Original Article
Protective Effect of the Bispiperazinedione ICRF-187 against Doxorubicin-Induced Cardiac Toxicity in Women with Advanced Breast Cancer
N Engl J Med 1988; 319:745-752September 22, 1988DOI: 10.1056/NEJM198809223191203
- Abstract
- Abstract
Studies in animals suggest that the bispiperazinedione ICRF-187 can prevent the development of dose-related doxorubicin-induced cardiac toxicity. In a randomized trial in 92 women with advanced breast cancer, we compared treatment with fluorouracil, doxorubicin, and cyclophosphamide (FDC), given every 21 days, with the same regimen preceded by administration of ICRF-187 (FDC+ICRF-187). Patients were withdrawn from the study when cardiac toxicity developed or the cancer progressed.
The mean cumulative dose of doxorubicin tolerated by patients withdrawn from study was 397.2 mg per square meter of body-surface area in the FDC group and 466.3 mg in the FDC+ICRF-187 group (no significant difference). Eleven patients on the FDC+ICRF-187 arm received cumulative doxorubicin doses above 600 mg per square meter, whereas one receiving FDC was able to remain in the study beyond this dose. Antitumor response rates were similar (FDC vs. FDC+ICRF-187, 3 vs. 4 complete responses; 17 vs. 17 partial responses; and 9.3 vs. 10.3 months to disease progression). Although myelosuppression was slightly greater in the FDC+ICRF-187 group, the incidence of fever, infections, alopecia, nausea and vomiting, or death due to toxicity did not differ between the groups.
Cardiac toxicity was evaluated by clinical examination, determination of the left ventricular ejection fraction by multigated nuclear scans, and endomyocardial biopsy. In comparisons of the FDC group with the FDC+ICRF-187 group, clinical congestive heart failure was observed in 11 as compared with 2 patients; the mean decrease in the left ventricular ejection fraction was 7 vs. 1 percent when the cumulative dose of doxorubicin was 250 to 399 mg per square meter (P = 0.02), 16 vs. 1 percent at 400 to 499 mg (P = 0.001), and 16 vs. 3 percent at 500 to 599 mg (P = 0.003); and the Billingham biopsy score was 2 or more in 5 of 13 patients undergoing biopsy vs. none of 13 (P = 0.03).
We conclude that ICRF-187 offers significant protection against cardiac toxicity caused by doxorubicin, without affecting the antitumor effect of doxorubicin or the incidence of noncardiac toxic reactions. (N Engl J Med 1988; 319:745–52.)
Media in This Article
Figure 1
Percentage of Patients Remaining Free of Disease Progression in the FDC Arm (Broken Line) and the FDC+ICRF-187 Arm (Solid Line).Figure 2
Mean Fall (Percent) from Base Line in the Resting LVEF as Determined by Nuclear Scan in the FDC Arm (Dark Bars) and the FDC+ICRF-187 Arm (Light Bars).Article Activity
- Article
THE clinical use of doxorubicin and related antitumor anthracyclines is often limited by the actual or potential development of cardiac toxicity. This toxicity, which is characterized by diffuse myocardial injury leading to irreversible cardiomyopathy, is dose related, with a probability of 10 percent that clinical evidence of congestive heart failure will develop when cumulative doses of doxorubicin rise above 450 mg per square meter of body-surface area.1 2 3 4 Other factors that increase the risk of cardiomyopathy are an age of more than 65 years, previous irradiation to the chest wall, and preexisting cardiac disease.1 Monitoring of the left ventricular ejection fraction (LVEF) by means of multigated nuclear scans has improved the ability to detect early cardiac toxicity. We previously demonstrated that a decrease in the LVEF was frequent among women with metastatic breast cancer treated with doxorubicin.5 Appreciable decrements in LVEF were often observed when cumulative doses of doxorubicin were less than 450 mg per square meter.
