Purpose:

Continuous intravenous infusion (CIV) of doxorubicin (DOX) versus bolus (BOL) may minimize dose-dependent DOX cardiomyopathy, but it is unclear whether this advantage is evident as employed in typical soft-tissue sarcoma (STS) treatment. The impact of administration mode on adverse events (AE) and efficacy were compared using data from a randomized trial of DOX-based therapy (SARC021/TH CR-406).

Experimental Design:

In this post hoc analysis, CIV versus BOL was at discretion of the treating physician. Likelihood of AEs, and objective responses were assessed by adjusted logistic regression. Progression-free (PFS) and overall survival (OS) were compared using Kaplan–Meier, log-rank test, and adjusted Cox regression.

Results:

DOX was administered by BOL to 556 and by CIV to 84 patients. Proportions experiencing hematologic, non-hematologic, or cardiac AEs did not differ by administration mode. Hematologic AEs were associated with age, performance status, and cumulative DOX. Non-hematologic AEs were associated with age, performance status, and cumulative evofosfamide. Cardiac AEs were only associated with cumulative DOX; there was no interaction between DOX dose and delivery mode. PFS and OS were similar (median PFS 6.14 months BOL vs. 6.11 months CIV, P = 0.47; median OS 18.4 months BOL vs. 21.4 months CIV, P = 0.62). PFS, OS, and objective responses were not associated with delivery mode.

Conclusions:

CIV was not associated with superior outcomes over BOL within DOX dosing limits of SARC021. Cardiac AEs were associated with increasing cumulative DOX dose. While not randomized with respect to DOX delivery mode, the results indicate that continued investigation of AE mitigation strategies is warranted.

Translational Relevance

Doxorubicin (DOX) remains a key agent in sarcoma treatment, but its use is hampered by dose-dependent cardiomyopathy. Prior randomized trials support continuous intravenous infusion (CIV) to decrease the risk of cardiomyopathy versus bolus (BOL), although BOL remains in widespread use. We analyzed data from a prospective phase III clinical trial, in which DOX was administered by CIV or BOL, at investigator discretion. No difference in efficacy or adverse events (AE), including cardiac AEs, was identified with respect to mode of DOX administration, within protocol-imposed DOX dosing limits. Cardiac AEs were associated only with cumulative DOX dose. These data suggest that BOL administration of DOX, limited to cumulative dose of 450 mg/m2, does not appear to be harmful versus CIV. The observation of cardiac AEs among treated patients, despite dosing limitation, highlights the need for continued attention in future research to strategies that might mitigate or prevent anthracycline cardiotoxicity.

Since its approval in the Unites States in 1974, doxorubicin (DOX; adriamycin) has been the backbone of soft-tissue sarcoma (STS) therapy. Estimated median overall survival (OS) of patients with STS treated with DOX was about 51 weeks in both a meta-analysis published in 1999 and the control arm of a large clinical trial published in 2014 (1, 2). More recently reported phase III trials, including the study analyzed herein, report median OS of 16.9 to 19.7 months (3–5).

Multiple attempts have been made to identify companion agents to increase the activity of DOX (2–6). As of November 2022, no DOX-based combination has demonstrated superior OS to DOX monotherapy in STS treatment. Combination therapy with ifosfamide increases the objective response rate (ORR) and prolongs progression-free survival (PFS), at the cost of increased incidence and severity of adverse events (AE; ref. 2).

The characteristic AE of anthracyclines, including DOX, is dose-dependent cardiomyopathy (7, 8). Several strategies have been employed to mitigate cardiomyopathy, including screening for preexisting cardiac dysfunction, use of alternative anthracycline preparations, use of cardioprotective agents, and use of alternative delivery strategies (9–12). In particular, DOX delivery by continuous intravenous infusion (CIV) versus bolus (BOL) administration has been proposed to decrease the incidence of cardiomyopathy (9, 10, 13–18). Four trials, three of which were randomized, indicated that CIV could mitigate cardiomyopathy. These studies varied in their CIV infusion durations, DOX dosing, indication (sarcoma, breast), cardiac assessment methods, primary study objectives, comparator groups, and statistical power (13, 14, 17, 18). A meta-analysis of these trials suggested an increased risk of congestive heart failure [CHF; OR, 4.13; 95% confidence interval (CI), 1.75–9.72] and reduced left ventricular ejection fraction (LVEF)/increased subclinical cardiotoxicity (OR, 3.04; 95% CI, 1.66–5.58) associated with BOL versus CIV delivery (16).

SARC021 was a randomized clinical trial assessing whether addition of evofosfamide (EVO), a novel, hypoxia-activated ifosfamide derivative, could enhance DOX activity in STS (3). The trial did not achieve its primary endpoint: improvement in OS among those treated with the combination versus DOX monotherapy. To accommodate heterogeneity in treatment patterns amongst the international investigators, the study design permitted administration of DOX by either BOL or CIV, at the discretion of the local investigator. This dichotomy allowed exploration of the effect of DOX delivery mode (CIV vs. BOL) on AEs and efficacy outcomes. Here, we present the results of a post hoc analysis of these data examining this issue.

A total of 640 patients were enrolled and randomized in SARC021, conducted by the Sarcoma Alliance for Research through Collaboration (SARC; ref. 3). Nineteen (19) randomized patients did not receive protocol treatment (4 DOX+EVO, 15 DOX). The analyses for this manuscript are based on those patients (n = 621) who received protocol-specified therapy. As part of conduct of the SARC021 trial, written informed consent was obtained from each participant or the participant's guardian; all human investigations were conducted after approval by a local Human Investigations Committee; and the study was conducted in accordance with the principles of the Declaration of Helsinki.

Eligible patients required a normal 12-lead electrocardiogram (ECG) and a LVEF considered normal (>50%), as assessed by either multi-gated acquisition scan (MUGA) or echocardiogram (ECHO). Pertinent to this analysis, patients were excluded from participation if they had received prior anthracycline treatment or mediastinal/cardiac radiation therapy, used drugs with known cardiotoxicity or interactions with DOX, or had preexisting cardiac dysfunction precluding use of DOX.

The primary study outcome of SARC021 was OS, defined as the time from randomization to death from any cause. Secondary efficacy endpoints were PFS, defined as the time from date of randomization to first occurrence of disease progression or death from any cause within 63 days of last response assessment or randomization, and ORR, defined as the proportion of partial and complete responses according to RECIST version 1.1 (19).

