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Liposome-encapsulated doxorubicin is less cardiotoxic than conventional doxorubicin for metastatic breast cancer
TREATMENT
Liposome-encapsulated doxorubicin is less cardiotoxic than conventional doxorubicin for metastatic breast cancer Abstracted from: Harris L, Batist G, Belt R, Rovira D, Navari R, Azarnia N, Welles L,Winer E, for theTLC D-99 Study Group. Liposomeencapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as ¢rst-line therapy of metastatic breast carcinoma.Cancer 2002; 94: 25^36.
BACKGROUND Anthracyclines are among the most e¡ective breast cancer therapies, but are limited by doserelated cardiomyopathy. Liposome-encapsulated doxorubicin was designed to preserve the anti-tumor e⁄cacy of doxorubicin while reducing cardiotoxicity. OBJECTIVE To compare the e⁄cacy and toxicity of liposome-encapsulated doxorubicin and conventional doxorubicin for ¢rst-line treatment of metastatic breast cancer. SETTING Forty-two North American centers; November 1992 to February 1999. METHOD Randomized controlled trial.
tional doxorubicin. Median cumulative doxorubicin dose at onset of cardiotoxicity was 785 mg/m2 for encapsulated doxorubicin and 570 mg/m2 for conventional doxorubicin (hazard ratio 3.56; p = 0.0001). There was no di¡erence in overall response, median time to progression or median survival (seeTables 1^3). AUTHORS’ CONCLUSIONS Single agent liposome-encapulated doxorubicin is as e¡ective as conventional doxorubicin and has lower cardiotoxicity for women with metastatic breast cancer. METHOD NOTES Power calculation
PARTICIPANTS Two hundred and four women with metastatic breast cancer and no prior therapy; median age 54 years. All had ECOG performance status less than 2, life expectancy of at least 3 months and adequate bone marrow, renal and liver function. Women were not eligible if they had bone disease only, prior adjuvant treatment with anthracyclines or anthracenediones, chemotherapy or myocardial infarction within 6 months; a history of congestive heart failure or serious cardiac arrhythmia; pregnancy or lactation.
INTERVENTION Liposome-encapsulated or conventional doxorubixin (75 mg/m2) as 1hour intravenous infusion every 3 weeks. Individual dose titration was allowed based on toxicity.
OUTCOMES Cardiotoxicity; progression; response (complete, partial and overall); survival.
Blinding Allocation concealment Generation of allocation sequence Balanced groups
Analysis
Calculation performed to detect 15% lower response rate in encapsulated doxorubicin with 80% power at 5% level of signi¢cance. Full sample was not recruited as study was stopped at third interim analysis Not speci¢ed Not speci¢ed Balanced block design Balanced for prognostic factors.There were more progesterone receptor positive women in the conventional doxorubicin group. Intention-to-treat
Sources offunding: Elan Pharmaceuticals, Princeton, New Jersey.
110
MAIN RESULTS Thirteen percent of women who received encapsulated doxorubicin experienced cardiotoxicity compared to 29% of those receiving conven-
Correspondence to: Lyndsay Harris, M.D., Dana-Farber Cancer Institute, Room D1210, 44 Binney Street, Boston, MA 02115, USA. (E-mail: lyndsay^[email protected])
Evidence-based Oncology (2002) 3,110 ^112 doi:10.1054/ebon.22, available online at http://www.idealibrary.com.on
1363- 4054/02/$ - see front matter & 2002 Elsevier Science Ltd. All rights reserved
Table 1 Time to progression in women with metastatic breast cancer treated with conventional or liposome-encapsulated doxorubicin
Outcome
Median time to outcome (months) with encapsulated doxorubicin (n = 108)
Median time to outcome (months) with conventional doxorubicin (n = 116)
Hazard ratio (timeframe not provided)
3.7 (2.6 to 4.8) 3.8 (2.6 to 5.3) 16 (13 to 18)
3.4 (2.7 to 4.3) 4.3 (3.1 to 6.0) 20 (15 to 27)
1.21 (0.9 to 1.63) 0.92 (0.66 to 1.26) 0.76 (0.56 to 1.04)
Treatment failure Progression Overall survival
P-Value 0.21 0.59 0.09
Note: 95% con¢dence intervals are in parentheses.
