Diferentes esquemas de dosis para la reducción de la cardiotoxicidad en pacientes con cáncer que reciben quimioterapia con antraciclina
References
Referencias de los estudios incluidos en esta revisión
Referencias de los estudios excluidos de esta revisión
Referencias de los estudios en espera de evaluación
Referencias adicionales
Referencias de otras versiones publicadas de esta revisión
Characteristics of studies
Characteristics of included studies [ordered by study ID]
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| Study characteristics | ||
| Methods | Method of randomisation not clear (stratified according to the type of primary surgery (mastectomy or lumpectomy), number of involved axillary lymph nodes (1 to 3, 4 to 9, or 10 or more), menopausal status (premenopausal or perimenopausal/postmenopausal), and estrogen receptor status (negative or positive)) | |
| Participants | 1032 women (median age 48 and 49 years in the peak dose 60 mg/m2 and 40 mg/m2 respectively) with unilateral stage II adenocarcinoma of the breast (T1N1M0/T2N1M0) treated with doxorubicin, cyclophosphamide, and 5‐fluorouracil. Also, if a lumpectomy was performed, women received radiotherapy of the entire breast (5040 cGy and a 1504 cGy boost on the area of the excision); mastectomy participants received no irradiation (the majority of women in both groups received a mastectomy, but exact numbers nm; location of the tumour nm). No prior anthracycline therapy; no prior cardiac radiotherapy; no prior cardiac dysfunction | |
| Interventions | Doxorubicin (infusion duration nm) with a peak dose of either 60 mg/m2 (N = 519; cumulative anthracycline dose nm; the planned cumulative dose was 240 mg/m2) or 40 mg/m2 (N = 513; cumulative anthracycline dose nm; the planned cumulative dose was 240 mg/m2) | |
| Outcomes | Heart failure (i.e. clinical heart failure defined as CALGB grade 3 to 5) OS (defined as time from study entry to death from any cause) Adverse effects other than cardiac damage (according to CALGB criteria) | |
| Notes | Some of the data presented in this table were obtained from an earlier article describing this study (Wood 1994). This article was excluded from the original version of the review because it was unknown if women in both treatment groups received the same cumulative anthracycline dose. In Budman 1998 it was stated that both treatment regimens delivered the same cumulative dose (even though the exact cumulative anthracycline dose is still not documented). There was a third treatment group in this study, i.e. a doxorubicin peak dose of 30 mg/m2. However, women in this group were excluded from this review because the cumulative doses of doxorubicin, cyclophosphamide, and 5‐fluorouracil were lower than the other treatment groups. Length of follow‐up nm (including the women in the third treatment group who were excluded from this review, the median follow‐up was 9 years; range 3.5 to 12.8 years). The study was supported in part by different Public Health Service grants from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, but no information on the influence of funders was provided. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | It was stated that this was a randomised study, but no further information on the methods of randomisation was provided |
| Allocation concealment (selection bias) | Unclear risk | It was stated that this was a randomised study, but no further information on the methods of randomisation was provided |
| Blinding of participants and personnel (performance bias) | Unclear risk | No information on blinding of participants and personnel was provided, although due to the nature of the interventions, this was most likely not the case |
| Blinding of outcome assessment (detection bias): clinical heart failure | Unclear risk | No information on blinding of outcome assessors was provided for clinical heart failure |
| Blinding of outcome assessment (detection bias): overall survival | Low risk | No information on blinding of outcome assessors was provided, but since this is not applicable for overall survival, we judged this as a low risk of bias. |
| Blinding of outcome assessment (detection bias): adverse effects other than cardiac damage | Unclear risk | No information on blinding of outcome assessors was provided for adverse effects other than cardiac damage |
| Incomplete outcome data (attrition bias): clinical heart failure | Low risk | Almost all women (99.1%) were included in the analysis of clinical heart failure |
| Incomplete outcome data (attrition bias): overall survival | Unclear risk | Not documented how many women were included in the analysis of overall survival |
| Incomplete outcome data (attrition bias): adverse effects other than cardiac damage | Unclear risk | Not documented how many women were included in the analysis of adverse effects other than cardiac damage |
| Selective reporting (reporting bias) | Low risk | There was no reference to a protocol provided in the manuscript (and we did not search for it), but all expected outcomes were reported |
| Other bias | Unclear risk | Baseline imbalance between treatment arms related to outcome (prior cardiotoxic treatment, age, sex, and/or prior cardiac dysfunction): no (all items were balanced between treatment groups) Difference in length of follow‐up between treatment arms: unclear (not reported) |
| Study characteristics | ||
| Methods | Method of randomisation not clear (stratified according to presence or absence of microscopically positive margins) | |
| Participants | 82 participants (aged 18 to 87 years; 39 women and 44 men) with high‐grade non‐metastatic soft tissue sarcoma treated with doxorubicin. No prior anthracycline therapy; prior cardiac radiotherapy possible for 2 participants in the bolus group and 3 participants in the continuous infusion group; no prior cardiac dysfunction | |
| Interventions | Doxorubicin (peak dose 60 mg/m2) every 3 weeks for a total of 9 cycles with either bolus (5 to 10 min) infusion (N = 39; median cumulative dose 420 mg/m2; range 60 to 540 mg/m2) or continuous infusion (72 h) (N = 43; median cumulative dose nm; range 120 to 540 mg/m2) | |
| Outcomes | Heart failure (i.e. clinical heart failure defined as congestive heart failure; subclinical heart failure defined as a 10% or more decrease in LVEF at rest as measured by radionuclide cineangiograms) OS (definition nm) | |
| Notes | One participant randomised to bolus therapy actually received the drug by continuous infusion. We performed an intention‐to‐treat analysis, but the data presented in this table are for 38 participants in the bolus and 44 participants in the continuous infusion group. One participant in the bolus group and 3 participants in the continuous infusion group never received treatment Length of follow‐up nm The study was supported by a grant from the National Institutes of Health, but no information on the influence of funders was provided | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | It was stated that this was a randomised study, but no further information on the methods of randomisation was provided |
| Allocation concealment (selection bias) | Unclear risk | It was stated that this was a randomised study, but no further information on the methods of randomisation was provided |
| Blinding of participants and personnel (performance bias) | Unclear risk | No information on blinding of participants and personnel was provided, although due to the nature of the interventions, this was most likely not the case |
| Blinding of outcome assessment (detection bias): clinical heart failure | Unclear risk | No information on blinding of outcome assessors was provided for clinical heart failure. |
| Blinding of outcome assessment (detection bias): subclinical heart failure (dichotomous and/or continuous) | Unclear risk | No information on blinding of outcome assessors was provided for subclinical heart failure |
| Blinding of outcome assessment (detection bias): overall survival | Low risk | No information on blinding of outcome assessors was provided, but since this is not applicable for overall survival, we judged this as a low risk of bias |
| Incomplete outcome data (attrition bias): clinical heart failure | Unclear risk | Not documented how many participants were included in the analysis of clinical heart failure |
| Incomplete outcome data (attrition bias): subclinical heart failure (dichotomous and/or continuous) | High risk | Only 84.1% of participants were included in the analysis |
| Incomplete outcome data (attrition bias): overall survival | Low risk | All participants were included in the analysis |