Therapy was administered according to a 21-day cycle. Patients were assigned 1:1 to receive either DOX (75 mg/m2 intravenously on day 1) as monotherapy for up to 6 cycles, or in combination with EVO (300 mg/m2 intravenously over 30–60 minutes on days 1 and 8 of each cycle). DOX was administered on day 1 of each cycle as either BOL (at least 5 minutes and generally no more than 20 minutes) on day 1, or as a CIV (at least 6 hours; range 6–96 hours). The choice of manner of DOX administration (CIV vs. BOL) was left to the discretion of the local investigator, and implemented according to local practice. For those receiving EVO, DOX was administered 2 to 4 hours after EVO. For those assigned to combination therapy, treatment with EVO monotherapy could continue after completion of maximal combination therapy (6 cycles) until disease progression. Use of the cardioprotectant dexrazoxane was permitted at the discretion of the local investigator. Prophylactic neutrophil growth factor support with either filgrastim or pegfilgrastim was mandated in those receiving combination therapy, and was recommended in those receiving DOX monotherapy.

AEs, regardless of attribution, were graded according to NCI Common Terminology Criteria for Adverse Events version 4.0 (20). AEs were collected from first dose of study treatment until 30 days after discontinuation of study treatment. Planned cardiac assessments consisted of ECG and LVEF measurement by either MUGA or ECHO. These were obtained at baseline prior to treatment, after completion of 4 cycles of DOX-based therapy, and at completion of DOX therapy after 6 cycles of treatment. At baseline, all patients had LVEF greater than 50%, as defined by MUGA or ECHO. Cardiac AEs were defined as either (i) an absolute decrease in LVEF of 10% or more from baseline, resulting in LVEF of <55%; (ii) LVEF of ≤45%; or (iii) decline in LVEF of 20% or more, irrespective of the baseline value.

Because cardiac AEs were of particular interest, information was abstracted regarding smoking history and use of potentially cardioprotective medications [angiotensin-converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB), and/or beta-blocker; ref. 12]. No information was available regarding other comorbidities potentially associated with cardiac AEs (coronary artery disease, ischemic heart disease, history of myocardial infarction, angina, diabetes mellitus, alcohol intake, or hypertension).

Statistical analyses

The primary comparisons of interest were between those receiving DOX by BOL versus CIV, using adjusted multivariable analyses. Comparisons of categorical values between groups were made with χ2 test, or Fisher exact test when more appropriate. Comparisons of continuous variables were performed with a two-group t test, or Wilcoxon rank sum test when more appropriate. Logistic regression evaluated associations, measured as ORs with corresponding CIs, between clinicopathologic characteristics and the dichotomous endpoints: occurrence or nonoccurrence of at least one episode of grade 3–5 hematologic/non-hematologic AE, cardiac AE (as defined above), and ORR. Kaplan–Meier curves with the log-rank test were used to compare survival times between groups. Cox model analyses were used to determine the HRs for survival outcomes and corresponding CIs in univariable and multivariable analyses. The primary analyses assessed the association between DOX delivery mode (BOL vs. CIV) and the occurrence of AEs and efficacy outcomes in adjusted models. Adjustment covariates included in multivariable models were selected on the basis of statistically significant associations in univariable analyses, differences by mode of DOX delivery in baseline characteristics (i.e., radiotherapy, age), or pertinence to research question (i.e., baseline LVEF in cardiac AE assessments). All statistical tests were two-sided and α ≤ 0.05 was designated as the threshold for null hypothesis rejection. For analyses of cardiac AEs, baseline LVEF and any reported use of a potentially cardioprotective medication (ACEi, ARB, or beta-blocker) were also included as covariates (12). Cumulative doses of DOX or EVO were analyzed in units of g/m2 in statistical analyses.

Only 621 patients of the 640 enrolled received any study treatment. A total of 618 of these 621 patients had a baseline cardiac assessment (i.e., had a LVEF value); for the remaining 3, a baseline LVEF was imputed as the average value. A total of 128 patients (20.6%) had no follow-up cardiac assessment. In our primary analyses, patients without a follow-up cardiac assessment were assumed not to have experienced a cardiac AE, as defined above.

Several multivariable, sensitivity analyses were conducted with respect to the cardiac AE analysis; except where indicated, these included all 621 patients. These included a complete case analysis (n = 493), excluding those without a follow-up cardiac assessment; assessment for interaction between cumulative DOX dose and mode of DOX delivery; exclusion of patients treated with dexrazoxane (n = 585); exclusion of patients receiving less than 300 mg/m2 (n = 403) or 400 mg/m2 (n = 293) of DOX; and analysis of the BOL group alone with respect to treatment with the cardioprotective drug dexrazoxane (n = 541).

Data availability

The data generated in this study are not publicly available due to patient privacy, but are available upon reasonable request from the SARC Clinical Data Repository (https://sarctrials.org).

Baseline characteristics

Patient clinicopathologic characteristics were compared with reference to mode of DOX delivery (Table 1). Only those receiving at least one cycle of study treatment are included in the analysis. The analysis group included 541 receiving DOX by BOL and 80 receiving DOX by CIV. In both groups, the majority of patients received treatment in the metastatic, as opposed to locally advanced, setting. A minority of patients in both groups received prior radiotherapy, with a higher proportion of BOL patients having had prior radiotherapy (39% BOL vs. 23% CIV, P = 0.002). The baseline mean LVEF in the CIV group was slightly higher than that in the BOL group (64.4% versus 62.9%; P = 0.022). The groups did not differ with respect to other variables, including smoking history and any reported use of ACEi, ARB, or beta-blockers.

Table 1.

Patient clinicopathologic characteristics compared with reference to mode of DOX delivery.

