Table 3.
Safety and Efficacy of Dexrazoxane in Clinical Studies
| First Author and Year of Publication | Population | Anthracycline Agent | Number of Subjects | Median Age (years) | Baseline CV Risk Factors | Dexrazoxane Administration Timing | Cardiotoxicity in Dexrazoxane Arm | Cardiotoxicity in Control Arm | Reduced anti-tumor efficacy | Incidence of Secondary Malignancy |
|---|---|---|---|---|---|---|---|---|---|---|
| Swain SM et al. 1997 [6] Prospective RCT, Dex vs. Placebo | Adult, Advanced breast cancer | Doxorubicin | 534 | 58 (study 088001) 56 (study 088006) | No difference between two groups | From the beginning of therapy | 15% (study 088001) 14% (study 088006) | 31% (study 088001) 31% (study 088006) | Lower response rate (14% difference) but no effect on overall time to progression or survival (study 088001) | Not evaluated |
| Swain SM et al. 1997 [7] Prospective RCT, Dex vs. Placebo | Adult, Advanced breast cancer | Doxorubicin | 201 | 57 | No difference between two groups | After a cumulative doxorubicin dose of 300 mg/m2 | 3% | 22% | No effect | Not evaluated |
| Rabinovich A et al. 2012 [34] Retrospective, comparing cancer outcomes in Dex vs. No-Dex | Adult, NHL | Doxorubicin | 193 | 70.35 | Dex group had more CV risk factors | 61.7% of the patients started dexrazoxane in the first or second chemotherapy cycle | Not evaluated | Not evaluated | No effect | Not evaluated |
| Limat S et al. 2014 [35] Retrospective, comparing two groups based on time of treatment (1994–2000 and 2001–2005) | Adult, NHL | Doxorubicin | 180 | 58 | No difference between two groups | From the beginning of therapy (Note: Only 45% patients in 2001–05 group received Dex) | 17% | 1.5% | Not evaluated | Not evaluated |
|
Vachhani P et al. 2017 [36] Retrospective, consecutive patients with AML treated with Dex, baseline LVEF 40–50% |
Adult, AML | Daunorubicin or Mitoxantrone | 6 | 61.5 | No control group | 50% (3/6) had Dex from the beginning of therapy. The rest 3 had Dex after median of 340 mg/m2 anthracycline | 16.67% (1/6 patients) | No control arm | Not evaluated | Not evaluated |
| Lopez M et al. 1998 [38] Prospective RCT, Dex vs. No Dex | Adult, Advanced breast cancer or soft tissue sarcoma | Epirubicin | Breast cancer – 95 Sarcoma - 34 | Breast cancer −58 Sarcoma - 51 | Not mentioned in the study. Dose of epirubicin was higher in Dex arm | From the beginning of therapy | 4.1% | 20.8% | No effect | Not evaluated |
|
Schuler MK et al. 2016 [39] Retrospective, Dex given for one of the following reasons: 1. Re-challenge, 2. Reaching the cumulative anthracycline dose and 3. Preexisting heart failure |
Adult, Sarcoma | Doxorubicin | 32 | 54 | No control group | 27/32 patients received Dex after a median dose of 450 mg/m2 of doxorubicin 5/32 patients received Dex from the beginning of therapy (Given baseline elevated cardiac risk – CHF, CAD or arrhythmia) | 7% | No control arm | Not evaluated | Not evaluated |
| Lipshultz SE et al. 2004 [3] Prospective RCT, Dex vs. No Dex | Children, Previously untreated high-risk ALL | Doxorubicin | 206 | 7.5 | Not mentioned in the study but median cumulative dose of doxorubicin was same in both groups | From the beginning of therapy | 21% (elevated cTnT) 10% (Extremely elevated cTnT level) | 50% (elevated cTnT 32% (Extremely elevated cTnT level) | No effect | Not evaluated |