Table 2 Response in women with metastatic breast cancer treated with conventional or liposome-encapsulated doxorubicin % Encapsulated doxorubicin (n = 108)
% Conventional doxorubicin (n = 116)
Change in absolute risk with encapsulated doxorubicin
Relative risk change with encapsulated doxorubicin
Complete response
0
2
Partial response
26
24
Overall response rate
26
26
One-year survival
64
69
2% harm (1% bene¢t to 5% harm) 2% bene¢t (9% harm to 13% bene¢t) 0% change (12% harm to 12% bene¢t) 5% harm (7% bene¢t to 17% harm)
100% RBR (CI not calculable) 8% RBI (40% RBR to 58% RBI) 0% change (44% RBI to 44% RBR) 8% RBR (12% RBI to 28% RBR)
Outcome
Note: 95% con¢dence intervals are in parentheses. Di¡erences are not statistically signi¢cant. Response timeframe is not speci¢ed. RBR = relative bene¢t reduction; RBI = relative bene¢t increase.
Table 3 Adverse e¡ects in women with metastatic breast cancer treated with conventional or liposome-encapsulated doxorubicin
Adverse e¡ects
% Encapsulated doxorubicin (n = 108)
% Conventional doxorubicin (n = 116)
P-Value
Number needed to treat with encapsulated doxorubicin to prevent outcome in one person
Cardiotoxicity
13
29
o0.05
6 (4 to 18)
Anemia
22
26
0.53
Not signi¢cant
Infection (grade 3^4)
5
12
0.09
Not signi¢cant
Nausea/vomiting (grade 3^4) Neutropenia
13
24
0.06
9 (5 to 103)
50
58
0.28
Not signi¢cant
Thrombocytopenia
13
10
0.53
Not signi¢cant
Diarrhea (grade 3^4)
1
4
0.22
Not signi¢cant
Stomatitis/mucositis (grade 3^4) Alopecia (grade 2)
9
14
0.21
Not signi¢cant
84
88
0.44
Not signi¢cant
Change in absolute risk with encapsulated doxorubicin
Relative risk change with encapsulated doxorubicin
16% ARR (5% to 26%) 4% ARR (7% ARI to 15% ARR) 7% ARR (0% to 14% ARR) 11% ARR (1% to 21% ARR) 8% ARR (5% ARI to 21% ARR) 3% ARI (5% ARR to 11% ARI) 3% ARR (1% ARI to 7% ARR) 5% ARR (3% ARI to 13% ARR) 4% ARR (5% ARI to 13% ARR)
55% RRR (30% to 80%) 15% RRR (24% RRI to 55% RRR) 58% RRR (18% to 98% RRR) 46% RRR (14% to 78% RRR) 14% RRR (7% RRI to 35% RRR) 30% RRI (65% RRR to 100% RRI) 75% RRR (23% to 100% RRR) 36% RRR (13% RRI to 84% RRR) 5% RRR (6% RRI to 15% RRR)
Note: 95% con¢dence intervals are in parentheses. Timeframe is not speci¢ed. ARR = absolute risk reduction; ARI = absolute risk increase; RRR = relative risk reduction; RRI = relative risk increase. Evidence-based Oncology (2002) 3,110 ^112
111
Commentary High cumulative doses of doxorubicin can cause myocardial cell damage, manifesting as cardiomyopathy.1 There are several methods to reduce the risk of cardiac toxicity. These include continuous infusion or lower weekly doses; co-administration of the cardioprotectant dexrazoxane; substituting epirubicin for doxorubicin, or encapsulating doxorubicin in liposomes.These strategies reduce cardiotoxicity and allow a greater cumulative drug dose compared to standard doxorubicin. The risk of cardiomyopathy increases after a cumulative doxorubicin dose of about 500 mg/m2.1 In this study, the median time to treatment response was 6 weeks for both encapsulated and standard doxorubicin. Time to treatment failure was about 15 weeks (3.5 months). Differences in the cardiotoxicity of encapsulated and standard doxorubicin began to appear at a cumulative dose of 525 mg/m2, which was reached at18 weeks.This suggests that for most women, response to treatment and subsequent treatment failure will occur before clinically relevant cardiotoxicity with either conventional or encapsulated doxorubicin. Encapsulated doxorubicin may substitute for doxorubicin if it can be combined safely with trastuzumab. Doxorubicin combined with trastuzumab is superior to doxorubicin alone, but has a high rate of cardiotoxicity.2 If encapsulated doxorubicin
112
Evidence-based Oncology (2002) 3,110 ^112
has fewer cardiac effects when combined with trastuzumab, this would be an option for HER-2/neu positive women. Encapsulated doxorubicin could also be used by older women with pre-existing cardiac problems, in whom the prevalence of breast cancer is likely to increase dramatically during the next 25 years.3 Dr Charles L. Shapiro Arthur G James Cancer Hospital and Richard J Solove Research Institute, Ohio, USA
Literature cited 1. Von Hoff DD, Layard MW, Basa P et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med1979; 91: 710--717. 2. Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344: 783--792. 3. Alberg A, Singh S. Epidemiology of breast cancer in older women: implications for future healthcare. Drugs Aging 2001; 18: 761--772. Level and Quality of Evidence: 2B
Liposome-encapsulated doxorubicin is less cardiotoxic than conventional doxorubicin for metastatic breast cancer Abstracted from: Harris L, Batist G, Belt R, Rovira D, Navari R, Azarnia N, Welles L,Winer E, for theTLC D-99 Study Group. Liposomeencapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as ¢rst-line therapy of metastatic breast carcinoma.Cancer 2002; 94: 25^36.