Total (n = 621)BOL DOX (n = 541)CIV DOX (n = 80)P
Age (years) 
 <65 413 (67) 367 (68) 46 (57) 0.07 
 ≥65 208 (33) 174 (32) 34 (42)  
Age, mean (SD) 57.3 (12.8) 57.0 (12.7) 59.1 (13.6) 0.20 
Age, median (range) 59 (20–89) 58 (20–89) 62 (22–82) 0.11 
Sex    0.10 
 Female 333 (54) 297 (55) 36 (45)  
 Male 288 (46) 244 (45) 44 (55)  
Ethnicity    0.25 
 Hispanic or Latino 32 (5) 30 (6) 2 (2)  
 Not Hispanic or Latino 589 (95) 511 (94) 78 (98)  
Race    0.78 
 White 566 (91) 492 (91) 74 (92)  
 Black 26 (4) 22 (4) 4 (5)  
 Asian 15 (2) 13 (2) 2 (2)  
 American Indian or Alaska Native 3 (0.5) 3 (1) 0 (0)  
 Other 11 (2) 11 (2) 0 (0)  
ECOG performance status    0.79 
 0 358 (58) 313 (58) 45 (56)  
 1 or 2a 263 (42) 228 (42) 35 (44)  
Extent of disease    0.051 
 Locally advanced 69 (11) 55 (10) 14 (18)  
 Metastatic 552 (89) 486 (90) 66 (82)  
Highest histologic gradeb    0.73 
 Low 1 (0) 1 (0) 0 (0)  
 Intermediate 198 (32) 168 (31) 30 (38)  
 Intermediate/high 16 (3) 15 (3) 1 (1)  
 High 405 (65) 356 (66) 49 (61)  
 Unknown 1 (0) 1 (0) 0 (0)  
Histologic classification site review    0.08 
 Leiomyosarcoma 222 (36) 201 (37) 21 (26)  
 Liposarcoma 111 (18) 91 (17) 20 (25)  
 Undifferentiated pleomorphic sarcoma 76 (12) 69 (13) 7 (9)  
 Other 212 (34) 180 (33) 32 (40)  
Prior radiotherapy    0.002 
 No 391 (63) 328 (61) 63 (79)  
 Yes 230 (37) 213 (39) 17 (21)  
Prior adjuvant/neoadjuvant systemic therapy    0.18 
 No 581 (94) 503 (93) 78 (98)  
 Yes 40 (6) 38 (7) 2 (2)  
Baseline LVEF (n = 618) 
 Mean (SD) 63.1 (6.0) 62.9 (6.0) 64.4 (5.8) 0.02 
 Median (min, max) 63 (50–84.2) 63 (50–84.2) 64 (50–77)  
Dexrazoxane    <0.01 
 Yes 36 (6) 36 (7) 0 (0)  
 No 585 (94) 505 (93) 80 (100)  
ACE inhibitor    0.83 
 Yes 111 (18) 96 (18) 15 (19)  
 No 510 (82) 445 (82) 65 (81)  
ARB    0.19 
 Yes 67 (11) 55 (10) 12 (15)  
 No 554 (89) 486 (90) 68 (85)  
Beta-blocker    0.80 
 Yes 133 (21) 115 (21) 18 (22)  
 No 488 (79) 426 (79) 62 (78)  
Smoking history    0.20 
 Current 57 (11) 47 (9) 10 (12)  
 Ex-smoker 219 (34) 198 (37) 21 (26)  
 Never/unknown 345 (64) 296 (55) 49 (61)  
Total (n = 621)BOL DOX (n = 541)CIV DOX (n = 80)P
Age (years) 
 <65 413 (67) 367 (68) 46 (57) 0.07 
 ≥65 208 (33) 174 (32) 34 (42)  
Age, mean (SD) 57.3 (12.8) 57.0 (12.7) 59.1 (13.6) 0.20 
Age, median (range) 59 (20–89) 58 (20–89) 62 (22–82) 0.11 
Sex    0.10 
 Female 333 (54) 297 (55) 36 (45)  
 Male 288 (46) 244 (45) 44 (55)  
Ethnicity    0.25 
 Hispanic or Latino 32 (5) 30 (6) 2 (2)  
 Not Hispanic or Latino 589 (95) 511 (94) 78 (98)  
Race    0.78 
 White 566 (91) 492 (91) 74 (92)  
 Black 26 (4) 22 (4) 4 (5)  
 Asian 15 (2) 13 (2) 2 (2)  
 American Indian or Alaska Native 3 (0.5) 3 (1) 0 (0)  
 Other 11 (2) 11 (2) 0 (0)  
ECOG performance status    0.79 
 0 358 (58) 313 (58) 45 (56)  
 1 or 2a 263 (42) 228 (42) 35 (44)  
Extent of disease    0.051 
 Locally advanced 69 (11) 55 (10) 14 (18)  
 Metastatic 552 (89) 486 (90) 66 (82)  
Highest histologic gradeb    0.73 
 Low 1 (0) 1 (0) 0 (0)  
 Intermediate 198 (32) 168 (31) 30 (38)  
 Intermediate/high 16 (3) 15 (3) 1 (1)  
 High 405 (65) 356 (66) 49 (61)  
 Unknown 1 (0) 1 (0) 0 (0)  
Histologic classification site review    0.08 
 Leiomyosarcoma 222 (36) 201 (37) 21 (26)  
 Liposarcoma 111 (18) 91 (17) 20 (25)  
 Undifferentiated pleomorphic sarcoma 76 (12) 69 (13) 7 (9)  
 Other 212 (34) 180 (33) 32 (40)  
Prior radiotherapy    0.002 
 No 391 (63) 328 (61) 63 (79)  
 Yes 230 (37) 213 (39) 17 (21)  
Prior adjuvant/neoadjuvant systemic therapy    0.18 
 No 581 (94) 503 (93) 78 (98)  
 Yes 40 (6) 38 (7) 2 (2)  
Baseline LVEF (n = 618) 
 Mean (SD) 63.1 (6.0) 62.9 (6.0) 64.4 (5.8) 0.02 
 Median (min, max) 63 (50–84.2) 63 (50–84.2) 64 (50–77)  
Dexrazoxane    <0.01 
 Yes 36 (6) 36 (7) 0 (0)  
 No 585 (94) 505 (93) 80 (100)  
ACE inhibitor    0.83 
 Yes 111 (18) 96 (18) 15 (19)  
 No 510 (82) 445 (82) 65 (81)  
ARB    0.19 
 Yes 67 (11) 55 (10) 12 (15)  
 No 554 (89) 486 (90) 68 (85)  
Beta-blocker    0.80 
 Yes 133 (21) 115 (21) 18 (22)  
 No 488 (79) 426 (79) 62 (78)  
Smoking history    0.20 
 Current 57 (11) 47 (9) 10 (12)  
 Ex-smoker 219 (34) 198 (37) 21 (26)  
 Never/unknown 345 (64) 296 (55) 49 (61)  

Note: P values calculated from Wilcoxon rank sum.

