and 500 mg/m2 of anthracycline. 1 patient in the CHOP
LVEF decreased from 61 k 8 % to 49 & 11% (mean k SD) during therapy in the CHOP group from baseline to a final dose level of up to 500 mg/m2 and the change was significant (p < 0.005), even though the patient who received one prior dose of doxorubicin and the patient who received prior mediastinal radiation were omitted. The change was smaller when basal results were compared to the mean results measured at levels of 400, 450, and 500 mg/m2, but was still statistically significant (p < 0.05). In the CEOP group the change in LVEF from 62 k 6% to 6 1 k 8 % during therapy was not significant. The difference in the LVEF changes between CHOP and CEOP groups was significant ( - 15 2 11% vs 0 k 13%, p < 0.005) when baseline values and those obtained at final dose levels from 400 to 500 mg/m2 were compared. An at least 10% decrease in LVEF was observed in half the patients (11/22) at the final cumulative level of 200-500 mg/m2- 7 of them from the CHOP group and 4 from the CEOP group. 1 patient in the CHOP group developed a severe cardiotoxicity with heart failure, at a cumulative level of 200 mg/m2 of doxorubicin, in whom the final LVEF was decreased to 19%. A chest x-ray of his heart revealed dilated left ventricle (heart size 740 cm2/m2). 6 wk later he experienced severe shortness of breath and was admitted to the district hospital where digitalis and diuretics were started. In addition, 1 patient in the CHOP group developed moderate cardiotoxicity with a LVEF decline from 69% to 40%. During follow-up, this patient did not develop a clinical heart failure. Mild cardiotoxicity (a decline of 10% or more in LVEF) was seen in 5 patients in the CHOP group and in 4 patients in the CEOP group. However, in 1 of the 4 CEOP patients LVEF decreased only after this patient had received doxorubicin in the M-BACOD regimen, given for neurorelapse developing during CEOP therapy. In 2 of CHOP patients with mild cardiotoxicity (LVEF decrease > 10%) doxorubicin was discontinued because of increased dyspnea in strain at cumulative levels of 400 and 450 mg/m2. In the CEOP group, no patient developed clinically manifest cardiotoxicity. In 5 patients, the final cumulative dose of anthracyclines was more than 500 mg/m2. In 2 of these, a 303
Lahtinen et al.
further decrease of LVEF was detected after 500 mg/m2. LVEF's of these 2 patients at a cumulative level of 500mg/m2 were 56 and 53% and at 650 mg/m2 were 50 and 46%, respectively. Both of these patients received doxorubicin. Epirubicin did not reduce LVEF when the cumulative dose increased from 500 to 650 mg/m2 (1 patient) and from 500 to 550 mg/m2 (2 patients). The 1st of these 3 patients belonged to the CHOP group initially and the LVEF of this patient at a level of 500mg/m2 doxorubicin was 47%. In relapse, this patient received M-BACOD courses with epirubicin and, at a cumulative level of 650 mg/m2 anthracyclines (Dx + epiDx), LVEF was still 68%. The numbers of patients who responded are shown according to treatment arm in Table 2 and durations of the complete remissions (CR) achieved with different therapies are shown in Table 3. The overall response rate in the CHOP group was 83% (10/12)andintheCEOPgroup66% (8/12). 16ofthe 24 patients achieved CR (67%) (7/12 with CHOP, 4/12 with CEOP and 5 patients with different salvage regimens). In December 1989, 11/24 (46%) patients were in complete remission. 9 of them were in the first CR, 4 achieved with CHOP, 2 with CEOP and 3 with salvage therapies. The duration of the first CR in December 1989 in the whole series, calculated after completion of CHOP or CEOP therapy, varied from 3 to 66 + months. 7 of 16 patients with CR have had a relapse of the disease. All except 1 patient relapsed within 16 months after completion of the induction therapy. The survival, calculated from the start of CHOP or CEOP therapy, varied from 5 to 78 months. There was no significant difference in the duration of CR or survival between CHOP and CEOP groups. In the whole series there were no significant correlations between response or survival and the clinical stage or the histopathologic classification determined before treatment. 10 patients have died so far during follow-up - 8 due to resistant lymphoma, 1due to a septic infection during agranulocytosis after a salvage cytostatic course, and 1 patient died suddenly of unknown causes. No fatal complications were observed that were attributable to CHOP or CEOP therapy. Discussion
