ICRF-187 permits longer treatment with doxorubicin in women with breast cancer.

1992 ◽  
Vol 10 (1) ◽  
pp. 117-127 ◽  
Author(s):  
J L Speyer ◽  
M D Green ◽  
A Zeleniuch-Jacquotte ◽  
J C Wernz ◽  
M Rey ◽  
...  

PURPOSE To test potential protection by ICRF-187 against cumulative doxorubicin-dose-related cardiac toxicity, we conducted a randomized clinical trial in 150 women with advanced breast cancer. PATIENTS AND METHODS Patients received fluorouracil (5FU) 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 every 21 days intravenously (IV) (control regimen, 74 patients), or the same regimen preceded by ICRF-187 1,000 mg/m2 IV (experimental regimen, 76 patients). RESULTS We previously reported that ICRF-187 in this dose and schedule provides cardiac protection and does not substantially alter the noncardiac toxicity or antitumor efficacy of the control regimen. In this updated analysis of the entire patient cohort, we provide additional support for these findings and demonstrate that patients in the ICRF-187 group received more cycles (median, 11) and higher cumulative doses (median, 500 mg/m2) of doxorubicin than patients in the control group (median, nine cycles, P less than .01; and 441 mg/m2, P less than .05). Twenty-six patients in the ICRF-187 group received doxorubicin doses of at least 700 mg/m2, and among them, 11 patients received 1,000 mg/m2 or more. Only three patients in the control group received doxorubicin doses of 700 mg/m2; the maximum dose administered to one patient in this group was 950 mg/m2. ICRF-187 cardiac protection was demonstrated by difference in incidence of clinical congestive heart failure (CHF; two patients in the ICRF-187 group v 20 in the control group; P less than .0001) and by differences in resting left ventricular ejection fraction (LVEF) determined by multigated radionuclide (MUGA) scan from baselines and that required patient removal from study (five patients in the ICRF-187 group had a decrease in LVEF to less than 0.45 or a decrease from the baseline LVEF of 0.20 or more v 32 in the control group; P less than .000001). Among the 30 patients who had an assessable endomyocardial biopsy at cumulative doxorubicin 450 mg/m2, none of 16 in the ICRF-187 group and six of 14 in the control group had a score of 2 (P less than .05). ICRF-187 cardiac protection was observed in patients with and without prior chest-wall radiation or other risk factors for developing doxorubicin cardiac toxicity. CONCLUSION By protecting against cumulative doxorubicin-induced cardiac toxicity, ICRF-187 permits significantly greater doses of doxorubicin to be administered to patients with greater safety.

1999 ◽  
Vol 17 (5) ◽  
pp. 1425-1425 ◽  
Author(s):  
Vicente Valero ◽  
Aman U. Buzdar ◽  
Richard L. Theriault ◽  
Nozar Azarnia ◽  
Gustavo A. Fonseca ◽  
...  

PURPOSE: To determine the efficacy and safety profile, including the risk for cardiac toxicity, of liposome-encapsulated doxorubicin (TLC D-99), fluorouracil (5-FU), and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-one women were registered in this phase II study. All patients had measurable disease and no previous chemotherapy for MBC. Treatment consisted of TLC D-99 60 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 and 5-FU 500 mg/m2 on days 1 and 8 every 3 weeks. Serial cardiac monitoring, including endomyocardial biopsies, was performed. RESULTS: The overall response rate was 73% (95% confidence interval, 57% to 86%). The median duration of response was 11.2 months, the median time to treatment failure was 8.1 months, and the median overall survival duration was 19.4 months. The median number of cycles per patient was 10. The median cumulative dose of TLC D-99 was 528 mg/m2. Ten patients required hospitalization for febrile neutropenia. Nausea/vomiting, stomatitis, and fatigue higher than grade 2 occurred in 12%, 15%, and 41% of patients, respectively. Twenty-one patients reached a cumulative doxorubicin dose greater than 500 mg/m2. Three patients (7%) were withdrawn from the study due to protocol-defined cardiac toxicity, two because of a decrease in left ventricular ejection fraction to ≤ 40%, and one because her endomyocardial biopsy result was grade 1.5. One patient had congestive heart failure that was probably nonanthracycline related. CONCLUSION: This chemotherapy regimen, including TLC D-99, was highly active against MBC and associated with low cardiac toxicity despite high cumulative doses of doxorubicin.