Unless otherwise indicated, values are absolute number in each category, with percent indicated within parentheses.

Abbreviations: min, minimum; max, maximum.

aOnly 4 patients had ECOG performance status = 2.

bOne patient lacked histologic grade information.

Treatment characteristics

The proportion of patients receiving CIV was similar between the two treatment arms of the trial: 39 (12.5%) and 41 (13.3%) in the DOX + EVO arm versus DOX arm, respectively. Patients in the CIV group received a mean of 4.44 cycles (SD = 1.87) of DOX-containing treatment with a mean administration time of 30.2 hours (SD = 24.6 hours; range 6–96 hours). The majority received their infusions over less than 48 hours. Patients receiving BOL administration received a mean of 4.46 cycles (SD = 1.91) of DOX-containing treatment with a mean administration time of 0.4 hours (SD = 0.25 hours; range 0.08–1.25 hours). The cumulative DOX doses were similar when comparing CIV and BOL: 320 mg/m2 (SD = 130) and 330 mg/m2 (SD = 140), respectively. More than 300 mg/m2 and 400 mg/m2 cumulative DOX was received by 50/80 (62%) and 33/80 (41%) of the CIV group and by 353/541 (65%) and 260/541 (48%) of the BOL group, respectively. Only 36 patients (5.8%) received dexrazoxane as cardioprotectant, all in the BOL group.

AEs by mode of DOX administration

The occurrence of grade 3–5 hematologic, non-hematologic, and cardiac AEs did not statistically differ with regard to manner of administration (Table 2). In univariable logistic regression, patient age and performance status were the only baseline characteristics associated with grade 3–5 hematologic AEs (Supplementary Table S1). The cumulative doses of either DOX or EVO were also associated with hematologic AEs. In a multivariable logistic regression model assessing impact of mode of DOX delivery and including as covariates age, baseline performance status, receipt of prior radiotherapy, cumulative DOX dose, and cumulative EVO dose, only age, performance status and cumulative DOX dose remained statistically significant; the manner of DOX delivery was not significantly associated with grade 3–5 hematologic AEs (Table 3).

Table 2.

Grade 3–5 AEs by mode of DOX administration.

BOL # (%)CIV # (%)
(n = 541)(n = 80)P
Hematologic   0.55 
 No 234 (43) 38 (48)  
 Yes 307 (57) 42 (52)  
Non-hematologic   0.72 
 No 238 (44) 37 (46)  
 Yes 303 (56) 43 (54)  
Cardiac   1.00 
 No 381 (70) 57 (71)  
 Yes 48 (9) 7 (9)  
 Missing 112 (21) 16 (20)  
Cardiac AEs 
 ≥10% Decrease in LVEF and LVEF <55% 48 (8.9) 7 (8.8) >0.99 
 LVEF ≤45% 14 (2.6) 2 (2.5) 1.00 
 Decrease in LVEF ≥20% 9 (1.7) 1 (1.3) 1.00 
BOL # (%)CIV # (%)
(n = 541)(n = 80)P
Hematologic   0.55 
 No 234 (43) 38 (48)  
 Yes 307 (57) 42 (52)  
Non-hematologic   0.72 
 No 238 (44) 37 (46)  
 Yes 303 (56) 43 (54)  
Cardiac   1.00 
 No 381 (70) 57 (71)  
 Yes 48 (9) 7 (9)  
 Missing 112 (21) 16 (20)  
Cardiac AEs 
 ≥10% Decrease in LVEF and LVEF <55% 48 (8.9) 7 (8.8) >0.99 
 LVEF ≤45% 14 (2.6) 2 (2.5) 1.00 
 Decrease in LVEF ≥20% 9 (1.7) 1 (1.3) 1.00 
Table 3.

Multivariable logistic regression of factors associated with grade 3–5 AEs.

VariableOR (95% CI)P
Hematologic n = 620 
Age (per year) 1.03 (1.01–1.04) <0.001 
Baseline ECOG: 1/2 vs. 0 1.80 (1.28–2.52) <0.001 
Delivery: CIV vs. BOL 0.79 (0.49–1.30) 0.36 
Prior radiotherapy: yes vs. no 1.13 (0.80–1.60) 0.48 
EVO cumulative dosea 1.03 (0.98–1.07) 0.21 
DOX cumulative dosea 5.43 (1.50–19.60) 0.01 
Non-hematologic n = 620 
Age (per year) 1.02 (1.01–1.03) 0.004 
Baseline ECOG: 1/2 vs. 0 2.09 (1.49–2.93) <0.001 
Delivery: CIV vs. BOL 0.92 (0.56–1.49) 0.71 
Prior radiotherapy: yes vs. no 1.47 (1.04–2.07) 0.03 
EVO cumulative dosea 1.06 (1.01–1.11) 0.01 
DOX cumulative dosea 1.32 (0.37–4.74) 0.67 
Cardiac n = 620b 
Age (per year) 1.01 (0.98–1.03) 0.54 
Delivery: CIV vs. BOL 1.10 (0.43–2.47) 0.83 
Prior radiotherapy: yes vs. no 1.61 (0.91–2.85) 0.10 
EVO cumulative dosea 1.00 (1.00–1.00) 0.77 
DOX cumulative dosea 729 (40–22,286) <0.001 
Baseline LVEF 0.99 (0.94–1.04) 0.67 
Any use of ACEi, ARB, beta-blocker: yes vs. no 1.51 (0.83–2.76) 0.17 
VariableOR (95% CI)P
Hematologic n = 620 
Age (per year) 1.03 (1.01–1.04) <0.001 
Baseline ECOG: 1/2 vs. 0 1.80 (1.28–2.52) <0.001 
Delivery: CIV vs. BOL 0.79 (0.49–1.30) 0.36 
Prior radiotherapy: yes vs. no 1.13 (0.80–1.60) 0.48 
EVO cumulative dosea 1.03 (0.98–1.07) 0.21 
DOX cumulative dosea 5.43 (1.50–19.60) 0.01 
Non-hematologic n = 620 
Age (per year) 1.02 (1.01–1.03) 0.004 
Baseline ECOG: 1/2 vs. 0 2.09 (1.49–2.93) <0.001 
Delivery: CIV vs. BOL 0.92 (0.56–1.49) 0.71 
Prior radiotherapy: yes vs. no 1.47 (1.04–2.07) 0.03 
EVO cumulative dosea 1.06 (1.01–1.11) 0.01 
DOX cumulative dosea 1.32 (0.37–4.74) 0.67 
Cardiac n = 620b 
Age (per year) 1.01 (0.98–1.03) 0.54 
Delivery: CIV vs. BOL 1.10 (0.43–2.47) 0.83 
Prior radiotherapy: yes vs. no 1.61 (0.91–2.85) 0.10 
EVO cumulative dosea 1.00 (1.00–1.00) 0.77 
DOX cumulative dosea 729 (40–22,286) <0.001 
Baseline LVEF 0.99 (0.94–1.04) 0.67 
Any use of ACEi, ARB, beta-blocker: yes vs. no 1.51 (0.83–2.76) 0.17 