Our double-blind, prospective randomized trial consisting of 24 patients with non-Hodgkin lymphoma treated with CHOP or CEOP regimens confirmed previous findings of lower cardiotoxicity of epirubicin as compared to its parent compound doxorubicin (13, 14, 15). The mean LVEF decreased significantly more in the CHOP group than in the 304
CEOP group at the cumulative level of 450 mg/m2 as compared with baseline values measured before these therapies. In addition, in the CHOP group 1 patient developed a heart failure at the cumulative dose level of 200 mg/m2 of doxorubicin. Changes in LVEF's were significantly different between the treatment groups, even after the patient with overt congestive heart failure was omitted from comparisons. LVEF decreased more than 10% in half the patients at cumulative levels up to 500 mg/m2 - 7 in the CHOP group and 4 in the CEOP group. However, in l patient in the CEOP group a decrease in LVEF was not detected before the patient had received doxorubicin in a salvage regimen given for a relapse. None of the patients in this series had a previous heart disease according to clinical examination, ECG and chest x-ray. 1 patient had previously received mediastinal irridation, but LVEF did not change during therapy in this case. In addition, 1 patient had previously received one dose of doxorubicin, but in his case LVEF had decreased significantly already at the cumulative level of 200 mg/m2. Previously, Torti and coworkers, by studying endomyocardial biopsies, observed that cardiac lesions induced by epirubicin and doxorubicin were identical, but that approximately 180 mg/m2 more epirubicin that doxorubicin had to be administered to achieve the same degree of anthracycline injury (14). Dardir et al. (16), when studying cardiac toxicity with biopsies in patients receiving epirubicin as a single chemotherapeutic agent, demonstrated an increased myocardial damage at cumulative doses beyond 450 mg/m2 of epirubicin, but when the dose was less than 450mg/m2 only minimal hemodynamic disturbances were observed (16). Also recent clinical studies on patients with breast cancer have shown that cardiotoxicity of epirubicin only becomes manifest by clearly larger cumulative doses than those of doxorubicin (13, 15, 17). In our series, the overall response rate ot CHOP therapy was in accordance with previous results of CHOP regimens (18). There were no significant differences in the response rate or survival between the treatment arms. However, some tendency to get more response with CHOP than with CEOP was observed (83 vs 66%). Previous pilot studies have shown the efficacy of epirubicin in the treatment of non-Hodgkin lymphomas (7, 9, 19). In a recent study, the response rate of high-grade lymphomas for CEOP compared favorably to the response rate for CHOP (84vs 7 1%) (20). The dose of epiDx per course was 60 mg/m2 in that study. It might be that the optimal dose of epirubicin in the CEOP regimen is higher than the 50 mg/m2 used in our study. However, the number of patients and the follow-up were too small and too
Epirubicin/doxorubicin cardiotoxicity short to allow any definite conclusions to be drawn with regard to the clinical effects of these two anthracyclines. In conclusion, a lower cardiotoxicity of epirubicin as compared with doxorubicin was demonstrated in a double-blind, randomized clinical trial involving 24 patients with non-Hodgkin lymphoma treated with CHOP or CEOP regimens. Although no clinically significant cardiotoxicity was seen in patients treated with epirubicin, 4 of 12 patients in the CEOP group showed a decrease of 10% or more in LVEF at a mean cumulative level of 450 mg/m2. It is suggested, therefore, that patients expected to receive epirubicin at more than 450 mg/m2 should be monitored for latent cardiotoxicity. References 1. LEFRAKEA, PITHAJ, ROSENHEIM S, GOTTLIEBJA. A
2. 3.
4. 5.