| Selective reporting (reporting bias) | Low risk | There was no reference to a protocol provided in the manuscript (and we did not search for it), but all expected outcomes were reported |
| Other bias | Unclear risk | Baseline imbalance between treatment arms related to outcome (prior cardiotoxic treatment, age, sex, and/or prior cardiac dysfunction): unclear (unclear if prior cardiotoxic treatment was balanced between treatment groups; all other items were balanced between treatment groups) Difference in length of follow‐up between treatment arms: unclear (not reported) |
| Study characteristics | ||
| Methods | Method of randomisation not clear (stratified according to white blood cell count < 25/nl or >= 25/nl) | |
| Participants | 178 children (of which 101 children were evaluable; these evaluable children were aged 1.1 to 17.9 years; 60 boys and 41 girls) with low‐ or high‐risk B‐precursor ALL or T‐ALL treated with a multidrug regimen including daunorubicin. No prior anthracycline therapy; no prior cardiac radiotherapy; prior cardiac dysfunction nm. | |
| Interventions | Daunorubicin (peak dose 36 mg/m2) on day 1 with either bolus (1 hour) infusion (N = 85; cumulative anthracycline dose 36 mg/m2 on day 7; see notes) or continuous (24 hours) infusion (N = 93; cumulative anthracycline dose 36 mg/m2 on day 7; see notes) | |
| Outcomes | Heart failure (i.e. clinical heart failure defined as clinical signs of cardiac insufficiency; subclinical heart failure defined as LVSF < 25%) Response rate (i.e. good response defined as an absolute blast cell count < 1000/µl at day 7) | |
| Notes | Only 101 of the 178 children were evaluable for in‐vivo cell kill; the other 77 children (42 in the 1‐hour infusion group and 35 in the 24‐hours infusion group) had incomplete data or insufficient smears. However, we performed an intention‐to‐treat analysis. After the first daunorubicin administration, all children received additional daunorubicin with an infusion duration of 1 hour. Therefore, only data for the first 7 days are eligible for this review. Length of follow‐up 7 days. The study was supported in part by Fördergemeinschaft Kinderkrebszentrum Hamburg e.V. and Elterninitiative Kinderkrebsklinik Düsseldorf e.V., but no information on the influence of funders was provided. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | It was stated that this was a randomised study, but no further information on the methods of randomisation was provided |
| Allocation concealment (selection bias) | Unclear risk | It was stated that this was a randomised study, but no further information on the methods of randomisation was provided |
| Blinding of participants and personnel (performance bias) | Unclear risk | No information on blinding of participants and personnel was provided, although due to the nature of the interventions, this was most likely not the case |
| Blinding of outcome assessment (detection bias): clinical heart failure | Unclear risk | No information on blinding of outcome assessors was provided for clinical heart failure |
| Blinding of outcome assessment (detection bias): subclinical heart failure (dichotomous and/or continuous) | Unclear risk | No information on blinding of outcome assessors was provided for subclinical heart failure |
| Blinding of outcome assessment (detection bias): tumour response | Unclear risk | No information on blinding of outcome assessors was provided for tumour response |
| Incomplete outcome data (attrition bias): clinical heart failure | High risk | 43% of children lost to follow‐up |
| Incomplete outcome data (attrition bias): subclinical heart failure (dichotomous and/or continuous) | High risk | 43% of children lost to follow‐up |
| Incomplete outcome data (attrition bias): tumour response | High risk | 43% of children lost to follow‐up |
| Selective reporting (reporting bias) | High risk | There was no reference to a protocol provided in the manuscript (and we did not search for it), but not all expected outcomes were reported in a useful manner |
| Other bias | Unclear risk | Baseline imbalance between treatment arms related to outcome (prior cardiotoxic treatment, age, sex, and/or prior cardiac dysfunction): unclear (unclear if prior cardiac dysfunction was balanced between treatment groups; the other items were balanced between treatment groups) Difference in length of follow‐up between treatment arms: no |
| Study characteristics | ||
| Methods | Randomisations were performed at the HeCOG Data Office (balanced by centre and stratified according to menopausal status (premenopausal versus postmenopausal), hormonal receptor status (positive versus negative), and number of positive nodes (1 to 3 versus 4 or more) | |
| Participants | 1086 women (aged 22 to 79 years) with non‐metastatic node‐positive epithelial breast cancer (T1‐4/N1‐2/M0) treated with epirubicin, paclitaxel, cyclophosphamide, methotrexate, and fluorouracil. Also, radiotherapy was mandatory for all women with breast‐conserving surgery (35% of women in both treatment groups) or for those with 4 or more positive lymph nodes (52% of women in the high peak dose group and 51% of women in the low peak dose group), and/or tumour size 5 cm or larger (irrespective of the initial operation type; 11% of women in both treatment groups). Radiation dose was 50 to 55 Gy on the entire breast or chest wall followed by a 10 to 15 Gy boost on the area where the tumour was initially located (Fountzilas 2005). Location of the tumour was nm. Prior anthracycline therapy nm; prior cardiac radiotherapy nm; no prior cardiac dysfunction | |
| Interventions | Epirubicin (infusion duration nm) with a peak dose of either 110 mg/m2 (N = 551; cumulative anthracycline dose nm; the planned cumulative dose was 330 mg/m2) or 83 mg/m2 (N = 535; cumulative anthracycline dose nm; the planned cumulative dose was 332 mg/m2) | |
| Outcomes | Heart failure (i.e. clinical heart failure defined as mild congestive heart failure responsive to therapy (WHO grade 3)) Adverse effects other than cardiac damage (according to WHO criteria) | |
| Notes | The data presented in this table are for the 1063 out of 1086 women (540 out of 551 women in the high peak dose group and 523 out of 535 in the low peak dose group); 14 women were excluded because they never started therapy and 9 women had incomplete treatment and toxicity data. However, we performed an intention‐to‐treat analysis. Although the cumulative anthracycline doses women in both treatment groups received were not documented, the authors of this study have stated that the median cumulative doses of all drugs were almost identical in both groups. Median length of follow‐up 40 months. No funding documented. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | It was stated that randomisation was performed at the HeCOG Data Office, but no further information on the method of randomisation was provided |
| Allocation concealment (selection bias) | Low risk | Randomisation was performed at the HeCOG Data Office |
| Blinding of participants and personnel (performance bias) | Unclear risk | No information on blinding of participants and personnel was provided, although due to the nature of the interventions, this was most likely not the case |
| Blinding of outcome assessment (detection bias): clinical heart failure | Unclear risk | No information on blinding of outcome assessors was provided for clinical heart failure |
| Blinding of outcome assessment (detection bias): adverse effects other than cardiac damage | Unclear risk | No information on blinding of outcome assessors was provided for adverse effects other than cardiac damage |
| Incomplete outcome data (attrition bias): clinical heart failure | Unclear risk | It was not documented in how many women clinical heart failure was assessed; at least 2.1% not analysed |
| Incomplete outcome data (attrition bias): adverse effects other than cardiac damage | Unclear risk | It was not documented in how many women adverse effects other than cardiac damage were assessed; at least 2.1% not analysed |
| Selective reporting (reporting bias) | High risk | There was no reference to a protocol provided in the manuscript (and we did not search for it), but not all expected outcomes were reported in a useful manner |
| Other bias | Unclear risk | Baseline imbalance between treatment arms related to outcome (prior cardiotoxic treatment, age, sex, and/or prior cardiac dysfunction): unclear (unclear if prior cardiotoxic treatment was balanced between treatment groups; the other items were balanced between treatment groups) Difference in length of follow‐up between treatment arms: unclear (not reported) |
| Study characteristics | ||