BACKGROUND Anthracyclines are among the most e¡ective breast cancer therapies, but are limited by doserelated cardiomyopathy. Liposome-encapsulated doxorubicin was designed to preserve the anti-tumor e⁄cacy of doxorubicin while reducing cardiotoxicity. OBJECTIVE To compare the e⁄cacy and toxicity of liposome-encapsulated doxorubicin and conventional doxorubicin for ¢rst-line treatment of metastatic breast cancer. SETTING Forty-two North American centers; November 1992 to February 1999. METHOD Randomized controlled trial.
tional doxorubicin. Median cumulative doxorubicin dose at onset of cardiotoxicity was 785 mg/m2 for encapsulated doxorubicin and 570 mg/m2 for conventional doxorubicin (hazard ratio 3.56; p = 0.0001). There was no di¡erence in overall response, median time to progression or median survival (seeTables 1^3). AUTHORS’ CONCLUSIONS Single agent liposome-encapulated doxorubicin is as e¡ective as conventional doxorubicin and has lower cardiotoxicity for women with metastatic breast cancer. METHOD NOTES Power calculation
PARTICIPANTS Two hundred and four women with metastatic breast cancer and no prior therapy; median age 54 years. All had ECOG performance status less than 2, life expectancy of at least 3 months and adequate bone marrow, renal and liver function. Women were not eligible if they had bone disease only, prior adjuvant treatment with anthracyclines or anthracenediones, chemotherapy or myocardial infarction within 6 months; a history of congestive heart failure or serious cardiac arrhythmia; pregnancy or lactation.
INTERVENTION Liposome-encapsulated or conventional doxorubixin (75 mg/m2) as 1hour intravenous infusion every 3 weeks. Individual dose titration was allowed based on toxicity.
OUTCOMES Cardiotoxicity; progression; response (complete, partial and overall); survival.
Blinding Allocation concealment Generation of allocation sequence Balanced groups
Analysis
Calculation performed to detect 15% lower response rate in encapsulated doxorubicin with 80% power at 5% level of signi¢cance. Full sample was not recruited as study was stopped at third interim analysis Not speci¢ed Not speci¢ed Balanced block design Balanced for prognostic factors.There were more progesterone receptor positive women in the conventional doxorubicin group. Intention-to-treat
Sources offunding: Elan Pharmaceuticals, Princeton, New Jersey.
110
MAIN RESULTS Thirteen percent of women who received encapsulated doxorubicin experienced cardiotoxicity compared to 29% of those receiving conven-
Correspondence to: Lyndsay Harris, M.D., Dana-Farber Cancer Institute, Room D1210, 44 Binney Street, Boston, MA 02115, USA. (E-mail: lyndsay^[email protected])
Evidence-based Oncology (2002) 3,110 ^112 doi:10.1054/ebon.22, available online at http://www.idealibrary.com.on
1363- 4054/02/$ - see front matter & 2002 Elsevier Science Ltd. All rights reserved
Table 1 Time to progression in women with metastatic breast cancer treated with conventional or liposome-encapsulated doxorubicin
Outcome
Median time to outcome (months) with encapsulated doxorubicin (n = 108)
Median time to outcome (months) with conventional doxorubicin (n = 116)
Hazard ratio (timeframe not provided)
3.7 (2.6 to 4.8) 3.8 (2.6 to 5.3) 16 (13 to 18)
3.4 (2.7 to 4.3) 4.3 (3.1 to 6.0) 20 (15 to 27)
1.21 (0.9 to 1.63) 0.92 (0.66 to 1.26) 0.76 (0.56 to 1.04)
Treatment failure Progression Overall survival
P-Value 0.21 0.59 0.09
Note: 95% con¢dence intervals are in parentheses.
Table 2 Response in women with metastatic breast cancer treated with conventional or liposome-encapsulated doxorubicin % Encapsulated doxorubicin (n = 108)
% Conventional doxorubicin (n = 116)
Change in absolute risk with encapsulated doxorubicin
Relative risk change with encapsulated doxorubicin
Complete response
0
2
Partial response
26
24
Overall response rate
26
26
One-year survival
64
69
2% harm (1% bene¢t to 5% harm) 2% bene¢t (9% harm to 13% bene¢t) 0% change (12% harm to 12% bene¢t) 5% harm (7% bene¢t to 17% harm)
100% RBR (CI not calculable) 8% RBI (40% RBR to 58% RBI) 0% change (44% RBI to 44% RBR) 8% RBR (12% RBI to 28% RBR)
Outcome
Note: 95% con¢dence intervals are in parentheses. Di¡erences are not statistically signi¢cant. Response timeframe is not speci¢ed. RBR = relative bene¢t reduction; RBI = relative bene¢t increase.