Initial attempts at reducing the cardiotoxicity of anthracyclines consisted of alterations in the dosing schedule, after weekly regimens had been reported to be less toxic.6 Subsequently, infusion of drugs for 48 to 96 hours4 or even longer7 was tested on the premise that high peak levels of drug were associated with myocardial injury. Analogues were introduced that had been reported to be less cardiotoxic in animal tumor models.8 9 10 While seeking to separate cardiotoxic from antitumor effects, Myers et al.11 demonstrated the deleterious effect of activated-oxygen species resulting from anthracycline-derived free radicals. This led to preclinical study of antioxidants and other protective agents, including alpha-tocopherol,11 N-acetylcysteine,12 and eventually ICRF-159 and ICRF-187.13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
The bispiperazinedione ICRF-187 is the more soluble (+) enantiomorph of the racemic mixture known as ICRF-159, or razoxane. It was originally synthesized by Creighton et al. as a possible antitumor agent22 and was extensively tested in animals19 , 23 24 25 26 and in humans by oral administration.27 These cyclic compounds are hydrolyzed intracellularly to form a bidentate chelator bearing a resemblance to EDTA. In Phase I trials, the limiting toxic effect of ICRF-187 was leukopenia, which occurred with doses of more than 4000 mg per square meter.28 29 30 31
In 1972, while testing chelating agents in dogs, Herman et al. used razoxane to prevent a doxorubicin-induced decrease in coronary-artery perfusion.32 The efficacy of razoxane in this system led to subsequent studies by Herman, Ferrans, and others, in which ICRF-187 or razoxane was found to protect against the cardiomyopathy induced by administration of doxorubicin or daunorubicin to mice,16 , 23 , 27 rats,17 guinea pigs,16 miniature swine,18 rabbits,14 and beagle dogs.20 , 21 Other toxic effects of doxorubicin, such as alopecia, mucositis, and myelosuppression, were unchanged. The test drugs did not interfere with the antitumor effect of daunomycin against L1210 leukemia.24 Cardiac protection could be achieved with ratios of ICRF-187 to doxorubicin that did not add appreciably to systemic toxicity, if the drugs were administered within a short time of each other (less than 1 to 2 hours).
We investigated whether ICRF-187 could selectively protect against doxorubicin-induced cardiotoxicity without altering the clinical efficacy of a standard antineoplastic regimen. We tested this in a prospective randomized clinical trial in women with advanced breast cancer.
Methods
Eligibility of Patients
All potential subjects had histologically confirmed advanced or metastatic carcinoma of the breast. Those who had been treated with doxorubicin or other anthracyclines were excluded; those treated with other drugs were eligible if they had received them as part of adjuvant treatment, provided that disease had recurred more than six months after the cessation of treatment. Subjects who had received hormonal therapy and radiotherapy were eligible, provided that radiation treatment had been completed at least two weeks before study entry and had been delivered to less than 50 percent of the pelvic bone structure and lower spine. All subjects had to have evaluable or measurable disease outside of radiation fields and to have recovered from the effects of all previous therapy.
We required that subjects have an adequate performance status (score of 0 to 3 according to the criteria of the Eastern Cooperative Oncology Group [ECOG]),33 bone marrow function (a white-cell count >4.0X 109 per liter, and a platelet count >100X 109 per liter), renal function (creatinine concentration ≤177 μmol per liter [2 mg per deciliter]), and hepatic function (total bilirubin concentration <51 μmol per liter [3 mg per deciliter] and aspartate aminotransferase concentration <1 μkat per liter [60 U per liter], unless the liver was the site of metastatic disease). We excluded patients who had active cardiac disease, including myocardial infarction occurring within 12 months, active angina pectoris, symptomatic valvular heart disease, or uncontrolled congestive heart failure. The base-line resting LVEF had to be greater than or equal to 0.45.
Informed consent, as stipulated by the institutional review board of New York University, was obtained from all patients.