| Methods | Method of randomisation not clear | |
| Participants | 48 men (aged 58 to 79 years) with metastatic hormone‐refractory prostate carcinoma treated with liposomal doxorubicin (Caelyx). No prior anthracycline therapy; prior cardiac radiotherapy nm; no prior cardiac dysfunction | |
| Interventions | Liposomal doxorubicin (Caelyx; 1‐hour infusion) with a peak dose of either 25 mg/m2 (N = 22; cumulative anthracycline dose 323.5 mg per man; range 50 to 600 mg per man) or 50 mg/m2 (N = 26; cumulative anthracycline dose 416.13 mg per man; range 100 to 1200 mg per man) | |
| Outcomes | Heart failure (i.e. clinical heart failure defined as congestive heart failure; subclinical heart failure defined as LVEF < 40% on echocardiography). Response rate (i.e. objective palliative response rate defined as a reduction in serum PSA levels by >= 50% relative to baseline, with this reduction persisting for >= 4 weeks and accompanied by stabilisation or improvement in the man's performance status). Quality of life (according to the 30‐item European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire). Adverse effects other than cardiac damage (according to the National Cancer Institute of Canada/CALGB grading system). | |
| Notes | Mean length of follow‐up 42 months. Anthracycline doses were not available as mg/m2. Some of the information provided in this table was not included in the article, but was provided by the author upon our request. No funding documented. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | It was stated that this was a randomised study, but no further information on the methods of randomisation was provided |
| Allocation concealment (selection bias) | Unclear risk | It was stated that this was a randomised study, but no further information on the methods of randomisation was provided |
| Blinding of participants and personnel (performance bias) | Unclear risk | No information on blinding of participants and personnel was provided, although due to the nature of the interventions, this was most likely not the case |
| Blinding of outcome assessment (detection bias): clinical heart failure | Unclear risk | No information on blinding of outcome assessors was provided for clinical heart failure |
| Blinding of outcome assessment (detection bias): subclinical heart failure (dichotomous and/or continuous) | Unclear risk | No information on blinding of outcome assessors was provided for subclinical heart failure |
| Blinding of outcome assessment (detection bias): tumour response | Unclear risk | No information on blinding of outcome assessors was provided for tumour response |
| Blinding of outcome assessment (detection bias): adverse effects other than cardiac damage | Unclear risk | No information on blinding of outcome assessors was provided for adverse effects other than cardiac damage |
| Blinding of outcome assessment (detection bias): quality of life | Unclear risk | No information on blinding of outcome assessors was provided for quality of life |
| Incomplete outcome data (attrition bias): clinical heart failure | Low risk | All men were included in the analysis |
| Incomplete outcome data (attrition bias): subclinical heart failure (dichotomous and/or continuous) | Low risk | All men were included in the analysis |
| Incomplete outcome data (attrition bias): tumour response | Low risk | Almost all men (96%) were included in the analysis of clinical heart failure |
| Incomplete outcome data (attrition bias): adverse effects other than cardiac damage | Low risk | All men were included in the analysis |
| Incomplete outcome data (attrition bias): quality of life | Unclear risk | It was not documented in how many men quality of life was assessed |
| Selective reporting (reporting bias) | High risk | There was no reference to a protocol provided in the manuscript (and we did not search for it), but not all expected outcomes were reported in a useful manner |
| Other bias | Unclear risk | Baseline imbalance between treatment arms related to outcome (prior cardiotoxic treatment, age, sex, and/or prior cardiac dysfunction): unclear (unclear if prior cardiotoxic treatment was balanced between treatment groups; the other items were balanced between treatment groups) Difference in length of follow‐up between treatment arms: unclear (not reported) |
| Study characteristics | ||
| Methods | Method of randomisation not clear (stratified according to performance status, number of organ sites involved by metastases, cumulative dose of prior anthracyclines, and whether prior anthracycline therapy had been given as postoperative adjuvant or as palliative treatment for metastatic disease) | |
| Participants | 52 women (aged 28 to 74 years) with progressive metastatic breast cancer treated with epirubicin. Prior anthracycline therapy in 21 women in the continuous infusion group and 12 women in the bolus infusion group; for 2 women in the bolus infusion group it was unclear; cumulative dose of prior anthracycline therapy nm. Prior cardiac radiotherapy nm; prior cardiac dysfunction possible (number of participants nm) | |
| Interventions | Epirubicin (peak dose 90 mg/m2) with either bolus (15 minutes) infusion (N = 25; median cumulative anthracycline dose including previous therapy 540 mg/m2; range 90 to 1055 mg/m2) or continuous (48 hours) infusion (N = 27; median cumulative anthracycline dose including previous therapy 630 mg/m2; range 110 to 1420 mg/m2) | |
| Outcomes | Heart failure (i.e. clinical heart failure defined as congestive heart failure; subclinical heart failure defined as a 15% or more decrease in LVEF as measured by cardiac scan or echocardiography). Tumour response (i.e. CR defined as disappearance of all clinical evidence of active tumour including symptoms and signs for a minimum of 4 weeks; PR defined as a greater than 50% decrease in the sum of the products of the longest perpendicular diameters of measurable lesions for at least 4 weeks. Simultaneous increase in the size of any lesion or the appearance of any new lesions was not permitted). Survival (OS was defined as survival from the initiation of present drug therapy). | |
| Notes | Length of follow‐up nm. The study was supported in part by a grant‐in‐aid from Farmitalia, but no information on the influence of funders was provided. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | It was stated that this was a randomised study, but no further information on the methods of randomisation was provided |
| Allocation concealment (selection bias) | Unclear risk | It was stated that this was a randomised study, but no further information on the methods of randomisation was provided |
| Blinding of participants and personnel (performance bias) | Unclear risk | No information on blinding of participants and personnel was provided, although, due to the nature of the interventions, this was most likely not the case |
| Blinding of outcome assessment (detection bias): clinical heart failure | Unclear risk | No information on blinding of outcome assessors was provided for clinical heart failure |
| Blinding of outcome assessment (detection bias): subclinical heart failure (dichotomous and/or continuous) | Unclear risk | No information on blinding of outcome assessors was provided for subclinical heart failure |
| Blinding of outcome assessment (detection bias): tumour response | Unclear risk | No information on blinding of outcome assessors was provided for tumour response |
| Blinding of outcome assessment (detection bias): overall survival | Low risk | No information on blinding of outcome assessors was provided, but since this is not applicable for overall survival we judged this as a low risk of bias |
| Incomplete outcome data (attrition bias): clinical heart failure | Low risk | Almost all participants (96.2%) were included in the analysis |
| Incomplete outcome data (attrition bias): subclinical heart failure (dichotomous and/or continuous) | Low risk | Almost all participants (96.2%) were included in the analysis |
| Incomplete outcome data (attrition bias): tumour response | Low risk | Almost all participants (96.2%) were included in the analysis |
| Incomplete outcome data (attrition bias): overall survival | Low risk | Almost all participants (96.2%) were included in the analysis |
| Selective reporting (reporting bias) | Low risk | There was no reference to a protocol provided in the manuscript (and we did not search for it), but all expected outcomes were reported |