2015 ◽  
Vol 1084 ◽  
pp. 426-429
Author(s):  
Vladimir Chernov ◽  
Tatiana Kravchuk ◽  
Roman Zelchan ◽  
Dmitriy Podoplekin ◽  
Victor Goldberg

The main focus of the paper is to estimate the possibility of trimethylhydrasine propionate application to prevent an acute doxorubicin-induced cardiotoxicity in breast cancer patients. The study included women with breast cancer. Main group were injected intravenously trimethylhydrasine propionate prior to chemotherapy. For the cancer treatment of these patients doxorubicin was used. All patients were examined by GATE SPECT before starting chemotherapy and 1 hour after the first administration of doxorubicin. After doxorubicin administration in the control group there was a decrease in left ventricular ejection fraction (LVEF), and an increase in left ventricular end-systolic volume. After administration of doxorubicin 40% of patients had a significant reduction in LVEF. Prophylactic use of trimethylhydrasine propionate allows reducing acute doxorubicin-induced cardiotoxicity incidences by 22.5%.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Estíbaliz Díaz-Balboa ◽  
Violeta González-Salvado ◽  
Beatriz Rodríguez-Romero ◽  
Amparo Martínez-Monzonís ◽  
Milagros Pedreira-Pérez ◽  
...  

Abstract Background Anthracyclines and monoclonal antibodies against human epidermal growth factor receptor-2 (HER2) are frequently used to treat breast cancer but they are associated with risk of developing cardiotoxicity. Implementation of cardioprotective strategies as part of breast cancer treatment are needed. To date, a limited number of studies have examined the effectiveness of cardiac rehabilitation programs or exercise programs in the prevention of cardiotoxicity through an integral assessment of cardiac function. The ONCORE study proposes an exercise-based cardiac rehabilitation program as a non-pharmacological tool for the management of chemotherapy-induced cardiotoxicity. Methods The study protocol describes a prospective, randomized controlled trial aimed to determine whether an intervention through an exercise-based CR program can effectively prevent cardiotoxicity induced by anthracyclines and/or anti-HER2 antibodies in women with breast cancer. Three hundred and forty women with breast cancer at early stages scheduled to receive cardiotoxic chemotherapy will be randomly assigned (1:1) to participation in an exercise-based CR program (intervention group) or to usual care and physical activity recommendation (control group). Primary outcomes include changes in left ventricular ejection fraction and global longitudinal strain as markers of cardiac dysfunction assessed by transthoracic echocardiography. Secondary outcomes comprise levels of cardiovascular biomarkers and cardiopulmonary function through peak oxygen uptake determination, physical performance and psychosocial status. Supervised exercise program-related outcomes including safety, adherence/compliance, expectations and physical exercise in- and out-of-hospital are studied as exploratory outcomes. Transthoracic echocardiography, clinical test and questionnaires will be performed at the beginning and two weeks after completion of chemotherapy. Discussion The growing incidence of breast cancer and the risk of cardiotoxicity derived from cancer treatments demand adjuvant cardioprotective strategies. The proposed study may determine if an exercise-based CR program is effective in minimizing chemotherapy-induced cardiotoxicity in this population of women with early-stage breast cancer. The proposed research question is concrete, with relevant clinical implications, transferable to clinical practice and achievable with low risk. Trial registration ClinicalTrials.gov Identifier: NCT03964142. Registered on 28 May 2019. Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT03964142


2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
C Lewinter ◽  
L R Edfors ◽  
T H Nielsen ◽  
E Hedayati ◽  
L Kober ◽  
...  

