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Table 2.

Cardiac events and rules for starting, holding, and discontinuing trastuzumab in four adjuvant trials

TrialNo. patientsEvents and no. patientsRule for starting HRule for holding HLVEF evaluation
NSABP B-31      
Cardiac safety analysis at 3-y follow-up (61, 65) Total = 1,664; AC-T arm = 814; AC-TH arm = 850 Asymptomatic decrease in LVEF requiring suspension of H*: data for control arm = NA; H arm = 102 (14%) Free of cardiac symptoms during AC, post-AC LVEF ≥ LLN, and absolute decline ≤15% LVEF declines of 10% to 15% and below LLN or ≥15% absolute fall in LVEF by MUGA 0, 3, 6, 9, 18 mo by MUGA 
  Cardiac events: control arm = 5 (0.8%); H arm = 31 (4.1%) Hazard ratio = 5.1   
  Cardiac deaths: control arm = 1; H arm = 0    
  CHF: control arm = 4; H arm = 31    
Cardiac safety analysis at 5-y follow-up (66) Total = 1845; AC-T arm = 898; AC-TH = 947 Cardiac events: control arm = 6 (0.9%); H arm = 35 (3.8%) Hazard ratio = 6.6   
  Cardiac deaths: control arm = 1; H arm = 0    
  CHF: control arm = 5; H arm = 35    
N-9831 Initial 3-y follow-up (61, 68) 3 y Total = 1967; AC-T arm = 670; AC-T-H arm = 718; AC-TH arm = 579 Asymptomatic decrease in LVEF requiring suspension of H§: control arm = NA; AC-T-Hb arm = 57 (10.8%); AC-TH arm = NA Free of cardiac symptoms during AC and post-AC LVEF ≥ LLN and absolute decline ≤15% LVEF < LLN or 15% absolute fall in LVEF 0, 3, 6, 9, 18 mo by MUGA or ECHO 
  Cardiac events: control arm = 2 (0.3%); AC-T-H arm = 17 (2.5%); AC-TH arm = 20 (3.5%)    
  CHF: control arm = 1; AC-T-H arm = 16; AC-TH arm = 20    
  Cardiac deaths: control arm = 1; AC-T-H arm = 1; AC-TH arm = 0    
Updated 3 y follow-up (67) AC-T arm = 767; AC-TH arm = 875 Updated 3 y follow-up;    
  Cardiac events: control arm = 2 (0.2%), AC-TH arm = 22 (2.5%)    
HERA(62, 69), 2-y follow-up, postadjuvant chemo at discretion of investigator Total = 3387; observation = 1708; 1-y H = 1678 Decrease in LVEF: control arm = 9 (0.5%); H arm = 51 (3.0%) LVEF ≥ 55% after all chemo and radiotherapy LVEF <45% or LVEF <50% and fall >10% 0, 3, 6, 12, 18, 24, 36 mo by MUGA or ECHO 
  Symptomatic CHF**, including severe CHF††: control arm = 2 (0.1%); H arm = 36 (2.0%)    
  Severe CHF††: control arm = 0; H arm = 10 (0.6)    
  Cardiac deaths‡‡: control arm = 1 (0.1%); H arm = 0    
BCIRG 006 (70), 23-mo follow-up Total = 3174; AC-D arm = 1050; AC-DH arm = 1068; DC*H arm = 1056 Cardiac events§§; control arm = 10 (0.95%); AC-T^H arm = 25; T^C*H arm = 14   0, 3, 6, 9, 18 mo by MUGA or ECHO 
  Cardiac deaths: none in any arm    
  CHF: control arm = 3 (0.3%); AC-T^H arm = 17; T^C*H arm = 4    
  Ischemia/infarction: control arm = 0; AC-T^H arm = 4; T^C*H arm = 1    
  Arrhythmias: control arm = 7 (0.7%); AC-T^H arm = 4; T^C*H arm = 9    
  Decline in LVEF >10%: control arm = 91 (9%); AC-T^H arm = 180 (9%); T^C*H arm = 82    
FinHeR (64), 3-y follow-up Total = 232 Decline in LVEF >10%: control arm = 0; H arm = 3 (2.6%)   Pre-chemo, post-FEC and at 12 and 36 mo after chemo by ECHO or MUGA 
  Decline in LVEF<50% or LVEF 15% less than baseline: control arm = 7 (6.0%); H arm = 4 (3.5%)    
  Cardiac infarction: control arm = 1 (0.86%); H arm = 0    
  Cardiac failure: control arm = 3 (2.6); H arm = 0    
TrialNo. patientsEvents and no. patientsRule for starting HRule for holding HLVEF evaluation
NSABP B-31      
Cardiac safety analysis at 3-y follow-up (61, 65) Total = 1,664; AC-T arm = 814; AC-TH arm = 850 Asymptomatic decrease in LVEF requiring suspension of H*: data for control arm = NA; H arm = 102 (14%) Free of cardiac symptoms during AC, post-AC LVEF ≥ LLN, and absolute decline ≤15% LVEF declines of 10% to 15% and below LLN or ≥15% absolute fall in LVEF by MUGA 0, 3, 6, 9, 18 mo by MUGA 
  Cardiac events: control arm = 5 (0.8%); H arm = 31 (4.1%) Hazard ratio = 5.1   
  Cardiac deaths: control arm = 1; H arm = 0    
  CHF: control arm = 4; H arm = 31    
Cardiac safety analysis at 5-y follow-up (66) Total = 1845; AC-T arm = 898; AC-TH = 947 Cardiac events: control arm = 6 (0.9%); H arm = 35 (3.8%) Hazard ratio = 6.6   
  Cardiac deaths: control arm = 1; H arm = 0    
  CHF: control arm = 5; H arm = 35    
N-9831 Initial 3-y follow-up (61, 68) 3 y Total = 1967; AC-T arm = 670; AC-T-H arm = 718; AC-TH arm = 579 Asymptomatic decrease in LVEF requiring suspension of H§: control arm = NA; AC-T-Hb arm = 57 (10.8%); AC-TH arm = NA Free of cardiac symptoms during AC and post-AC LVEF ≥ LLN and absolute decline ≤15% LVEF < LLN or 15% absolute fall in LVEF 0, 3, 6, 9, 18 mo by MUGA or ECHO 
  Cardiac events: control arm = 2 (0.3%); AC-T-H arm = 17 (2.5%); AC-TH arm = 20 (3.5%)    
  CHF: control arm = 1; AC-T-H arm = 16; AC-TH arm = 20    
  Cardiac deaths: control arm = 1; AC-T-H arm = 1; AC-TH arm = 0    
Updated 3 y follow-up (67) AC-T arm = 767; AC-TH arm = 875 Updated 3 y follow-up;    
  Cardiac events: control arm = 2 (0.2%), AC-TH arm = 22 (2.5%)    
HERA(62, 69), 2-y follow-up, postadjuvant chemo at discretion of investigator Total = 3387; observation = 1708; 1-y H = 1678 Decrease in LVEF: control arm = 9 (0.5%); H arm = 51 (3.0%) LVEF ≥ 55% after all chemo and radiotherapy LVEF <45% or LVEF <50% and fall >10% 0, 3, 6, 12, 18, 24, 36 mo by MUGA or ECHO 
  Symptomatic CHF**, including severe CHF††: control arm = 2 (0.1%); H arm = 36 (2.0%)    
  Severe CHF††: control arm = 0; H arm = 10 (0.6)    
  Cardiac deaths‡‡: control arm = 1 (0.1%); H arm = 0    
BCIRG 006 (70), 23-mo follow-up Total = 3174; AC-D arm = 1050; AC-DH arm = 1068; DC*H arm = 1056 Cardiac events§§; control arm = 10 (0.95%); AC-T^H arm = 25; T^C*H arm = 14   0, 3, 6, 9, 18 mo by MUGA or ECHO 
  Cardiac deaths: none in any arm    
  CHF: control arm = 3 (0.3%); AC-T^H arm = 17; T^C*H arm = 4    
  Ischemia/infarction: control arm = 0; AC-T^H arm = 4; T^C*H arm = 1    
  Arrhythmias: control arm = 7 (0.7%); AC-T^H arm = 4; T^C*H arm = 9    
  Decline in LVEF >10%: control arm = 91 (9%); AC-T^H arm = 180 (9%); T^C*H arm = 82    
FinHeR (64), 3-y follow-up Total = 232 Decline in LVEF >10%: control arm = 0; H arm = 3 (2.6%)   Pre-chemo, post-FEC and at 12 and 36 mo after chemo by ECHO or MUGA 
  Decline in LVEF<50% or LVEF 15% less than baseline: control arm = 7 (6.0%); H arm = 4 (3.5%)    
  Cardiac infarction: control arm = 1 (0.86%); H arm = 0    
  Cardiac failure: control arm = 3 (2.6); H arm = 0    