| Other bias | High risk | Baseline imbalance between treatment arms related to outcome (prior cardiotoxic treatment, age, sex, and/or prior cardiac dysfunction): high (prior anthracycline use was not balanced between treatment arms; unclear if prior cardiac radiotherapy and prior cardiac dysfunction were balanced between treatment groups; all other items were balanced between treatment groups) Difference in length of follow‐up between treatment arms: no |
| Study characteristics | ||
| Methods | Method of randomisation not clear (no stratification factors were used due to large sample size) | |
| Participants | 3114 women (aged 21.9 to 76.9 years) with high‐risk stage I or II breast cancer treated with doxorubicin and cyclophosphamide. Also, if less than a mastectomy was performed, women received external beam radiation therapy (39% of the women in the low peak dose group and 38% of women in the high peak dose group; location of the tumour nm; dose nm). No prior anthracycline therapy; no prior cardiac radiotherapy; no prior cardiac dysfunction | |
| Interventions | Doxorubicin (infusion duration nm) with a peak dose of either 54 mg/m2 (N = 1590; cumulative anthracycline dose nm; the planned cumulative dose was 324 mg/m2) or 81 mg/m2 (N = 1524; cumulative dose nm; the planned cumulative dose was 324 mg/m2) | |
| Outcomes | Heart failure (i.e. clinical heart failure defined as congestive heart failure grade 3 or 4 according to SWOG criteria) OS (defined as time from registration to time of death due to any cause) Adverse effects other than cardiac damage (according to SWOG criteria) | |
| Notes | Although the cumulative anthracycline doses women in both treatment groups received were not documented, the authors of this study have stated that women in both groups received identical total doses of chemotherapeutic agents. Length of follow‐up nm (median follow‐up for women still alive at the time of analysis is 7.2 years). The study was supported in part by the US Public Health Service Cooperative Agreement grants, but no information on the influence of funders was provided. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | It was stated that this was a randomised study, but no further information on the methods of randomisation was provided |
| Allocation concealment (selection bias) | Unclear risk | It was stated that this was a randomised study, but no further information on the methods of randomisation was provided |
| Blinding of participants and personnel (performance bias) | Unclear risk | No information on blinding of participants and personnel was provided, although due to the nature of the interventions, this was most likely not the case |
| Blinding of outcome assessment (detection bias): clinical heart failure | Unclear risk | No information on blinding of outcome assessors was provided for clinical heart failure |
| Blinding of outcome assessment (detection bias): overall survival | Low risk | No information on blinding of outcome assessors was provided, but since this is not applicable for overall survival we judged this as a low risk of bias |
| Blinding of outcome assessment (detection bias): adverse effects other than cardiac damage | Unclear risk | No information on blinding of outcome assessors was provided for adverse effects other than cardiac damage |
| Incomplete outcome data (attrition bias): clinical heart failure | Low risk | Almost all women (99.3%) were included in the analysis of clinical heart failure |
| Incomplete outcome data (attrition bias): overall survival | Unclear risk | Not documented how many women were included in the analysis of overall survival |
| Incomplete outcome data (attrition bias): adverse effects other than cardiac damage | Low risk | Almost all women (99.3%) were included in the analysis of adverse effects other than cardiac damage |
| Selective reporting (reporting bias) | Low risk | There was no reference to a protocol provided in the manuscript (and we did not search for it), but all expected outcomes were reported |
| Other bias | Unclear risk | Baseline imbalance between treatment arms related to outcome (prior cardiotoxic treatment, age, sex, and/or prior cardiac dysfunction): no (all items were balanced between treatment groups) Difference in length of follow‐up between treatment arms: unclear (not reported) |
| Study characteristics | ||
| Methods | Randomisations were performed centrally; in Lipshultz 2012 it was reported that a permuted‐block algorithm stratified by institution was used | |
| Participants | 145 children who had at least 1 follow‐up echocardiogram obtained before 1 April 1997 out of an RCT with 240 participants (Silverman 2001) (age 0.4 to 17.9 years; 53 girls and 68 boys) with high risk ALL treated with doxorubicin (all children received 30 mg/m2 doxorubicin on each of 2 days as a bolus infusion during induction therapy; this information was only reported in the long‐term follow‐up study), steroids, cytarabine, vincristine, methotrexate, 6‐MP, and asparaginase. No prior anthracycline therapy; no prior cardiac radiotherapy; no prior clinical cardiac dysfunction, in both groups prior asymptomatic cardiac dysfunction on echocardiography present (number of children nm) | |
| Interventions | Doxorubicin (peak dose 30 mg/m2) every 3 weeks with either bolus (less than 1 hour; see notes) infusion (N = 64; median cumulative anthracycline dose 336 mg/m2; range 228 to 360 mg/m2) or continuous (48 hours) infusion (N = 57; median cumulative anthracycline dose 340 mg/m2; range 222 to 360 mg/m2) | |
| Outcomes | Heart failure (i.e. clinical heart failure defined as congestive heart failure; subclinical heart failure defined as median fall in left ventricular characteristics) | |
| Notes | The data presented in this table are for the 121 of the 145 children who had an echocardiogram of good quality. It was not documented to which group the 24 excluded children were randomised, so it was not possible to perform an intention‐to‐treat analysis. Median follow‐up was 1.5 years (range 0 to 4.7 years). Long‐term follow‐up data of this study have been published on 92 participants (N = 43 in bolus group and N = 49 in the continuous infusion group) who had at least 1 follow‐up echocardiogram at least 3 years after infusion duration assignment, had a baseline echocardiogram, and were in continuous complete remission (Lipshultz 2012). Median age at diagnosis was 4.6 years (range 1.6 to 16.2 years) in the bolus group and 3.7 years (range 0.7 to 16.9 years) in the continuous infusion group. It should be noted that in Lipshultz 2012 it was stated that a bolus infusion was given within 15 minutes instead of a 1‐hour infusion duration documented in the primary publication of this study (Lipshultz 2002). The authors provided the following clarification: "all infusions were less than 1 hour and basically this was less than 15 minutes". The median length of follow‐up was 8 years with a range of 3 to 13 years (8.3 years in the bolus group and 8.2 years in the continuous infusion group). Results of baseline echocardiograms were not reported, so it is unclear if there were children with prior cardiac dysfunction. The median cumulative doxorubicin dose in the bolus group was 342 mg/m2 (range 196 to 360 mg/m2); in the continuous infusion group it was 352 mg/m2 (range 204 to 360 mg/m2). The study was supported in part by National Institutes of Health grants, Children's Cardiomyopathy Foundation, Women's Cancer Association, Lance Armstrong Foundation, STOP Children's Cancer Foundation, Scott Howard Fund, and the Michael Garil Fund, but no information on the influence of funders was provided. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | It was stated that this was a randomised study, but no further information on the methods of randomisation was provided |
| Allocation concealment (selection bias) | Low risk | Randomisations were performed centrally |
| Blinding of participants and personnel (performance bias) | High risk | Participants and treating physicians were not blinded |
| Blinding of outcome assessment (detection bias): clinical heart failure | Unclear risk | No information on blinding of outcome assessors was provided for clinical heart failure |
| Blinding of outcome assessment (detection bias): subclinical heart failure (dichotomous and/or continuous) | Low risk | The outcome assessors of subclinical heart failure were blinded |
| Incomplete outcome data (attrition bias): clinical heart failure | High risk | Only 50.4% of children were included in the analysis |
| Incomplete outcome data (attrition bias): subclinical heart failure (dichotomous and/or continuous) | High risk | Less than 38% of children evaluated for the different cardiac parameters |
| Selective reporting (reporting bias) | High risk | There was no reference to a protocol provided in the manuscript (and we did not search for it), but not all expected outcomes were reported in a useful manner |