Abstract Background Trastuzumab and anthracyclines are conventional chemotherapies used in breast cancer. Unfortunately, they are associated with a decrease in left ventricular function potentially leading to heart failure (HF). In order to prevent this, randomised controlled trials (RCTs) assess the preventive effect of concomitant beta-blocker (BB), angiotensin receptor blocker (ARB) and angiotensin converting enzyme inhibitor (ACEI) therapy during chemotherapy. Purpose To assess the preventive effect of BB, ARB or ACEIs on left ventricular ejection fraction (LVEF) during trastuzumab and anthracycline treatment in patients without HF. Methods Our primary outcomes were the effect of BBs or ARB/ACEIs during 1) trastuzumab and 2) anthracycline treatment. Secondary outcomes were the distinct effects of 1) BBs and 2) ARB/ACEIs in either trastuzumab or anthracycline treatments. Through the search term “(RCTs), prevention, cancer chemotherapy and cardiotoxicity” in PubMed, studies were selected, excluding those without randomising to a BB, ARB/ACEI and a placebo control group during chemotherapy. Means of the LVEF and the standard deviation (SD) post-chemotherapy were applied. Meta-analyses estimated the standardised mean difference (SMD) in the LVEF. Heterogeneity was calculated as the I2. Results A total of 7 studies (Table 1) were included in the analysis. Between 93 and 100% were woman. Age varied from 41 to 51 years. Treatment time varied from 12 to 52 weeks. Concomitant BB or ARB/ACEI therapy during trastuzumab treatment was not associated with the LVEF, significantly (Fig. 1A; p=0.07). Oppositely, in the anthracycline regime the LVEF remained significant higher in the concomitant BB and ARB/ACEI groups as compared to controls (Fig. 1B). BB and ARB/ACEI separation in the analysis showed both to influence the LVEF positively independent of chemotherapy (P=0.03 & p=0.005). Table 1 Study reference Year Chemotherapies Preventive drugs Pituskin et al., “Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research (MANTICORE 101-Breast): A Randomized Trial for the Prevention of Trastuzumab-Associated Cardiotoxicity.” 2017 Trastuzumab Perindopril. bisoprolol Gulati et al., “Prevention of Cardiac Dysfunction during Adjuvant Breast Cancer Therapy (PRADA).” 2016 Trastuzumab Candesartan, metoprolol Boekhout et al., “Angiotensin II-Receptor Inhibition With Candesartan to Prevent Trastuzumab-Related Cardiotoxic Effects in Patients With Early Breast Cancer: A Randomized Clinical Trial.” 2016 Trastuzumab Candesartan Janbabai et al., “Effect of Enalapril on Preventing Anthracycline-Induced Cardiomyopathy.” 2017 Anthracycline Enalapril Nabati et al., “Cardioprotective Effects of Carvedilol in Inhibiting Doxorubicin-Induced Cardiotoxicity.” 2017 Anthracycline Carvedilol Tashakori Beheshti et al., “Carvedilol Administration Can Prevent Doxorubicin-Induced Cardiotoxicity: A Double-Blind Randomized Trial.” 2016 Anthracycline Carvedilol Kaya et al., “Protective Effects of Nebivolol against Anthracycline-Induced Cardiomyopathy: A Randomized Control Study.” 2013 Anthracycline Nebivolol Figure 1 Conclusions Concomitant BB and ARB/ACEI therapy both favoured maintenance of the LVEF during trastuzumab and anthracyclines regimens as compared to controls.


2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11514-e11514
Author(s):  
Luigi Rossi ◽  
Federica Tomao ◽  
Anselmo Papa ◽  
Federica Zoratto ◽  
Fabio Ricci ◽  
...  

e11514 Background: Anthracycline is very effective in treatment of breast cancer, however it can cause cardiac toxicity events. nPLD has greater safety profile and comparable efficacy than conventional anthracyclines. We evaluated safety and efficacy, in neoadjuvant setting, of nPLD in pts with LABC. Methods: 11 pts (median age 57 years). Their clinical stage was: stages IIA and IIB 1 pt respectively, IIIB 7 pts, IIIC 2 pts. 8 pts presented at diagnosis with cT4 disease. All pts were treated with nPLD (50 mg/mq, d1q21) plus Docetaxel (75 mg/mq, d1q21) and Cyclophosphamide (500 mg/mq, d1q21); only 1 pt received Cyclophosphamide, nPLD and Trastuzumab. At beginning of therapy, overall population had left ventricular ejection fraction (LVEF) ≥55%. Results: After a median of 4 chemotherapy cycles, we observed following clinical response: stable disease 2 pts (18%); partial response 7 pts (64%); complete response 2 pts (18%). 9 pts were evaluable for radiological response: objective response rate and clinical benefit were 78 % and 100% respectively. 8 pts underwent surgery, in 3 pts was performed breast-conserving surgery. At the definitive histological examination pathologic stage was: IA 4 pts (50%), IIIA 1 pts (12,5%), IIIB 2 pts (25%) and IIIC 1 pts (12,5%). 2 pts experienced cardiac toxicity: 1 pt had an atrial fibrillation G2 while 1 pt had an symptomatic decline of LVEF G3 after first cycle, causing interruption of treatment. Other pts not showed clinically significant reduction of LVEF (>5%). Conclusions: Despite small number of pts, our experience suggests a safety profile and efficacy of nPLD in neoadjuvant settings for LABC; breast conservation was possible in 3 pts, in other pts (73%) this was not possible mainly for the advanced stage (T4).