Stratification and Randomization
All patients were stratified according to whether they had previously received adjuvant chemotherapy (yes/no) and whether they had cardiac risk factors (yes/no). These risk factors were an age of more than 65; previous irradiation to the heart, mediastinum, or chest wall; and a history of hypertension (blood pressure > 140/90 mm Hg), cardiac failure, diabetes mellitus, angina, rheumatic heart disease, or an abnormality on electrocardiography. According to the scheme for randomization, patients were placed in blocks of 10 within each stratum, to receive a standard regimen of fluorouracil, doxorubicin, and cyclophosphamide (FDC)34 alone or the same regimen preceded by administration of ICRF-187.
Therapy and Dose Modification
The chemotherapy regimen consisted of intravenous doxorubicin (a bolus dose of 50 mg per square meter, given over 5 to 15 minutes [Adria Laboratories, Columbus, Ohio]) followed by intravenous cyclophosphamide (500 mg per square meter [Mead Johnson, Evansville, Ind.]) and intravenous fluorouracil (500 mg per square meter [Roche Laboratories, Nutley, N.J.]). ICRF-187 (1000 mg per square meter [obtained from the National Cancer Institute, Bethesda, Md.]) was given intravenously over 15 minutes, 30 minutes before FDC. Treatment was repeated every 21 days. In order to keep the dose of doxorubicin equivalent in each study arm, dose reductions in the initial two treatment cycles were made only in the levels of fluorouracil and cyclophosphamide. Treatment was delayed for one week if the white-cell count on the first day of each planned treatment cycle was less than 4.0 X 109 per liter or the platelet count was less than 100X109 per liter. If the nadir white-cell count was less than 1.5X109 or if the granulocyte count was less than 1.0X109 and the platelet count ranged from 75X109 to 100X 109, 75 percent of the dose of fluorouracil and cyclophosphamide was given. If the nadir white-cell count was less than 1.5X 109 or if the granulocyte count was less than 1X109 and the platelet count was less than 75 X 109, 50 percent of the dose of fluorouracil and cyclophosphamide was given. If nadir counts remained low after reductions were made during the first two cycles, the dose of doxorubicin was reduced according to the same guidelines. The dose of ICRF-187 was not modified. If the total bilirubin level was ≥34 μmol per liter (2 mg per deciliter) or the aspartate aminotransferase level was between 1.0 and 2.5 μkat per liter (60 and 150 U per liter), the dose of doxorubicin was reduced by 50 percent. If the bilirubin was between 34 and 51 μmol per liter (2 and 3 mg per deciliter) and the aspartate aminotransferase was greater than 2.5 μkat per liter (150 U per liter), the dose of doxorubicin was reduced by 75 percent. If the white-cell nadir was greater than 1.5X 109 after the cycle in which the dose of doxorubicin was reduced because of inadequate hepatic function, doxorubicin was increased to the full dose. If stomatitis of ECOG Grade 233 was present, the doses of fluorouracil, doxorubicin, and cyclophosphamide were reduced by 25 percent; for stomatitis of Grade 3, all three doses were reduced by 50 percent.
Clinical and Cardiologic Evaluation
The results of history taking and physical examination, including the measurement of weight and performance status, were reported before each course of therapy and at withdrawal from the study. Patients were examined individually by the study cardiologist at base line, when gated radionuclide cardiac scans were obtained, and when the patients left the study. Chest x-ray films and electrocardiograms were obtained at base line, at the time of nuclear scans, and when patients left the study. Noncardiac toxic reactions were monitored by the oncologist before each treatment cycle and by means of weekly blood counts during the first two cycles. Serum chemistries were determined every other cycle.
The cardiologists, nuclear medicine physicians, and pathologists who performed the cardiac evaluations were blinded to the patients' treatment group; the oncologists and patients were not.