aChemotherapy dosing was coded in g/m2 cumulative dose.

bMissing values coded as no cardiac AEs.

Baseline characteristics associated with grade 3–5 non-hematologic AEs included age, baseline performance status [Eastern Cooperative Oncology Group (ECOG) 1/2 vs. 0], and histologic subtype (Supplementary Table S2). Classification of patients with pleomorphic sarcomas or malignant fibrous histiocytomas (MFH) was associated with a higher probability of non-hematologic AEs. Treatment factors associated with non-hematologic AEs included receipt of prior radiotherapy, treatment assignment to combination DOX/EVO therapy, and cumulative EVO dose. In a multivariable model that included these variables, cumulative DOX dose (included in the model due to its relationship to the subject of primary interest) and manner of DOX administration were not statistically associated with non-hematologic AEs (Table 3). Treatment group assignment was not included in the multivariable model due to collinearity with cumulative EVO dose received.

Neither the incidence of patients experiencing cardiac AEs (n = 48/8.9% BOL vs. n = 7/8.8% CIV; P = 1.00) nor the time-to-cardiac AE (log-rank P > 0.99) differed between the two DOX delivery groups (Table 2). Only two variables were significantly associated with cardiac AEs in univariable analyses: cumulative DOX dose (OR = 773; 95% CI, 32.1–18,595; P < 0.001) and any reported use of an ACEi (OR = 2.34; 95% CI, 1.26–4.21; P = 0.006; Supplementary Table S3).

In a multivariable logistic regression model, mode of DOX administration was not statistically associated with cardiac AEs (OR = 1.10; 95% CI, 0.43–2.47; P = 0.83; Table 3). Indeed, the only variable associated with cardiac AEs was cumulative DOX dose received (OR = 729; 95% CI, 40.0–22,286; P < 0.001). Any use of ACEi, ARB, or beta-blocker did not retain statistical significance in the multivariable model (OR = 1.51; 95% CI, 0.83–2.76; P = 0.17). There was also no statistically significant interaction between cumulative DOX dose and manner of DOX administration (P = 0.50).

Several sensitivity analyses were conducted with respect to cardiac AEs using the same adjustment variables. A complete case analysis was conducted to determine whether the results might have been affected by the assumption that patients did not experience a cardiac AE if they were missing a follow-up cardiac assessment (n = 493). The manner of DOX delivery was not significantly associated with cardiac AEs (OR = 1.10; 95% CI, 0.43–2.48; P = 0.83). Again, only the cumulative DOX dose (OR = 88.8; 95% CI, 3.83–3571; P = 0.009) was associated with cardiac AEs.

Because investigators had the option of using dexrazoxane as a cardio-protectant agent, the impact of such use on cardiac AEs was assessed by repeating the full analysis with the exclusion of the 36 cases receiving dexrazoxane (n = 585), all of whom were in the BOL group. The results are consistent with those above: mode of DOX delivery was not associated with cardiac AEs (OR = 1.08; 95% CI, 0.42–2.44; P = 0.86); cumulative DOX remained the only covariate statistically associated with cardiac AEs (OR = 1,035; 95% CI, 51.0–37,039; P < 0.001).

The effect of dexrazoxane in the BOL (n = 541) subpopulation was also assessed, adding dexrazoxane use as a covariate to the multivariable model described above. Dexrazoxane use was not associated with cardiac AEs (OR = 0.42; 95% CI, 0.07–1.47; P = 0.25); cumulative DOX dose remained associated with cardiac AEs (OR = 460; 95% CI, 21.7–17,386; P < 0.001). There were not, however, enough patients treated with dexrazoxane to provide adequate statistical power to detect a difference in cardiac AEs with respect to this variable.

The analysis was also repeated limiting the population to those who had received at least 300 mg/m2 (n = 403) or 400 mg/m2 (n = 293) cumulative DOX, as higher doses of this drug are associated with cardiac AEs/toxicity. In both of these analyses, none of the adjustment variables was associated with cardiac AEs, including cumulative DOX dose. CIV DOX administration remained unassociated with cardiac AEs (OR = 1.35; 95% CI, 0.52–3.14; P = 0.50 and OR = 1.26; 95% CI, 0.40–3.38; P = 0.57, respectively).

Efficacy outcomes by mode of DOX administration

There was no difference in PFS (CIV median PFS = 6.11 months, BOL median PFS = 6.14 months; P = 0.47; Fig. 1) or OS (CIV median OS = 21.4 months, BOL median OS = 18.4 months; P = 0.62; Fig. 2) when segregating patients by mode of DOX administration. In univariable Cox analyses, performance status, and histologic grade were associated with PFS (Supplementary Table S4). In multivariable Cox analysis that included age, baseline performance status, histologic grade, treatment arm, and mode of DOX administration as the variable of interest, the mode of DOX administration was not significantly associated with PFS (HR = 0.91; 95% CI, 0.69–1.21; P = 0.527; Table 4).

Figure 1.

Kaplan–Meier analysis of PFS by mode of DOX administration. mPFS, median PFS.

Figure 1.

Kaplan–Meier analysis of PFS by mode of DOX administration. mPFS, median PFS.

Close modal
Figure 2.

Kaplan–Meier analysis of OS by mode of DOX administration. mOS, median OS.