| Other bias | Unclear risk | Baseline imbalance between treatment arms related to outcome (prior cardiotoxic treatment, age, sex, and/or prior cardiac dysfunction): unclear (unclear if prior cardiac dysfunction was balanced between treatment groups; the other items were balanced between treatment groups) Difference in length of follow‐up between treatment arms: no |
| Study characteristics | ||
| Methods | Randomisations were performed according to the last digit of the national identification number | |
| Participants | 62 women (age nm) with stage III or stage IV breast cancer (N = 36) or ovarian cancer (N = 26) treated with doxorubicin, cyclophosphamide, and either 5‐FU (breast cancer) or cisplatin (ovarian cancer). No prior anthracycline therapy; prior cardiac radiotherapy possible for 1 woman in the short infusion group and 3 women in the prolonged infusion group; no prior cardiac dysfunction | |
| Interventions | Doxorubicin (peak dose 50 mg/m2) every 3 weeks with either short infusion (15 to 20 minutes) (N = 31; mean cumulative dose 410 mg/m2; range 200 to 550 mg/m2) or prolonged infusion (6 hours) (N = 31; mean cumulative dose 428 mg/m2; range 250 to 600 mg/m2) | |
| Outcomes | Heart failure (i.e. clinical heart failure defined as symptoms of congestive heart failure; subclinical heart failure defined as a fall in LVEF of more than 20% as measured by gated pool radionuclide angiography and defined as the mean fall in LVEF) Adverse effects other than cardiac damage (according to SWOG criteria) | |
| Notes | Length of follow‐up nm No funding documented | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | Randomisations were performed according to the last digit of the national identification number |
| Allocation concealment (selection bias) | High risk | Randomisations were performed according to the last digit of the national identification number |
| Blinding of participants and personnel (performance bias) | Unclear risk | No information on blinding of participants and personnel was provided, although due to the nature of the interventions, this was most likely not the case |
| Blinding of outcome assessment (detection bias): clinical heart failure | Unclear risk | No information on blinding of outcome assessors was provided for clinical heart failure |
| Blinding of outcome assessment (detection bias): subclinical heart failure (dichotomous and/or continuous) | Unclear risk | No information on blinding of outcome assessors was provided for subclinical heart failure |
| Blinding of outcome assessment (detection bias): adverse effects other than cardiac damage | Unclear risk | No information on blinding of outcome assessors was provided for adverse effects other than cardiac damage |
| Incomplete outcome data (attrition bias): clinical heart failure | Low risk | Almost all women (93.5%) were included in the analysis of clinical heart failure |
| Incomplete outcome data (attrition bias): subclinical heart failure (dichotomous and/or continuous) | Low risk | Almost all women (93.5%) were included in the analysis of subclinical heart failure |
| Incomplete outcome data (attrition bias): adverse effects other than cardiac damage | Low risk | Almost all women (93.5%) were included in the analysis of adverse effects other than cardiac damage |
| Selective reporting (reporting bias) | High risk | There was no reference to a protocol provided in the manuscript (and we did not search for it), but not all expected outcomes were reported in a useful manner |
| Other bias | Unclear risk | Baseline imbalance between treatment arms related to outcome (prior cardiotoxic treatment, age, sex, and/or prior cardiac dysfunction): unclear (unclear if age and prior cardiotoxic treatment were balanced between treatment groups; the other items were balanced between treatment groups) Difference in length of follow‐up between treatment arms: unclear (not reported) |
| Study characteristics | ||
| Methods | Method of randomisation not clear (stratified according to risk group, degree of leukocyte count elevation, age, FAB morphology, and presence or absence of lymphoma syndrome) | |
| Participants | 44 participants (aged 1 to 19 years; median 7 years; 11 girls and 33 boys) with ALL (31 high risk and 13 average risk) treated with daunorubicin, cytosine arabinoside, cyclophosphamide, vincristine, prednisone, L‐asparaginase, methotrexate, 6‐MP, thioguanine, and sometimes spinal (12 Gy for participants with CNS disease at diagnosis; N = 3, nm in which treatment group) and /or cranial irradiation. No prior anthracycline therapy; no prior cardiac radiotherapy; prior cardiac dysfunction nm | |
| Interventions | Daunorubicin (peak dose 120 mg/m2) with either bolus (push) infusion (N = 22; median cumulative dose 360 mg/m2 (range 120 to 585 mg/m2) for 18 participants with an echocardiogram) or continuous (48 hours) infusion (N = 22; median cumulative dose 400 mg/m2 (range 120 to 558 mg/m2) for 18 participants with an echocardiogram) | |
| Outcomes | Heart failure (i.e. subclinical heart failure defined as a LVSF of less than 29% or a 10% unit or more decrease from baseline to 29% (borderline function) or median change in LVSF as measured by echocardiography) | |
| Notes | Median length of follow‐up 54+ months (minimal 25+ months) No funding documented | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | It was stated that this was a randomised study, but no further information on the methods of randomisation was provided |
| Allocation concealment (selection bias) | Unclear risk | It was stated that this was a randomised study, but no further information on the methods of randomisation was provided |
| Blinding of participants and personnel (performance bias) | Unclear risk | No information on blinding of participants and personnel was provided, although due to the nature of the interventions, this was most likely not the case |
| Blinding of outcome assessment (detection bias): subclinical heart failure (dichotomous and/or continuous) | Unclear risk | No information on blinding of outcome assessors was provided for subclinical heart failure |
| Incomplete outcome data (attrition bias): subclinical heart failure (dichotomous and/or continuous) | Low risk | All participants were included in the analysis |
| Selective reporting (reporting bias) | High risk | There was no reference to a protocol provided in the manuscript (and we did not search for it), but not all expected outcomes were reported in a useful manner |
| Other bias | Unclear risk | Baseline imbalance between treatment arms related to outcome (prior cardiotoxic treatment, age, sex, and/or prior cardiac dysfunction): unclear (unclear if age, sex, and prior cardiac dysfunction were balanced between treatment groups; no prior cardiotoxic treatment) Difference in length of follow‐up between treatment arms: unclear (not reported) |
| Study characteristics | ||
| Methods | Randomisation was performed through the SWOG statistical centre (not stratified) | |
| Participants | 240 participants (aged 17 to 83 years; 121 women and 119 men) with metastatic soft tissue sarcoma treated with doxorubicin and dacarbazine. No prior anthracycline therapy; prior cardiac radiotherapy possible for 36 participants in bolus group and 31 participants in continuous infusion group; no prior cardiac dysfunction | |
| Interventions | Doxorubicin (60 mg/m2) repeated at 21‐day intervals by either bolus (N = 118; median cumulative dose 240 mg/m2) or continuous (96 hours) infusion (N = 122; median cumulative dose 221 mg/m2) | |
| Outcomes | Heart failure (i.e. clinical heart failure defined as drug‐related cardiac death and clinical cardiac events; subclinical heart failure defined as a decrease in LVEF as measured by non‐invasive testing. It was not documented what the exact method of non‐invasive testing was). Tumour response (i.e. CR defined as disappearance of all clinical evidence of tumour for a minimum of 4 weeks; PR defined as a 50% or greater reduction in the sum of the products of the perpendicular diameters of all measured lesions, no simultaneous increase in the size of any lesion could occur and no new lesions could occur. The response had to be maintained for at least 4 weeks). Survival (OS was defined as measured from the time of randomisation to death). | |