Nuclear Scans
All scans were performed in the same laboratory by the same group of cardiologists and nuclear medicine physicians. Resting multigated nuclear scans were performed in all patients at base line and when the cumulative dose of doxorubicin reached 300 and 450 mg per square meter and each increment of 100 mg thereafter. Resting equilibrium gated blood-pool studies were performed with 20 to 30 mCi of 99mTc-labeled red cells according to the following "in vivo" method. One milligram of stannous chloride was injected intravenously, and the [99mTc]pertechnetate 20 minutes later. The gamma-camera acquisition was gated over a 16-frame interval in the left and right anterior oblique projections until a count density of approximately 250 counts per pixel was attained over the left ventricle. Scans in the left anterior oblique projection were also obtained with the patient exercising, when possible. The LVEF was calculated from the end-diastolic and end-systolic frames of the left anterior oblique views, after subtraction for background activity. Regions of interest were drawn manually. Segmental wall motion was assessed qualitatively from both the right and left anterior oblique views. The reproducibility of the LVEF measurements was 1.0±0.04 percent.
Endomyocardial Biopsies
Endomyocardial specimens were to be obtained in the cardiac catheterization laboratory whenever the cumulative dose of doxorubicin reached 450 mg per square meter. (Biopsy was performed with separate informed consent as approved by the institutional review board.) Right heart catheterization was performed with a triple linear thermodilution catheter, inserted through the internal jugular or femoral vein. With the position of the catheter confirmed fluoroscopically, five biopsy specimens of the right ventricular septum were obtained with a No. 9 French endomyocardial bioptome (Scholton Surgical Supplies, Redwood, Calif.) and placed immediately in glutaraldehyde. Histologic sections were prepared and stained with hematoxylin and eosin and also prepared for electron microscopy. Doxorubicin-induced changes were assessed by the study pathologist according to the Billingham scale.35 An average score for the five samples was determined.
Assessment of Antitumor Effect
Tumor status was assessed at base line, and whenever possible the tumor was measured in two dimensions. Radiographs and scans for assessment of tumors were required every three treatment cycles.
Standard ECOG criteria were used to assess tumor response.33 A complete response was defined as the complete disappearance of all tumor and normal results on scans and for laboratory values for at least 30 days. A partial response was represented by a decrease of more than 50 percent in the sum of the products of the measurement of the largest diameter of each tumor nodule and its perpendicular, for at least 30 days, and by healing of osteolytic lesions as observed on radiographs. A partial response of evaluable disease was indicated by a decrease of 50 percent in the evaluable disease or of at least 30 percent in lesions measured in one dimension.
Criteria for Stopping Treatment
Treatment was continued until the development of disease progression or toxicity. There was no predetermined cumulative dose at which to stop doxorubicin. The cardiologie criteria for stopping treatment were clinical signs of congestive heart failure, a fall in the resting LVEF to less than 0.45 or a fall from the base-line resting LVEF of 0.20 or more, and a Billingham biopsy grade of 2 or above.34
Statistical Analysts
For each patient, the change in the LVEF was calculated as the difference between the initial measurement at entry and subsequent measurements at each of several ranges of cumulative doses of doxorubicin. For each dose range, the statistical significance of the difference between the two treatment groups with respect to the fall in LVEF was determined by both the two-sample t-test and the rank-sum test. In general, P values are reported for the t-test only; however, if there were discrepancies between the results of these two methods of determining statistical significance, the result of the rank-sum test was preferred.
Similarly, statistical comparisons between the two treatment groups with respect to other continuous variables, such as the cumulative dose of doxorubicin, were made with both the t-test and the rank-sum test. The reported P values for the differences in means were derived from the t-test, whereas those for the differences in medians were derived from the rank-sum test. The chi-square statistic, corrected for continuity, was used to analyze differences in categorical variables between the treatment groups. Chi-square tests for linear trend were used to assess ordered categorical variables. Life-table analysis was used in comparisons involving time to disease progression and survival. The log-rank test was used to assess the significance of differences in survival curves. In general, results were considered significant if P<0.05. All P values are two-sided.