2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e12537-e12537
Author(s):  
Natalia Camejo ◽  
Cecilia Castillo ◽  
Nora Artagaveytia ◽  
Crisitian Etcheverría ◽  
Jessica Ferradaz ◽  
...  

e12537 Background: To estimate the prevalence of Trastuzumab (TTZ) induced cardiotoxicity in Uruguayan women diagnosed with early HER – 2 positive breast cancer (BC) over a period of ten years, treated under the financial coverage of the National Resource Fund (FNR). Methods: A prospective descriptive observational study based on the analysis of an anonymized database provided by the FNR of Uruguayan HER-2 positive early BC patients treated with TTZ between 2006 and 2016. Variables analyzed included: age, menopausal status, stage, presence of cardiovascular risk factors, use or not of anthracyclines, left ventricular ejection fraction prior and during treatment, and temporary or permanent suspension of treatment. Statistical analysis was performed using SPSS Statistics version 25. The variables were assessed through the use of measures of central tendency, dispersion, contingency tables and proportions. To analyze the relationship between the different variables, the Chi-Square test of independence was performed. Results: The analysis included 1401 patients diagnosed with HER-2 + stage I to III breast cancer who received adjuvant TTZ. The mean age at diagnosis was 52.45 years. The prevalence of cardiotoxicity in evaluable patients (1065 pts) was 20.3%. The proportion of patients who had symptomatic heart failure was 3% (32 pts) and in those who discontinued treatment for asymptomatic cardiac toxicity managed to resume trastuzumab prevalence was 92.6 %. About 9,7 % (21 pts) of patients had drop of left ventricular ejection fraction (LVEF) below 50%, whilst 10% drop of LVEF below their baseline levels were found in 75% of patients (162 pts) There is significant difference in the risk of cardiotoxicity according to the type of chemotherapy (anthracycline containing vs non-anthracycline based) (Chi-square = 3.9, p-value < 0.005). There was no evidence of a relationship between cardiovascular risk factors and the development of cardiotoxicity as well there was no evidence between sequential or concurrent use of TTZ with chemotherapy. Conclusions: The prevalence of cardiotoxicity in this study was similar to that reported internationally. The majority of patients did not develop cardiac toxicity and those who presented it did so asymptomatically and reversibly.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e13009-e13009
Author(s):  
Jamal Zekri ◽  
Haleem J. Rasool ◽  
Syed Azhar J Rizvi ◽  
Ehab Mosaad Abdel Ghany Mahmoud ◽  
Ayman Ahamd Rasmy ◽  
...  

e13009 Background: Chemotherapy regimens (C) containing a combination of anti-Her2 antibodies are associated with a risk of cardiac toxicity in landmark clinical trials. We evaluate the cardiac function of patients with Her2 over-expressed (Her2OE) breast cancer (BC) receiving C combined with trastuzumab (T) and pertuzumab (P) in routine clinical practice setting. Methods: The initial cohort of patients who started C in combination with TP (CTP) in standard doses and schedules before September 2019 in 4 cancer units were included. All patients had regular measurement of left ventricular ejection fraction (LVEF) by Doppler ultrasound studies. Data was collected retrospectively and was limited to the first 24 months after initiation of CTP treatment. The paired sample T-test was used to test the significance of the difference in LVEF. Results: Sixty seven patients were identified. CTP treatment was administered in the neoadjuvant and palliative settings in 28 (41.8%) and 39 (58.2%) respectively. None of the patients received concomitant anthracycline with TP. All patients underwent LVEF assessment prior to starting CTP treatment and at 3 and 6 months later. Subsequently LVEF was measured at 9, 12, 15, 18, 21 and 24 months as long as patients are still receiving CTP treatment (table). LVEF was measured in 11 patients for 24 months. Compared to baseline, mean LVEF was not significantly different at any of the subsequent time points (range; decrease by -0.936% to increase by 1.087%) (Table). Dual anti-Her2 antibodies (TP) administration was omitted temporarily once for 2 patients due to clinically suspected cardiac toxicity which was excluded on further investigations. Conclusions: In this cohort describing our limited initial experience, dual anti-Her2 antibodies (T&P) combined with chemotherapy is not associated with significant cardiac toxicity when LVEF is measured every 3 months. Further studies investigating less frequent LVEF monitoring (e.g. every 5-6 months) may be warranted.[Table: see text]


2016 ◽  
Vol 34 (6) ◽  
pp. 581-587 ◽  
Author(s):  
Pooja P. Advani ◽  
Karla V. Ballman ◽  
Travis J. Dockter ◽  
Gerardo Colon-Otero ◽  
Edith A. Perez