| Notes | One participant randomised to the continuous infusion group received bolus infusion by mistake, and only 233 started therapy. However, we performed an intention‐to‐treat analysis. Length of follow‐up nm. The study was supported in part by different Public Health Service Cooperative Agreement grants awarded by the National Cancer Institute, National Institutes of Health, and Department of Health and Human Services, but no information on the influence of funders was provided. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | It was stated that this was a randomised study, but no further information on the methods of randomisation was provided |
| Allocation concealment (selection bias) | Low risk | Randomisation was performed through the SWOG statistical centre |
| Blinding of participants and personnel (performance bias) | Unclear risk | No information on blinding of participants and personnel was provided, although due to the nature of the interventions, this was most likely not the case |
| Blinding of outcome assessment (detection bias): clinical heart failure | Unclear risk | No information on blinding of outcome assessors was provided for clinical heart failure |
| Blinding of outcome assessment (detection bias): subclinical heart failure (dichotomous and/or continuous) | Unclear risk | No information on blinding of outcome assessors was provided for subclinical heart failure |
| Blinding of outcome assessment (detection bias): tumour response | Unclear risk | No information on blinding of outcome assessors was provided for tumour response |
| Blinding of outcome assessment (detection bias): overall survival | Low risk | No information on blinding of outcome assessors was provided, but since this is not applicable for overall survival we judged this as a low risk of bias |
| Incomplete outcome data (attrition bias): clinical heart failure | Low risk | Almost all participants (97.1%) were included in the analysis |
| Incomplete outcome data (attrition bias): subclinical heart failure (dichotomous and/or continuous) | Low risk | Almost all participants (97.1%) were included in the analysis |
| Incomplete outcome data (attrition bias): tumour response | Low risk | Almost all participants (97.1%) were included in the analysis |
| Incomplete outcome data (attrition bias): overall survival | Low risk | Almost all participants (97.1%) were included in the analysis |
| Selective reporting (reporting bias) | Low risk | There was no reference to a protocol provided in the manuscript (and we did not search for it), but all expected outcomes were reported |
| Other bias | Unclear risk | Baseline imbalance between treatment arms related to outcome (prior cardiotoxic treatment, age, sex, and/or prior cardiac dysfunction): unclear (unclear if prior cardiac radiotherapy and anthracycline was balanced between treatment arms; all other items were balanced between treatment groups) Difference in length of follow‐up between treatment arms: unclear (not reported) |
5‐FU = 5‐fluorouracil
6‐MP = 6‐mercaptopurine
ALL = acute lymphoblastic leukaemia
CALGB = Cancer and Leukemia Group B
CNS = central nervous system
CR = complete remission
FAB = French American British
LVEF = left ventricular ejection fraction
LVSF = left ventricular shortening fraction
HeCOG = Hellenic Cooperative Oncology Group
nm = not documented
OS = overall survival
PR = partial remission
PSA = prostate‐specific antigen
RCT = randomised controlled trial
SWOG = Southwest Oncology Group
T‐ALL = T‐cell acute lymphoblastic leukaemia
WHO = World Health Organization
Characteristics of excluded studies [ordered by study ID]
Jump to:
| Study | Reason for exclusion |
| No randomised controlled trial. | |
| Conference proceeding of Advani 2015. | |
| Study does not evaluate different anthracycline dosage schedules. | |
| Difference in chemotherapy other than anthracyclines between intervention and control group. | |
| Cumulative anthracycline dosis of intervention and control group not mentioned. | |
| No randomised controlled trial. | |
| No randomised controlled trial. | |
| Heart failure not mentioned. | |
| Difference in chemotherapy other than anthracyclines between intervention and control group. | |
| No randomised controlled trial. | |
| Difference in actually received cumulative anthracycline dosis between intervention and control group. | |
| No randomised controlled trial. | |
| Article describes two studies: one is no randomised controlled trial; one does not evaluate different anthracycline dosage schedules, but different anthracycline derivates. | |
| Difference in therapy other than anthracyclines between intervention and control group; difference in cumulative anthracycline dosis between intervention and control group. | |
| No randomised controlled trial. | |
| Difference in chemotherapy other than anthracyclines between intervention and control group; duplicate publication of Sutton 1989. | |
| Number of patients with heart failure not mentioned. | |
| No randomised controlled trial. | |
| Cumulative anthracycline dosis of intervention and control group not mentioned; cardiotoxicity not stated for patients with different anthracycline peak doses; pharmacokinetics study. | |
| No randomised controlled trial. | |
| Difference in cumulative anthracycline dosis between intervention and control group | |
| Difference in cumulative anthracycline dosis between intervention and control group. | |
| No randomised controlled trial. | |
| Difference in cumulative anthracycline dosis between intervention and control group. | |
| Difference in therapy other than anthracyclines between intervention and control group. | |
| Difference in cumulative anthracycline dosis between intervention and control group; similar anthracycline peak dosis and infusion duration between intervention and control group. | |
| Cumulative anthracycline dosis of intervention and control group not mentioned. | |
| Difference in chemotherapy other than anthracyclines between intervention and control group. | |
| Ongoing trial which does not contain unconfounded information on anthracycline cardiotoxicity; difference in chemotherapy other than anthracyclines between intervention and control group. | |
| No randomised controlled trial. | |
| Similar anthracycline peak dosis between intervention and control group; anthracycline infusion duration not mentioned; difference in cumulative anthracycline dosis between intervention and control group. | |
| Difference in cumulative anthracycline dosis between intervention and control group. | |
| Difference in cumulative anthracycline dosis between intervention and control group; dose‐finding study. | |
| No randomised controlled trial. | |
| No randomised controlled trial. | |
| No randomised controlled trial; duplicate publication of Luck (study B) 1997. | |
| No randomised controlled trial; duplicate publication of Luck (study A) 1997. | |
| No randomised controlled trial. | |
| Difference in cumulative anthracycline dosis between intervention and control group. | |
| Heart failure not mentioned. | |
| Difference in cumulative anthracycline dosis between intervention and control group. | |
| Similar anthracycline peak dosis and infusion duration between intervention and control group. | |
| Similar anthracycline peak dosis and infusion duration between intervention and control group. Only a part of the patients received the same cumulative anthracycline dosis and no separate results were given for these patients; the investigators were not able to provide this information. | |
| Difference in cumulative anthracycline dosis between intervention and control group. | |
| Difference in planned cumulative anthracycline dosis between intervention and control group. | |
| Difference in therapy other than anthracyclines between intervention and control group; similar anthracycline peak dosis between intervention and control group; anthracycline infusion duration not mentioned. | |
| Difference in chemotherapy other than anthracyclines between intervention and control group. | |
| No randomised controlled trial. | |
| Difference in chemotherapy other than anthracyclines between intervention and control group; duplicate publication of Ehrlich 1979. | |
| No randomised controlled trial. | |
| Difference in chemotherapy other than anthracyclines between intervention and control group; ongoing study. | |
| No randomised controlled trial. | |
| Difference in both anthracycline peak dosis and infusion duration between intervention and control group. | |
| Number of patients with abnormal cardiac function not mentioned. | |
| Difference in therapy other than anthracyclines between intervention and control group; similar anthracycline peak dosis between intervention and control group; anthracycline infusion duration not mentioned. | |
| Cumulative anthracycline dosis of intervention and control group not mentioned. | |
| No randomised controlled trial. | |