Figure 2.

Kaplan–Meier analysis of OS by mode of DOX administration. mOS, median OS.

Close modal
Table 4.

Multivariable regression analyses of efficacy outcomes.

VariableHR (95% CI)P
PFS 
Age (per year) 0.99 (0.99–1) 0.114 
Mode of DOX delivery 
 CIV vs. BOL 0.91 (0.69–1.21) 0.527 
Treatment arm 
 DOX+EVO vs. DOX 0.83 (0.68–1.00) 0.055 
Baseline ECOG 
 1 or 2 vs. 0 1.39 (1.14–1.69) 0.001 
Highest histologic grade 
 High vs. other 1.32 (1.07–1.62) 0.009 
OS 
Age (per year) 1.00 (1.00–1.01) 0.24 
Mode of DOX delivery 
 CIV vs. BOL 0.88 (0.66–1.18) 0.403 
Treatment arm 
 DOX+EVO vs. DOX 1.07 (0.88–1.30) 0.51 
Baseline ECOG 
 1 or 2 vs. 0 1.97 (1.62–2.40) <0.001 
Highest histologic grade 
 High vs. other 1.31 (1.07–1.62) 0.01 
Objective responses (PR+CR) 
Variable OR (95% CI) P 
Mode of DOX delivery 
 CIV vs. BOL 0.93 (0.52–1.67) 0.812 
Treatment arm 
 DOX+EVO vs. DOX 1.73 (1.19–2.53) 0.004 
Prior radiotherapy 
 Yes vs. no 1.69 (1.15–2.47) 0.007 
VariableHR (95% CI)P
PFS 
Age (per year) 0.99 (0.99–1) 0.114 
Mode of DOX delivery 
 CIV vs. BOL 0.91 (0.69–1.21) 0.527 
Treatment arm 
 DOX+EVO vs. DOX 0.83 (0.68–1.00) 0.055 
Baseline ECOG 
 1 or 2 vs. 0 1.39 (1.14–1.69) 0.001 
Highest histologic grade 
 High vs. other 1.32 (1.07–1.62) 0.009 
OS 
Age (per year) 1.00 (1.00–1.01) 0.24 
Mode of DOX delivery 
 CIV vs. BOL 0.88 (0.66–1.18) 0.403 
Treatment arm 
 DOX+EVO vs. DOX 1.07 (0.88–1.30) 0.51 
Baseline ECOG 
 1 or 2 vs. 0 1.97 (1.62–2.40) <0.001 
Highest histologic grade 
 High vs. other 1.31 (1.07–1.62) 0.01 
Objective responses (PR+CR) 
Variable OR (95% CI) P 
Mode of DOX delivery 
 CIV vs. BOL 0.93 (0.52–1.67) 0.812 
Treatment arm 
 DOX+EVO vs. DOX 1.73 (1.19–2.53) 0.004 
Prior radiotherapy 
 Yes vs. no 1.69 (1.15–2.47) 0.007 

Notes: 620 cases for Cox regression analyses of PFS and OS; 424 and 411 survival events, respectively. 621 cases included for logistic regression analysis of response.

Abbreviations: CR, complete response; PR, partial response.

For OS, univariable Cox regression identified age, baseline performance status, histologic subtype, and histologic grade as being associated with OS (Supplementary Table S5). Multivariable Cox regression with age, performance status, histologic grade, treatment arm, and mode of DOX administration as the variable of interest did not demonstrate a statistically significant association between mode of DOX administration and OS (HR = 0.88; 95% CI, 0.66–1.18; P = 0.403; Table 4).

Assignment to the DOX+EVO treatment arm was associated with an increased likelihood of an objective treatment response, as previously noted in the primary study report (Supplementary Table S6; ref. 3). Receipt of prior radiotherapy, and a pleomorphic sarcoma or MFH subtype were also associated with an increased likelihood of response. In multivariable analysis, mode of DOX delivery was not associated with an objective treatment response (OR = 0.93; 95% CI, 0.52–1.67; P = 0.812; Table 4).

The SARC021 protocol accommodated different practices that exist in DOX administration and employment of cardioprotective strategies (CIV vs. BOL; addition of dexrazoxane). This provided an opportunity to examine whether the manner of DOX administration affected either AEs or efficacy outcomes in the treatment of a large number of STS patients, using high-quality data from a registration trial. The results of this analysis do not provide a rationale for using DOX other than by BOL, with limits on cumulative DOX dosing currently employed in typical STS treatment, as implemented in the trial. AEs were associated with patient and treatment factors, notably cumulative chemotherapy doses. Efficacy measures were associated with tumor biology and host status.

Although derived from a randomized study, patients were not randomized with respect to DOX delivery. This was at the investigator's discretion. The rationale for choosing a particular method of administration in a given patient was not recorded, and thus could not be assessed. Lack of knowledge, or trust in, prior published literature, local norms of practice, adoption of alternate mitigation strategies (e.g., dexrazoxane, although not adopted to any great extent in SARC021), and patient/clinical convenience may have played a role.

EVO was a statistically significant covariate only in multivariable models describing non-hematologic AEs and objective responses. EVO dose was not associated with cardiac AEs. Cardiac AEs had not been noted in the antecedent phase I EVO monotherapy and phase I/II studies of EVO combined with DOX (21–23).

Serial cardiac assessments were planned, but not all patients received follow-up LVEF assessments. The proportion with missing cardiac assessment was essentially identical with respect to mode of DOX delivery [112 BOL (20.7%) vs. 16 CIV (20%); Table 2]. In the primary analysis, those without follow-up LVEF assessment were assumed not to have experienced a cardiac AE. A complete case analysis, excluding these 128 patients, yielded conclusions similar to the primary analysis.

Planned LVEF assessments for patients participating in SARC021 were after 4 cycles of DOX and at completion of DOX therapy (i.e., after 6 cycles of combined therapy, at most). Hematologic and non-hematologic AEs generally occur in relatively close proximity to treatment. In contrast, anthracycline-mediated cardiac toxicity may occur months, years, or even decades after treatment (24). As this trial was conducted in those with metastatic disease, generally considered incurable, cardiac AEs observed during treatment, or shortly thereafter, are likely to be most relevant. Our findings may be less relevant in populations receiving anthracycline therapy as part of neoadjuvant or adjuvant therapy, in which long-term survival or cure is a treatment objective.