Purpose Significant improvement in survival outcomes has been established with the addition of trastuzumab to adjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2) –positive early breast cancer treatment. However, trastuzumab may increase the risk of cardiac toxicity, and long-term evaluation of its incidence and risk factors are warranted. Methods NCCTG (Alliance) N9831 trial compared adjuvant doxorubicin and cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab followed by trastuzumab alone (arm C) in patients with HER2-positive breast cancer. Cumulative incidence of cardiac events (CE) and left ventricular ejection fraction (LVEF) were evaluated in 1,944 women who proceeded to post-AC therapy. Risk factors for trastuzumab-induced cardiac toxicity were identified by Cox regression models. Results The 6-year cumulative incidence of CE was 0.6% in arm A, 2.8% in arm B, and 3.4% in arm C. At a median follow-up of 9.2 years, only two additional CHF diagnoses (of 1,046 patients) occurred beyond our previously reported follow-up time of 3.75 years. LVEF recovered in the majority of the patients who developed CHF. There were two cardiac deaths in arm A and one each in arms B and C. Age of 60 years or older, registration LVEF less than 65%, and use of antihypertensive medications were associated with an increased risk of CE in arms B and C. Conclusion The cumulative incidence of CE at 6 years was slightly higher with the addition of trastuzumab; however, the late development of CE is infrequent. Trastuzumab (in the context of anthracycline- and taxane-based therapy) continues to have a favorable benefit-risk ratio.


2020 ◽  
Vol 28 (3) ◽  
pp. 290-299
Author(s):  
Kira A. Ageeva ◽  
Evgenii V. Filippov

Aim. To study the prognostic value of the results of dynamic capnography in the complex assessment of parameters of the respiratory system in 6-minute walk test in patients with chronic heart failure (CHF). Materials and Methods. 73 Patients were examined: the group of study included 48 patients with IIA or IIB stage CHF (mean age 57.94.6 years, 23 men), the control group included 25 practically healthy volunteers (mean age 47.63.5 years, 9 men). The patients were conducted complex determination of parameters of the respiratory system: clinical scaling before and after 6-minute walk test (6MWT), instrumental examinations including spirometry, capnography and pulse oximetry before, during and after physical activity. The analysis of survival was conducted on the basis of the dynamic follow-up of patients within 5 years (60 months). Results. In the analysis of parameters of dyspnea at rest, all the parameters were higher in the group of patients with CHF (р0.05). The distance walked by the patients with CHF in 6 minutes was 488.2390.84 m, which was significantly less than in the control group (815.6053.89 m, р=0.009). Dyspnea as the cause of stoppage/slowing down of walking in 6MWT, was also more often recorded in patients with CHF (93.83.0% and 48.05.1%, р=0.049). Besides, in 6MWT the patients noted: weakness in legs (50.15.0% in the group of CHF and 40.05.0% in the control group, р=0.014), palpitation (29.04.6% and 20.04.1%, respectively, р=0.004). Worsening of dyspnea parameters in 6MWT was more evident in patients with CHF than in the control group (р0.01). In the CHF group, hypocapnic type of ventilation was revealed in 6MWT, analysis of РЕТСО2 trend graphs revealed a wave-like increase in the parameters, the so called periodic breathing (PB). CO2 trend was recorded in CHF group in 58.31.0% of cases (the difference with the control group with р=0.046), the trend of heart rate in 18.80.3% of cases (р=0.027). Cox proportional hazards regression analysis of mortality in patients with CHF showed a prognostic significance of a complex model comprising the following parameters of a patient: body mass index (р=0.005), left ventricular end-diastolic dimension (р=0.034), left ventricular end-systolic dimension (р=0.002), left ventricular ejection fraction (р=0.041), 6MWT distance (р=0.004), desaturation (р=0.009), and the presence of signs of PB during 6MWT (р=0.005). Model coefficients were statistically significant at р0.0001. Conclusions. Dynamic capnography and pulse oximetry allow to identify signs of PB in patients with CHF during 6MWT which may deepen a complex assessment of parameters of the cardio-respiratory system in patients with CHF in order to determine tolerance to physical exercise as well as the effectiveness of the conducted treatment. Complex assessment of survival of patients with CHF showed prognostic significance of the following parameters of a patient: body mass index, left ventricular end-diastolic dimension, left ventricular end-systolic dimension, left ventricular ejection fraction, 6MWT distance, desaturation, PB during 6MWT.


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