| Difference in cumulative anthracycline dosis between intervention and control group. |
Characteristics of studies awaiting classification [ordered by study ID]
Jump to:
| Methods | Method of randomisation unclear |
| Participants | 11 participants (median age 50 years; sex nm) with metastatic breast cancer treated with pegylated liposomal doxorubicin. Prior anthracycline therapy nm; prior cardiac radiotherapy possible for 4 participants (number of participants in each treatment group nm); no prior cardiac dysfunction |
| Interventions | Pegylated liposomal doxorubicin with a peak dose of either 50 mg/m2 or 60 mg/m2 (infusion duration nm; number of participants in each treatment group nm; cumulative anthracycline dose nm) |
| Outcomes | Response rate: 1/4 evaluable participants in the 50 mg/m2 group achieved a partial response (definition nm) as did 2/4 evaluable participants in the 60 mg/m2 group. PFS (definition nm): median time to progression was 104 days in the 50 mg/m2 group and 168 days in the 60 mg/m2 group. Toxicity: not presented for each treatment group separately; unclear if cardiotoxicity has been evaluated. |
| Notes | Not all randomised participants were evaluated. Median length of follow‐up was 9.2 months. This study has not been published in full text (29 December 2015); from the currently available data it is unclear if this study is eligible for inclusion in this review |
nm: not mentioned
PFS: progression‐free survival
Data and analyses
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Clinical heart failure Show forest plot | 5 | 557 | Risk Ratio (M‐H, Random, 95% CI) | 0.27 [0.09, 0.81] |
| Analysis 1.1  Comparison 1: Infusion duration less than 6 hours versus infusion duration 6 hours or more, Outcome 1: Clinical heart failure | ||||
| 1.2 (Sub)clinical heart failure combined Show forest plot | 4 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| Analysis 1.2  Comparison 1: Infusion duration less than 6 hours versus infusion duration 6 hours or more, Outcome 2: (Sub)clinical heart failure combined | ||||
| 1.2.1 (Sub)clinical heart failure combined (subclinical defined as >=10% decrease in LVEF) | 1 | 82 | Risk Ratio (M‐H, Random, 95% CI) | 0.76 [0.46, 1.26] |
| 1.2.2 (Sub)clinical heart failure combined (subclinical defined as >=15% decrease in LVEF) | 1 | 52 | Risk Ratio (M‐H, Random, 95% CI) | 0.31 [0.03, 2.78] |
| 1.2.3 (Sub)clinical heart failure combined (subclinical defined as a fall in LVEF of > 20%) | 1 | 62 | Risk Ratio (M‐H, Random, 95% CI) | 0.04 [0.00, 0.60] |
| 1.2.4 (Sub)clinical heart failure combined (subclinical defined as a decrease in LVEF) | 1 | 240 | Risk Ratio (M‐H, Random, 95% CI) | 0.36 [0.15, 0.90] |
| 1.3 Response rate Show forest plot | 3 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| Analysis 1.3  Comparison 1: Infusion duration less than 6 hours versus infusion duration 6 hours or more, Outcome 3: Response rate | ||||
| 1.3.1 Response rate (defined as complete or partial remission) | 2 | 292 | Risk Ratio (M‐H, Random, 95% CI) | 1.20 [0.65, 2.22] |
| 1.3.2 Response rate (defined as good response) | 1 | 178 | Risk Ratio (M‐H, Random, 95% CI) | 1.23 [0.91, 1.66] |
| 1.4 Overall survival Show forest plot | 2 | 322 | Hazard Ratio (IV, Random, 95% CI) | 1.42 [0.61, 3.30] |
| Analysis 1.4  Comparison 1: Infusion duration less than 6 hours versus infusion duration 6 hours or more, Outcome 4: Overall survival | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Clinical heart failure Show forest plot | 2 | 4146 | Risk Ratio (M‐H, Random, 95% CI) | 0.65 [0.23, 1.88] |
| Analysis 2.1  Comparison 2: Doxorubicin peak dose less than 60 mg/m2 versus 60 mg/m2 or more, Outcome 1: Clinical heart failure | ||||
| 2.2 Overall survival Show forest plot | 2 | 4146 | Hazard Ratio (IV, Random, 95% CI) | 1.06 [0.93, 1.22] |
| Analysis 2.2  Comparison 2: Doxorubicin peak dose less than 60 mg/m2 versus 60 mg/m2 or more, Outcome 2: Overall survival | ||||
| 2.3 Adverse effects other than cardiac damage Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| Analysis 2.3  Comparison 2: Doxorubicin peak dose less than 60 mg/m2 versus 60 mg/m2 or more, Outcome 3: Adverse effects other than cardiac damage | ||||
| 2.3.1 Treatment‐related death | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 0.19 [0.01, 3.99] |
| 2.3.2 Death attributable to chemotherapy | 1 | 1032 | Risk Ratio (M‐H, Random, 95% CI) | 0.34 [0.01, 8.26] |
| 2.3.3 Leukopenia grade 4 | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 0.58 [0.53, 0.64] |
| 2.3.4 Leukopenia grade 3 or 4 | 1 | 1032 | Risk Ratio (M‐H, Random, 95% CI) | 0.26 [0.21, 0.31] |
| 2.3.5 Granulocytopenia grade 4 | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 0.67 [0.61, 0.73] |
| 2.3.6 Thrombocytopenia grade 4 | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 0.45 [0.34, 0.59] |
| 2.3.7 Diarrhoea grade 3 or 4 | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 0.34 [0.19, 0.60] |
| 2.3.8 Dyspnoea grade 3 or 4 | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 0.51 [0.28, 0.93] |
| 2.3.9 Infection grade 3 or 4 | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 0.61 [0.42, 0.86] |
| 2.3.10 Malaise/fatigue/lethargy grade 3 or 4 | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 0.66 [0.49, 0.91] |
| 2.3.11 Nausea grade 3 or 4 | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 1.19 [0.98, 1.44] |
| 2.3.12 Stomatitis grade 3 or 4 | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 0.40 [0.27, 0.61] |
| 2.3.13 Vomiting grade 3 or 4 | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 1.31 [1.07, 1.59] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 Response rate (defined as objective palliative tumour response (i.e. decrease in PSA levels of >= 50%)) Show forest plot | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 0.07 [0.00, 1.13] |
| Analysis 3.1  Comparison 3: Liposomal doxorubicin (Caelyx) peak dose 25 mg/m2 versus 50 mg/m2, Outcome 1: Response rate (defined as objective palliative tumour response (i.e. decrease in PSA levels of >= 50%)) | ||||
| 3.2 Adverse effects other than cardiac damage Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| Analysis 3.2  Comparison 3: Liposomal doxorubicin (Caelyx) peak dose 25 mg/m2 versus 50 mg/m2, Outcome 2: Adverse effects other than cardiac damage | ||||
| 3.2.1 Gastrointestinal toxicity grade 3 or 4 | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 0.17 [0.01, 3.08] |
| 3.2.2 Tachycardia grade 3 or 4 | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 0.06 [0.00, 1.00] |
| 3.2.3 Arrhythmia grade 3 or 4 | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 0.39 [0.04, 3.52] |
| 3.2.4 Dyspnoea grade 3 or 4 | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 0.47 [0.10, 2.20] |
| 3.2.5 Palmar‐plantar erythrodysesthesia grade 3 or 4 | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 5.91 [1.45, 24.16] |
| 3.2.6 Hepatic toxicity grade 3 or 4 | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 0.20 [0.05, 0.79] |
| 3.2.7 Leukopenia grade 3 or 4 | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 0.24 [0.03, 1.87] |
| 3.2.8 Thrombocytopenia grade 3 or 4 | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 0.39 [0.02, 9.15] |
| 3.2.9 Haemoglobin‐related toxicity grade 3 or 4 | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 0.07 [0.00, 1.13] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 4.1 Clinical heart failure Show forest plot | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.06, 15.48] |
| Analysis 4.1  Comparison 4: Epirubicin peak dose 110 mg/m2 versus 83 mg/m2, Outcome 1: Clinical heart failure | ||||
| 4.2 Adverse effects other than cardiac damage Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| Analysis 4.2  Comparison 4: Epirubicin peak dose 110 mg/m2 versus 83 mg/m2, Outcome 2: Adverse effects other than cardiac damage | ||||
| 4.2.1 Anaemia grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 2.91 [0.79, 10.70] |
| 4.2.2 Leukopenia grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 1.06 [0.75, 1.49] |
| 4.2.3 Neutropenia grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 1.05 [0.84, 1.31] |
| 4.2.4 Febrile neutropenia grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 0.78 [0.47, 1.31] |
| 4.2.5 Thrombocytopenia grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 12.62 [0.71, 223.52] |
| 4.2.6 Nausea/vomiting grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.45, 1.82] |
| 4.2.7 Fatigue grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 0.32 [0.07, 1.60] |
| 4.2.8 Infection grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 0.79 [0.48, 1.31] |
| 4.2.9 Central nervous system grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 2.91 [0.12, 71.35] |