| Chow EJ at al. 2015 [40] Long term follow-up (median 12.6 years) of 3 prospective RCT patients to evaluate effect of Dex on long-term survival | Children, (T-cell acute lymphoblastic leukemia/ lymphoma, intermediate/ high-risk Hodgkin lymphoma, and low-risk Hodgkin lymphoma) | Doxorubicin | 1008 | 12.6 | Not mentioned in the study but median cumulative dose of doxorubicin was same in both groups in each trial | From the beginning of therapy | Not reported in the study but no difference in CV mortality | Not reported in the study but no difference in CV mortality | No effect | No effect |
| Asselin BL et al. 2016 [41] Prospective RCT, Dex vs. No Dex | Children, T-ALL or L-NHL | Doxorubicin | 537 | 9.8 | Not mentioned in the study but median cumulative dose of doxorubicin was same in both groups | From the beginning of therapy | Acute cardiotoxicity: 1 patient Elevated cTnT: 2.4% z scores for LV fractional shortening (3 years): −0.05 (normal) | Acute cardiotoxicity: 4 patient Elevated cTnT: 8.8% z scores for LV fractional shortening (3 years): − 0.77 (abnormal) | No effect | No effect |
| Tebbi CK et al. 2007 [8] Prospective RCT, Dex vs. No Dex | Children, Hodgkin’s disease treated with ABVE or dose-intensified ABVE-PC followed by low-dose radiation | Doxorubicin | 478 | 12.9 | Not reported | From the beginning of therapy | Not reported | Not reported | No effect | 8/10 patients with secondary malignancy in Dex arm. Standardized incidence rate was 41.86 with Dex versus 10.08 without Dex (P = 0.0231) |
| Shaikh F et al. 2016 [9] Meta-analysis of 17 studies (5 RCT and 12 NRSs to evaluate effects of Dex for cardioprotection and secondary malignancy | Children, Variety of hematological and solid malignancies | Multiple agents (predominantly doxorubicin) | 4639 | Variable among studies (< 18) | Not reported | All but one NRS administered Dex from the beginning of anthracycline therapy | Dex reduced clinical or subclinical cardiotoxicity among RCTs (RR = 0.29, P = .003, NNT = 41) and NRSs (RR = 0.43, P < .001, NNT = 7) | No control arm | No effect | RCT: Dex: 2.7% No Dex: 1.1% (RR = 2.37, P = .06). Two RCTs that used concurrent etoposide reported an increased risk of AML, while one that used cranial radiation reported an increased risk of brain tumors. NRSs: No effect |
| Kim H et al. 2018 [42] Retrospective, Dex vs. No Dex | Children, Variety of hematological and solid malignancies | Multiple agents (predominantly doxorubicin) | 1453 | 6 | Not reported but anthracycline dose was higher in Dex arm (210 mg/m2 in Dex arm vs. 150 mg/m2 in No Dex arm, p < 0.01) | From the beginning of therapy | Cardiac event-free survival rate of patients with more than 400 mg/m2 of anthracyclines was significantly higher in Dex group | No control arm | Not evaluated | No effect |
| Getz KD et al. 2018 [43] Prospective, Comparing various treatments in children with AML, Dex given as per descrition of treating physician | Children, AML | Daunorubicin | 1014 (only 96 had Dex) | Not reported in abstract | Not reported | From the beginning of therapy | Less declines in EF (∆EF: 0 to −4.0) Early LVSD – 6.3% | More significant decline in EF (∆EF: 0 to −6.4; p < 0.05) Early LVSD – 19.2% (p = 0.005) | Dex arm had non-significantly higher 3-year OS (71.9% vs 63.0%, p = 0.093) and EFS (54.4% vs 44.2%, p = 0.070) | Not evaluated |
ABVE Adriamycin (doxorubicin), bleomycin, vincristine, etoposide, ABVE-PC Adriamycin (doxorubicin), bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide, AML acute myeloid leukemia, ALL acute lymphoblastic leukemia, cTn cardiac troponin, CV cardiovascular, Dex dexrazoxane, NHL non-Hodgkin’s lymphoma, LVEF left ventricular ejection fraction, LVSD left ventricular systolic dyscuntion, NRS non-randomized study, RCT randomized control trial