Results
Between July 1985 and September 1987, 92 patients admitted to our institution entered this study. Their characteristics are shown in Table 1Table 1
Characteristics of the Study Groups.. Forty-five patients received fluorouracil, doxorubicin, and cyclophosphamide (FDC), and 47 received this chemotherapy and ICRF-187 (FDC + ICRF-187). Both treatment arms were balanced in terms of age, performance status, previous adjuvant chemotherapy, radiation therapy, and hormonal therapy, and preexisting cardiac disease (Table 1).Table 2Table 2
Cycles of Treatment Received and Dose of Doxorubicin. shows the treatment received by all patients and those withdrawn from the study. Patients in the FDC arm who were withdrawn received a median of 8.9 cycles of therapy (range, 1 to 16), a median cumulative dose of doxorubicin of 448.3 mg per square meter (range, 50 to 650), and a mean of 397.2 mg per square meter. Those in the FDC + ICRF-187 arm who were withdrawn received a median of 9.3 cycles (range, 1 to 20), a median cumulative dose of doxorubicin of 450.3 mg per square meter (range, 50 to 1000), and a mean of 466.3 mg per square meter. These differences are not statistically significant.The projected dose of fluorouracil and cyclophosphamide was derived by multiplying the number of cycles of treatment received by the dose per cycle (500 mg per square meter). The percentage of the projected dose received was defined as the ratio of the actual cumulative dose to the projected dose. Because of dose modifications, the mean percentage of the projected dose of fluorouracil and cyclophosphamide that was received by the patients was 90 percent in the FDC arm and 82 percent in the FDC + ICRF-187 arm (P = 0.05).
The antitumor effect of the regimen was similar in both treatment arms. There were 44 patients who could be evaluated for response in each arm. There were 3 complete responses and 17 partial responses in the FDC arm, and 4 complete and 17 partial responses in the FDC + ICRF-187 arm. The overall response rates were 45 and 48 percent, respectively. The median time to the progression of disease was 9.3 months in the FDC arm and 10.3 months in the FDC + ICRF-187 arm patients (no significant difference) (Fig. 1Figure 1
Percentage of Patients Remaining Free of Disease Progression in the FDC Arm (Broken Line) and the FDC+ICRF-187 Arm (Solid Line).).Most measures of noncardiac toxicity did not differ significantly between the two treatment groups (Table 3Table 3
Noncardiac Toxic Effects.). The nadir counts in the first cycle reflected treatment given without dose modifications, and those in the second cycle reflected adjustments in the given dose that were based on the toxicity observed during the first cycle. The mean nadir white-cell counts (XlO9 per liter) in the first and second cycles were, respectively, 3.0 (range, 0.4 to 10.0) and 2.8 (range, 0.3 to 6.2) in the FDC arm and 2.4 (range, 0.1 to 10.0) and 2.4 (range, 0.8 to 9.9) in the FDC + ICRF-187 arm. Although the differences in the mean nadir white-cell count were not statistically significant (by t-test), the difference between the medians in the second cycle was significant (FDC vs. FDC + ICRF-187, 2.5 vs. 2.2; P = 0.03, rank-sum test). The mean platelet nadir in the FDC arm in both the first and second cycles (230) was similar to that in the FDC + ICRF-187 arm (210 and 212). The mean hematocrit in the FDC in the first and second cycles (0.35 and 0.33) was also similar to the value in the FDC + ICRF-187 arm (0.34 and 0.33). The incidence of mucositis, infection, fever with neutropenia, alopecia, nausea, and vomiting was similar in the two arms of the study.Six treatment-related deaths occurred: four in the FDC arm (one due to cardiac causes, two due to sepsis, and one due to infection without positive blood cultures), and two in the FDC + ICRF-187 arm (one due to intracerebral hemorrhage and one due to sepsis).