| 4.2.10 Pulmonary grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 2.91 [0.12, 71.35] |
| 4.2.11 Peripheral neuropathy grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 4.50 [2.37, 8.54] |
| 4.2.12 Hepatotoxicity grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 1.70 [0.50, 5.77] |
| 4.2.13 Hypersensitivity reactions grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 3.88 [1.71, 8.82] |
| 4.2.14 Mucositis grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 1.05 [0.48, 2.28] |
| 4.2.15 Pain grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 0.32 [0.01, 7.93] |
| 4.2.16 Arthralgias/myalgias grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 3.88 [1.31, 11.54] |
| 4.2.17 Treatment‐related death | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 2.91 [0.12, 71.35] |
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1: Infusion duration less than 6 hours versus infusion duration 6 hours or more, Outcome 1: Clinical heart failure
Comparison 1: Infusion duration less than 6 hours versus infusion duration 6 hours or more, Outcome 2: (Sub)clinical heart failure combined
Comparison 1: Infusion duration less than 6 hours versus infusion duration 6 hours or more, Outcome 3: Response rate
Comparison 1: Infusion duration less than 6 hours versus infusion duration 6 hours or more, Outcome 4: Overall survival
Comparison 2: Doxorubicin peak dose less than 60 mg/m2 versus 60 mg/m2 or more, Outcome 1: Clinical heart failure
Comparison 2: Doxorubicin peak dose less than 60 mg/m2 versus 60 mg/m2 or more, Outcome 2: Overall survival
Comparison 2: Doxorubicin peak dose less than 60 mg/m2 versus 60 mg/m2 or more, Outcome 3: Adverse effects other than cardiac damage
Comparison 3: Liposomal doxorubicin (Caelyx) peak dose 25 mg/m2 versus 50 mg/m2, Outcome 1: Response rate (defined as objective palliative tumour response (i.e. decrease in PSA levels of >= 50%))
Comparison 3: Liposomal doxorubicin (Caelyx) peak dose 25 mg/m2 versus 50 mg/m2, Outcome 2: Adverse effects other than cardiac damage
Comparison 4: Epirubicin peak dose 110 mg/m2 versus 83 mg/m2, Outcome 1: Clinical heart failure
Comparison 4: Epirubicin peak dose 110 mg/m2 versus 83 mg/m2, Outcome 2: Adverse effects other than cardiac damage
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Clinical heart failure Show forest plot | 5 | 557 | Risk Ratio (M‐H, Random, 95% CI) | 0.27 [0.09, 0.81] |
| 1.2 (Sub)clinical heart failure combined Show forest plot | 4 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.2.1 (Sub)clinical heart failure combined (subclinical defined as >=10% decrease in LVEF) | 1 | 82 | Risk Ratio (M‐H, Random, 95% CI) | 0.76 [0.46, 1.26] |
| 1.2.2 (Sub)clinical heart failure combined (subclinical defined as >=15% decrease in LVEF) | 1 | 52 | Risk Ratio (M‐H, Random, 95% CI) | 0.31 [0.03, 2.78] |
| 1.2.3 (Sub)clinical heart failure combined (subclinical defined as a fall in LVEF of > 20%) | 1 | 62 | Risk Ratio (M‐H, Random, 95% CI) | 0.04 [0.00, 0.60] |
| 1.2.4 (Sub)clinical heart failure combined (subclinical defined as a decrease in LVEF) | 1 | 240 | Risk Ratio (M‐H, Random, 95% CI) | 0.36 [0.15, 0.90] |
| 1.3 Response rate Show forest plot | 3 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.3.1 Response rate (defined as complete or partial remission) | 2 | 292 | Risk Ratio (M‐H, Random, 95% CI) | 1.20 [0.65, 2.22] |
| 1.3.2 Response rate (defined as good response) | 1 | 178 | Risk Ratio (M‐H, Random, 95% CI) | 1.23 [0.91, 1.66] |
| 1.4 Overall survival Show forest plot | 2 | 322 | Hazard Ratio (IV, Random, 95% CI) | 1.42 [0.61, 3.30] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Clinical heart failure Show forest plot | 2 | 4146 | Risk Ratio (M‐H, Random, 95% CI) | 0.65 [0.23, 1.88] |
| 2.2 Overall survival Show forest plot | 2 | 4146 | Hazard Ratio (IV, Random, 95% CI) | 1.06 [0.93, 1.22] |
| 2.3 Adverse effects other than cardiac damage Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2.3.1 Treatment‐related death | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 0.19 [0.01, 3.99] |
| 2.3.2 Death attributable to chemotherapy | 1 | 1032 | Risk Ratio (M‐H, Random, 95% CI) | 0.34 [0.01, 8.26] |
| 2.3.3 Leukopenia grade 4 | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 0.58 [0.53, 0.64] |
| 2.3.4 Leukopenia grade 3 or 4 | 1 | 1032 | Risk Ratio (M‐H, Random, 95% CI) | 0.26 [0.21, 0.31] |
| 2.3.5 Granulocytopenia grade 4 | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 0.67 [0.61, 0.73] |
| 2.3.6 Thrombocytopenia grade 4 | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 0.45 [0.34, 0.59] |
| 2.3.7 Diarrhoea grade 3 or 4 | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 0.34 [0.19, 0.60] |
| 2.3.8 Dyspnoea grade 3 or 4 | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 0.51 [0.28, 0.93] |
| 2.3.9 Infection grade 3 or 4 | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 0.61 [0.42, 0.86] |
| 2.3.10 Malaise/fatigue/lethargy grade 3 or 4 | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 0.66 [0.49, 0.91] |
| 2.3.11 Nausea grade 3 or 4 | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 1.19 [0.98, 1.44] |
| 2.3.12 Stomatitis grade 3 or 4 | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 0.40 [0.27, 0.61] |
| 2.3.13 Vomiting grade 3 or 4 | 1 | 3114 | Risk Ratio (M‐H, Random, 95% CI) | 1.31 [1.07, 1.59] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 Response rate (defined as objective palliative tumour response (i.e. decrease in PSA levels of >= 50%)) Show forest plot | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 0.07 [0.00, 1.13] |
| 3.2 Adverse effects other than cardiac damage Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 3.2.1 Gastrointestinal toxicity grade 3 or 4 | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 0.17 [0.01, 3.08] |
| 3.2.2 Tachycardia grade 3 or 4 | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 0.06 [0.00, 1.00] |
| 3.2.3 Arrhythmia grade 3 or 4 | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 0.39 [0.04, 3.52] |
| 3.2.4 Dyspnoea grade 3 or 4 | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 0.47 [0.10, 2.20] |
| 3.2.5 Palmar‐plantar erythrodysesthesia grade 3 or 4 | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 5.91 [1.45, 24.16] |
| 3.2.6 Hepatic toxicity grade 3 or 4 | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 0.20 [0.05, 0.79] |
| 3.2.7 Leukopenia grade 3 or 4 | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 0.24 [0.03, 1.87] |
| 3.2.8 Thrombocytopenia grade 3 or 4 | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 0.39 [0.02, 9.15] |
| 3.2.9 Haemoglobin‐related toxicity grade 3 or 4 | 1 | 48 | Risk Ratio (M‐H, Random, 95% CI) | 0.07 [0.00, 1.13] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 4.1 Clinical heart failure Show forest plot | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.06, 15.48] |
| 4.2 Adverse effects other than cardiac damage Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 4.2.1 Anaemia grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 2.91 [0.79, 10.70] |
| 4.2.2 Leukopenia grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 1.06 [0.75, 1.49] |
| 4.2.3 Neutropenia grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 1.05 [0.84, 1.31] |
| 4.2.4 Febrile neutropenia grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 0.78 [0.47, 1.31] |
| 4.2.5 Thrombocytopenia grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 12.62 [0.71, 223.52] |
| 4.2.6 Nausea/vomiting grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.45, 1.82] |
| 4.2.7 Fatigue grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 0.32 [0.07, 1.60] |
| 4.2.8 Infection grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 0.79 [0.48, 1.31] |
| 4.2.9 Central nervous system grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 2.91 [0.12, 71.35] |
| 4.2.10 Pulmonary grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 2.91 [0.12, 71.35] |
| 4.2.11 Peripheral neuropathy grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 4.50 [2.37, 8.54] |
| 4.2.12 Hepatotoxicity grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 1.70 [0.50, 5.77] |
| 4.2.13 Hypersensitivity reactions grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 3.88 [1.71, 8.82] |
| 4.2.14 Mucositis grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 1.05 [0.48, 2.28] |
| 4.2.15 Pain grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 0.32 [0.01, 7.93] |
| 4.2.16 Arthralgias/myalgias grade 3 or 4 | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 3.88 [1.31, 11.54] |
| 4.2.17 Treatment‐related death | 1 | 1086 | Risk Ratio (M‐H, Random, 95% CI) | 2.91 [0.12, 71.35] |