NOTE: All trials used the National Cancer Institute's Clinical toxicity criteria version 2.0 except NSABP trial B-31 (65), which used Cardiac Review and Evaluation Committee toxicity criteria (5).

Abbreviations: A, doxorubicin; C, cyclophosphamide; C*, carboplatin; H, trastuzumab; T, paclitaxel; D, docetaxel; CE, cardiac event; HERA, Herceptin Adjuvant trial; FEC, 5-flurouracil, epirubicin, and cyclophosphamide; NA, not available; chemo, chemotherapy.

*

A decrease in LVEF of <10% and ≥6% less than the LLN or of 10% to 15% and less than the LLN or of ≥15%.

Repeat MUGA after 4 wk. If two consecutive holds or total of three holds occur, discontinue trastuzumab treatment.

NYHA class III or class IV symptoms with absolute LVEF decrease of ≥10% to ≤55% or a decrease of >5% to less than the LLN.

§

LVEF decrease of ≥15% or of <15% and less than the LLN.

Patients enrolled before April 25, 2004, with satisfactory post-AC LVEF and completed paclitaxel (n = 528).

Absolute decrease of ≥10% to an LVEF of <50%.

**

CHF was considered symptomatic by a cardiologist and decrease in LVEF of ≥10% to <50%.

††

NYHA functional class III or class IV confirmed by cardiologist and decrease in LVEF ≥10% to <50%.

‡‡

Death due to CHF, cardiac infarction, documented primary arrhythmia, sudden unexpected death within 24 h of a definite or probable cardiac event.

§§

Clinically significant cardiac events as per independent review panel; Cardiac death or grade 3 or grade 4 toxicities (CHF, cardiac ischemia, cardiac infarction, arrhythmias).

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