The study population must be considered when generalizing the results. The age distribution, with a median of 59, was similar to the population of those with STS. On the other hand, the study primarily enrolled a Caucasian, non-Hispanic population. Other than smoking history, comorbidities that might predispose to anthracycline AEs were not captured. Frequencies of such comorbidities might differ substantially in other racial or ethnic populations. We cannot exclude different findings if this study were conducted in a demographically different population.

Cardiac AEs were observed among about 9% of those enrolled (Table 2), and were strongly associated with increasing DOX exposure, as would be predicted (7, 9, 10, 24). This provides validation for our analytic strategy. No statistically significant effect was associated with mode of DOX administration, either as a main effect, or as an interaction with cumulative DOX exposure. In addition, sensitivity analyses did not identify a subpopulation in which mode of DOX administration altered cardiac AEs. We cannot exclude a delayed effect of administration mode, outside of the study's observational window for AEs.

The major justification for CIV administration is to decrease cardiac toxicity of anthracyclines. This is at the cost of increased logistical complexity, evidenced by the prolonged median DOX administration times in SARC021 (30 hours CIV vs. 0.3 hours BOL). Use of CIV for DOX administration was supported by 4 randomized studies, published 1989–1991 (13, 14, 17, 18). These studies varied in their CIV infusion times (6, 48, 72, and 96 hours), DOX doses (both episodic and cumulative), diseases treated (breast, ovarian, STS), treatment objectives (adjuvant versus metastatic), sample sizes (44–240), prior cardiac history, prior anthracycline exposure, cardiac assessment methods, and definitions of cardiac AEs. For one trial, BOL epirubicin, rather than DOX, was compared with CIV DOX (15). A meta-analysis of these studies found that BOL administration was associated with increased clinical and subclinical cardiotoxicity (16). This led to a moderate strength recommendation for the use of CIV in American Society of Clinical Oncology Clinical Practice Guidelines (10).

Because of the size of SARC021, and the consistent effect reported in these prior studies, it seemed surprising that mode of DOX delivery was not associated with a reduction of cardiac AEs. However, three of the prior studies reported significantly larger cumulative DOX (median BOL 410–420 mg/m2; CIV 428–570 mg/m2) doses than SARC021 (median BOL 325 mg/m2; CIV 319 mg/m2), although cumulative DOX in the Zalupski study, most closely matching SARC021 in population and setting, was lower (median BOL 240 mg/m2; CIV 221 mg/m2; refs. 13, 15, 17, 18). All of these antecedent clinical trials permitted patients to exceed the 450 mg/m2 DOX dose limit imposed by the SARC021 protocol, if judged to be in patients’ best interest. SARC021 did not make this accommodation.

The study of Shapira and colleagues is notable (17). This randomized study compared the shortest assessed CIV of 6 hours (n = 30), versus BOL (n = 28), of 50 mg/m2 DOX per cycle. A planned assessment of LVEF was made at 300 mg/m2 cumulative DOX, equivalent to 4 cycles of conventional BOL dosing in SARC021 at 75 mg/m2 per cycle. At this time point, there was a dramatic difference between the two groups, with 13/28 (46%) in the BOL group demonstrating at least a 20% decrease in LVEF, versus none in the CIV group (see Shapira and colleagues, Fig. 1; ref. 17). Thus, approximately half of the BOL patients in the Shapira trial would have met criteria for experiencing a cardiac AE, according to only the strictest of the SARC021 criteria for cardiac AE, after receiving only 300 mg/m2 of DOX. In contrast, only 9% of patients in SARC021 met criteria for cardiac AE, of whom only 1.6% met the criterion requiring a 20% or greater decrease in LVEF (Table 2). It is not clear why the results for BOL-treated patients in the study of Shapira and colleagues diverged so markedly from the SARC021 experience. Parenthetically, the Shapira study demonstrated the most extreme effect when comparing CIV with BOL, among the four randomized studies included in meta-analysis of this issue, and may have had an outlier effect, potentially leading the meta-analysis to overestimate benefit from CIV (16).

Early studies of risk factors for DOX cardiomyopathy found a nonlinear relationship between cumulative DOX dose and development of cardiomyopathy (7, 8). While no threshold value for cardiomyopathy development was identified, a cut-off value for lifetime DOX of 550 mg/m2 was proposed on the basis of upward inflection of the dose response curve at this value. A limitation of dosing to 450 mg/m2 has generally been observed in BOL dosing, as was specified in this protocol (3).

In the Zalupski trial, median dose of DOX associated with cardiotoxicity was 480 mg/m2 BOL (range 60–625 mg/m2) and 411 mg/m2 CIV (range 189–615 mg/m2; ref. 13). In the Casper trial, higher proportions of BOL patients developed cardiotoxicity versus CIV only when DOX doses exceeded about 300 mg/m2 (18). It is possible that protective effects of CIV administration become evident at higher cumulative DOX doses than administered in SARC021. Again, this was not due to an inability to associate patient factors with cardiac AEs: cumulative DOX dose was clearly associated with cardiac AEs in SARC021.

Lack of an observed difference between the groups in SARC021 was also not due to use of dexrazoxane in the BOL group. This was employed only minimally [7% (n = 36) of BOL patients]. The international nature of the trial may have precluded some sites from obtaining this compound. Sensitivity analysis excluding patients treated with dexrazoxane yielded the same conclusions as the primary analysis: mode of DOX delivery was not associated with cardiac AEs.

Several recent analyses have suggested that dexrazoxane may allow administration of higher cumulative DOX doses, without compromising efficacy and with relatively low rates of cardiac toxicity (25, 26). In the ANNOUNCE trial, more aggressive dosing of DOX, up to 600 mg/m2, was preplanned. Dexrazoxane therapy was received in the majority of patients treated with more than 450 mg/m2 DOX. There did not appear to be excessive cardiac AEs among those receiving higher DOX doses. A prospective trial to assess the use of dexrazoxane at DOX initiation was preliminarily reported after an interim analysis of 33 patients, indicating no reduction in PFS when dexrazoxane was added, and a low rate of cardiac AEs, despite more aggressive DOX dosing (25). Final results of this trial are awaited. Dexrazoxane therefore may provide a means to supplant other cardioprotective measures in DOX treatment, although the results are currently preliminary (27).