Cardiac Toxicity
There were 11 episodes of clinical cardiac toxicity in the FDC arm and 2 episodes in the FDC + ICRF-187 arm (P = 0.02). According to the New York Heart Association classification of cardiac status,36 the numbers of patients in the FDC arm with clinical evidence of toxicity were three with Grade 1 status, one with Grade 2, two with Grade 3, and five with Grade 4. Both of the patients in the FDC + ICRF-187 arm who had clinical toxicity had Grade 2 status.
Nuclear Scans
The change in the resting LVEF as measured by multigated nuclear scans was expressed as the difference from the base-line value for each patient. Changes are reported for all patients. The group means for the change from base line are shown in Figure 2Figure 2
Mean Fall (Percent) from Base Line in the Resting LVEF as Determined by Nuclear Scan in the FDC Arm (Dark Bars) and the FDC+ICRF-187 Arm (Light Bars)., in relation to the cumulative dose of doxorubicin. The mean base-line LVEF in the FDC arm was 66.1 percent, and that in the FDC + ICRF-187 arm was 63.6 percent. At dose ranges of 250 to 599 mg per square meter, the mean fall from base line was significantly less in the FDC + ICRF-187 arm. For the range from 250 to 399 mg per square meter, the mean fall was 1.6 percent for FDC + ICRF-187 and 6.6 percent for FDC (P = 0.02); for 400 to 499 mg, it was 1.4 versus 15.4 percent (P<0.001); and for 500 to 599 mg, it was 3.0 versus 15.8 percent (P = 0.003). At dose ranges above 600 mg per square meter, only one patient in the FDC arm remained in the study, as compared with 11 patients in the FDC + ICRF-187 arm. There was no apparent decrease in the LVEF in these 12 patients.A similar analysis of exercise gated radionuclide cardiac scans gave similar results. However, since the patients were unable to complete the exercise protocol because of metastatic disease, the sample size was decreased and, consequently, the power of these comparisons was less.
Endomyocardial Biopsies
Twenty-eight biopsies were performed: 15 in the patients who received FDC alone and 13 in those who received FDC + ICRF-187. These represent 52 and 48 percent, respectively, of the patients in whom the cumulative dose of doxorubicin reached 450 mg per square meter. One biopsy in the FDC arm and two biopsies in the FDC + ICRF-187 arm were performed when the cumulative dose reached 550 mg per square meter, because of a problem in scheduling, and one other biopsy was done at 300 mg per square meter (FDC arm). Two of the biopsies, both in patients in the FDC arm, yielded tissue inadequate for evaluation.
The Billingham biopsy scores in the FDC arm were Grade 2 in five patients, Grade 1.5 in one, Grade 1 in three, Grade 0.5 in One, and Grade 0 in three. In the FDC + ICRF-187 arm, the scores were Grade 1 in six patients and Grade 0 in seven. Biopsy scores were significantly higher in the FDC arm (P = 0.03, test for linear trend).
Discussion
The data from this prospective randomized clinical trial at a single institution support the hypothesis that ICRF-187 protects against the development of chronic doxorubicin-induced cardiac toxicity without adding to the toxicity of the regimen or decreasing its antitumor activity.
In animal studies, the heart was protected when the ratio of the dose of ICRF-187 to that of doxorubicin was between 10:1 and 15:1.13 14 15 16 17 18 19 20 21 22 , 24 25 26 For our patients, we chose a dose of 1000 mg of ICRF-187 per square meter, which was 20 times the dose of doxorubicin.
ICRF-187 contributed only slightly to the decrease in the nadir white-cell count; this result represented the major noncardiac toxic effect of the FDC regimen and did add appreciably to the incidence of fever, infection, or treatment-related death. That ICRF-187 had minimal additive toxicity is further demonstrated by an analysis of percentage of the predicted cumulative dose of fluorouracil and cyclophosphamide that was actually received (90 percent for FDC vs. 82 percent for FDC + ICRF-187). Since dose reductions were made preferentially for these two drugs, cumulative doses of doxorubicin were not different early in the study.