6. 7.
clinicopathologic analysis of Adriamycin cardiotoxicity. Cancer 1973: 32: 302-314. S, et al. Adriamycin LEFRAKEA, PITHAJ, ROSENHEIM (NSC-123 127) cardiomyopathy. Cancer Chemother Rep Part 3 1975: 6: 203-208. MINOWRA, BENJAMINRS, GOTTLIEBJA. Adriamycin (NSC- 123127) cardiomyopathy an overview with determination of risk factors. Cancer Chemother Rep Part 3 1975: 6: 195-201. MINOWRA, BENJAMIN RS, LEEET, GOTTLIEB GA. Adriarisk factors. Cancer 1977: 39: mycin cardiomyopathy 1397-1402. BRISTOWMR, MASONJW, BILLINGHAM ME, DANIELS JR. Doxorubicin cardiomyopathy: Evaluation by phonocardiography, endomyocardial biopsy, and cardiac catheterization. Ann Intern Med 1978: 88: 168-175. E. NonLAHTINEN R, UUSITUPA M, KUIKKA J, LANSIMIES invasive evaluation of anthracycline-induced cardiotoxicity in man. Acta Med Scand 1982: 212: 201-206. G. Toxic and theraBONFANTE V, VILLANI F, BONADONNA peutic activity of 4'-epi-doxorubicin. Tumori 1982: 68:
-
-
8. GANZINA F. 4'-epi-doxorubicin, a new analogue of doxorubicin: a preliminary overview of preclinical and clinical data. Cancer Treat Rev 1983: 10: 1-22. 9. CERSOIMO RJ, HONG WK. Epirubicin: a review of the pharmacology, clinical activity, and adversed effects of an Adriamycin analogue. J Clin Oncol 1986: 4: 425-439. 10. LENNERTK. Principles of the classification. In: Histopathology of Non-Hodgkin's Lymphomas (based on the Kiel classification). New York: Springer-Verlag, 1981: 7-1 I . 11. The Non-Hodgkin's Lymphoma Pathologic Classification Project. National Cancer Institute Sponsored Study of Classification of Non-Hodgkin's Lymphomas. Summary and Description of a Working Formulation for Clinical Usage. Cancer 1982: 49: 2112-2135. 12. MUSTONENJ. Left ventricular function in middle-aged diabetic patients without clinically evident cardiovascular disease. Thesis. Kuopio, Finland: University of Kuopio, 1988. 13. JAINKK, CASPERES, GELLERNL, et al. A prospective randomized comparison of epirubicin and doxorubicin in patients with advanced breast cancer. J Clin Oncol 1985: 3: 818-826. 14. TORTIFM, BRISTOW MM, LUMBL, et al. Cardiotoxicity of epirubicin and doxorubicin: assessment by endomyocardial biopsy. Cancer Res 1986: 46: 3722-3727. 15. The French Epirubicin Study Group. A prospective randomized phase 111 trial comparing combination chemotherapy with cyclophosphamide, fluorouracil, and either doxorubicin or epirubicin. J Clin Oncol 1988: 6: 679-688. VJ, MIKHAEL YS, et a]. Cardiac 16. DARDIRMD, FERRANS morphologic and functional changes induced by Epirubicin chemotherapy. J Clin Oncol 1989: 7: 947-948. 17. The Italian multicentre breast cancer study with epirubicin. J Clin Oncol 1988: 6: 976-982. 18. JONESSE, GROZEAPN, METZ EN, et al. Superiority of Adriamycin-containing combination chemotherapy in the treatment of diffuse lymphoma. Cancer 1979: 43: 417-425. 19. LOPEZM, DILAUROL, CANZINA F, PERNOC-F, PAPALDO P, DIPIETRON. Epirubicin in non-Hodgkin's lymphomas. Am J Clin Oncol 1985: 8: 151-153. 20. AL-ISMAILSAD, WHITTAKER JA, COUGHJ. Combination chemotherapy including epirubicin for the management of non-Hodgkin's lymphoma. Eur J Cancer Clin Oncol 1987: 23: 1379-1384.
105-1 11.
305