Table 3 Adverse e¡ects in women with metastatic breast cancer treated with conventional or liposome-encapsulated doxorubicin
Adverse e¡ects
% Encapsulated doxorubicin (n = 108)
% Conventional doxorubicin (n = 116)
P-Value
Number needed to treat with encapsulated doxorubicin to prevent outcome in one person
Cardiotoxicity
13
29
o0.05
6 (4 to 18)
Anemia
22
26
0.53
Not signi¢cant
Infection (grade 3^4)
5
12
0.09
Not signi¢cant
Nausea/vomiting (grade 3^4) Neutropenia
13
24
0.06
9 (5 to 103)
50
58
0.28
Not signi¢cant
Thrombocytopenia
13
10
0.53
Not signi¢cant
Diarrhea (grade 3^4)
1
4
0.22
Not signi¢cant
Stomatitis/mucositis (grade 3^4) Alopecia (grade 2)
9
14
0.21
Not signi¢cant
84
88
0.44
Not signi¢cant
Change in absolute risk with encapsulated doxorubicin
Relative risk change with encapsulated doxorubicin
16% ARR (5% to 26%) 4% ARR (7% ARI to 15% ARR) 7% ARR (0% to 14% ARR) 11% ARR (1% to 21% ARR) 8% ARR (5% ARI to 21% ARR) 3% ARI (5% ARR to 11% ARI) 3% ARR (1% ARI to 7% ARR) 5% ARR (3% ARI to 13% ARR) 4% ARR (5% ARI to 13% ARR)
55% RRR (30% to 80%) 15% RRR (24% RRI to 55% RRR) 58% RRR (18% to 98% RRR) 46% RRR (14% to 78% RRR) 14% RRR (7% RRI to 35% RRR) 30% RRI (65% RRR to 100% RRI) 75% RRR (23% to 100% RRR) 36% RRR (13% RRI to 84% RRR) 5% RRR (6% RRI to 15% RRR)
Note: 95% con¢dence intervals are in parentheses. Timeframe is not speci¢ed. ARR = absolute risk reduction; ARI = absolute risk increase; RRR = relative risk reduction; RRI = relative risk increase. Evidence-based Oncology (2002) 3,110 ^112
111
Commentary High cumulative doses of doxorubicin can cause myocardial cell damage, manifesting as cardiomyopathy.1 There are several methods to reduce the risk of cardiac toxicity. These include continuous infusion or lower weekly doses; co-administration of the cardioprotectant dexrazoxane; substituting epirubicin for doxorubicin, or encapsulating doxorubicin in liposomes.These strategies reduce cardiotoxicity and allow a greater cumulative drug dose compared to standard doxorubicin. The risk of cardiomyopathy increases after a cumulative doxorubicin dose of about 500 mg/m2.1 In this study, the median time to treatment response was 6 weeks for both encapsulated and standard doxorubicin. Time to treatment failure was about 15 weeks (3.5 months). Differences in the cardiotoxicity of encapsulated and standard doxorubicin began to appear at a cumulative dose of 525 mg/m2, which was reached at18 weeks.This suggests that for most women, response to treatment and subsequent treatment failure will occur before clinically relevant cardiotoxicity with either conventional or encapsulated doxorubicin. Encapsulated doxorubicin may substitute for doxorubicin if it can be combined safely with trastuzumab. Doxorubicin combined with trastuzumab is superior to doxorubicin alone, but has a high rate of cardiotoxicity.2 If encapsulated doxorubicin
112
Evidence-based Oncology (2002) 3,110 ^112
has fewer cardiac effects when combined with trastuzumab, this would be an option for HER-2/neu positive women. Encapsulated doxorubicin could also be used by older women with pre-existing cardiac problems, in whom the prevalence of breast cancer is likely to increase dramatically during the next 25 years.3 Dr Charles L. Shapiro Arthur G James Cancer Hospital and Richard J Solove Research Institute, Ohio, USA
Literature cited 1. Von Hoff DD, Layard MW, Basa P et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med1979; 91: 710--717. 2. Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344: 783--792. 3. Alberg A, Singh S. Epidemiology of breast cancer in older women: implications for future healthcare. Drugs Aging 2001; 18: 761--772. Level and Quality of Evidence: 2B