Treatment with ACEi, ARB, or beta-blockers has been proposed as one approach to prevent anthracycline-associated cardiac toxicity (12). Information regarding receipt of these medications at any time during the study was available. In univariable analysis, receipt of an ACEi was associated with an increased risk of cardiac AE, and receipt of a beta-blocker was marginally associated with increased risk of cardiac AEs. In multivariable analysis, receipt of one of these classes of medications at any time was no longer statistically significant. The positive findings for ACEi therapy in univariable analysis may reflect their surrogacy for underlying cardiac morbidities that predispose to cardiac AEs. Our results did not suggest a protective effect from their use.

As noted above, randomized studies were conducted to assess the value of CIV versus BOL administration of DOX. This analysis does not question the results of those studies. It does however cast doubt on their relevance, in a setting where cumulative DOX administration is generally limited. Further randomized studies are unlikely, and also are perhaps not the best approach to investigating what is actually an issue with translation of findings from randomized experiments into the reality of everyday cancer treatment.

Other datasets can be examined to explore the question of mode of DOX delivery. For example, a study published by one the of the authors (LDC) using an insurance claims database was similarly unable to identify benefit from CIV administration of DOX in preventing cardiac AEs (28). The randomized study of Judson and colleagues, comparing DOX plus ifosfamide with DOX monotherapy, allowed DOX monotherapy to be administered by either BOL or CIV over 72 hours (2). The decision regarding which mode of administration was used had to be made at the level of treatment center, and prior to recruiting patients. The numbers treated in different ways and cardiac AEs are not indicated in the primary report, but could provide another dataset to investigate this question.

In conclusion, manner of DOX administration, whether by BOL or CIV, was not associated with efficacy or AEs, including cardiac AEs, in the SARC021 study. Only the cumulative dose of DOX was positively associated with cardiac AEs. CIV administration to prevent cardiac AEs may only be relevant at cumulative doses higher than the 450 mg/m2 limit imposed in SARC021.

Anthracyclines will likely continue as cornerstones of sarcoma therapy for the foreseeable future. Despite promising findings with respect to dexrazoxane, patients will continue to receive DOX for sarcoma treatment without dexrazoxane coadministration. This may occur, for example, if this drug is unavailable in the locality of treatment. BOL administration of DOX does not appear to impose a greater burden of AEs, including cardiac AEs, vis-à-vis CIV dosing, subject to the cumulative DOX dosing limitations of SARC021. The observation of cardiac AEs despite dosing limitations highlights the need for continued investigation of strategies to allow safer anthracycline administration.

L.D. Cranmer reports grants and personal fees from AADi Bioscience, Avacta, and Blueprint Medicines; grants from Merck, Trillium, Exelixis, Eli Lilly, Iterion, Gradalis, Philogen, AdvenChen, Boehringer Ingelheim, and CBA Pharma; and personal fees from Daiichi Sankyo and Regeneron outside the submitted work. K.V. Ballman reports grants from SARC during the conduct of the study, as well as personal fees from Mylan Pharmaceuticals, Johnson and Johnson, Sanofi, Takeda, Ariad, and Janssen Pharmaceuticals outside the submitted work; in addition, K.V. Ballman has a patent for Prostate Cancer Recurrence Predictor issued and with royalties paid. E.T. Loggers reports other support from Springworks, BioAtla, and Epizyme outside the submitted work. S.M. Pollack reports personal fees from AADi Bioscience, Springworks, Sensei, Bayer, Obsidian, Epizyme, Deciphera, and T-knife outside the submitted work. M.J. Wagner reports personal fees and other support from Adaptimmune and Deciphera; other support from Incyte, GSK, Athenex, Eli Lilly, Inhibrx, Foghorn, and Shasqi; and personal fees from Epizyme and AADi Bioscience outside the submitted work. D.K. Reinke reports grants from Threshold Pharmaceuticals during the conduct of the study. W.D. Tap reports other support from Threshold Pharmaceuticals during the conduct of the study, as well as personal fees from Eli Lilly, EMD Serono, Mundipharma, C4 Therapeutics, Daiichi Sankyo, Deciphera, Adcendo, Ayala, Kowa, Servier, Bayer, Epizyme, Cogent, Medpacto, Foghorn Therapeutics, Amgen, AmMax Bio, Boehringer Ingelheim, BioAtla, and Inhibrx outside the submitted work. W.D. Tap also reports scientific advisory board and stock ownership at Certis Oncology Solutions, cofounder and stock ownership at Atropos Therapeutics, and scientific advisory board at Innova Therapeutics; in addition, W.D. Tap has a patent for Companion Diagnostic for CDK4 Inhibitors - 14/854,329 pending to MSK/SKI and a patent for Enigma and CDH18 as Companion Diagnostics for CDK4 Inhibition – SKI2016-021-03 pending to MSK/SKI. No disclosures were reported by the other authors.

L.D. Cranmer: Conceptualization, formal analysis, supervision, methodology, writing–original draft, project administration, writing–review and editing, submission. Y. Lu: Resources, data curation, formal analysis, methodology, writing–original draft, project administration, writing–review and editing. R.S. Heise: Data curation, formal analysis, writing–review and editing. K.V. Ballman: Resources, data curation, formal analysis, supervision, methodology, writing–original draft, project administration, writing–review and editing. E.T. Loggers: Investigation, writing–original draft, writing–review and editing. S.M. Pollack: Conceptualization, investigation, writing–original draft, writing–review and editing. M.J. Wagner: Writing–original draft, writing–review and editing. D.K. Reinke: Conceptualization, resources, supervision, investigation, writing–original draft, project administration, writing–review and editing. P. Schöffski: Investigation, writing–original draft, writing–review and editing. W.D. Tap: Conceptualization, resources, investigation, writing–original draft, project administration, writing–review and editing.

Conduct of the SARC021/TH CR-406 trial was sponsored and funded by Threshold Pharmaceuticals.

We would like to thank the patients, their families and caregivers, the investigators and study teams, SARC, and the international network of sarcoma centers that participated in the original study.

Dr. Cranmer's work is supported, in part, by the Curt and Elizabeth Anderson Endowed Professorship in Sarcoma Research, and by funding from Jane and Steve Urner.

The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

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