ICRF-187 did not reduce the antitumor activity of the FDC regimen. The observed rates of objective response and the time to disease progression were similar to those observed by other investigators in patients with metastatic breast cancer who were treated with the FDC regimen, including patients in whom adjuvant therapy had failed.37
Our study is based on the ability to separate the antitumor activity of doxorubicin from the cardiotoxic effects of the drug.11 , 20 , 21 In vitro studies with ICRF-18719 , 38 have demonstrated no loss of antitumor effect and possible synergy when this agent was combined with doxorubicin. It should be noted, however, that our study was not designed to test whether an interaction occurs between the antitumor effects of doxorubicin and ICRF-187. A much larger trial would be required.
Whether survival was increased by the protective effect of ICRF-187 cannot be determined from the present data. A therapeutic advantage would be expected only in the patients who received a dose of doxorubicin that was greater than the usual dose for stopping treatment, 450 mg per square meter. Since this dose was reached just after the median time to disease progression and since many patients were treated with "salvage" regimens, larger trials are required to test for improved survival.
All three methods of cardiac evaluation confirmed that ICRF-187 protected against chronic doxorubicininduced cardiac damage. Clinical congestive heart failure occurred in 11 of the patients in the FDC arm who left the study, but in only 2 of the patients in the FDC + ICRF-187 arm. Two patients who received FDC were removed from study for "clinical cardiac reasons" by their primary physicians, without objective documentation. Neither had a fall in the LVEF (13 and 4 percentage points, respectively) that met our criteria for withdrawal. At cardiac biopsy in one of these patients, the biopsy score was Grade 1.
The overall rate of clinical congestive heart failure (18 percent) was slightly higher than previously reported; however, we were looking carefully for the development of toxicity and may have detected it at an earlier stage. Retrospective studies may underestimate the true incidence of cardiac toxicity. Only 7.6 percent of patients (all receiving FDC) had a New York Heart Association score above 2. Although doxorubicin administration was continued so that cumulative doses were more than 450 mg per square meter, the use of careful clinical follow-up and frequent multigated nuclear scans allowed severe toxicity to be minimized.
The protective effects of ICRF-187 were clearly documented by the more sensitive nuclear scans. Protection was apparent even when doses of doxorubicin were low (250 to 399 mg per square meter) (Fig. 2). Twelve patients receiving ICRF-187 have remained in the study after receiving doses of doxorubicin of more than 500 mg per square meter, with little evidence of cardiac compromise as shown by the resting LVEF.
A decrease in the resting LVEF to a value below the normal range is the strongest predictor of clinical toxicity; 9 of 13 patients with clinical toxicity had a fall from base line to less than 0.45 (8 in the FDC arm and 1 in the FDC + ICRF-187 arm). Four of these nine patients, all of whom received FDC only, underwent endomyocardial biopsy; their biopsy scores were 2, 2, 2, and 0.5. Three of these four patients also had subsequent clinical heart failure. We5 and others3 have recommended that the magnitude of the fall from base-line LVEF in each patient be examined, as well as the absolute value. A decrease in the LVEF of more than 0.2 certainly represents an altered cardiac response even though this value is still in the "normal" range. If only "abnormal" LVEF values of less than 0.45 were recorded or if patients were evaluated only if they received high cumulative doses of doxorubicin, then important doxorubicin-induced changes in cardiac function would be missed. We chose a fall in the LVEF of 0.2 as a criterion for study withdrawal since our trials had shown that a fall of 0.1 was rarely associated with a clinical event and might prompt premature termination of potentially useful therapy.5 If one examines smaller falls in the resting LVEF, the incidence of abnormality increases but the protection persists — e.g., at the cutoff points of 0.15 (P = 0.001) and 0.10 (P = 0.0005). If the scan-determined criteria for removal from the study — i.e., a fall in the LVEF of 3=0.2 and a fall to less than 0.45 — are combined, cardiac protection is still evident (P = 0.001).
Endomyocardial biopsy is regarded by some investigators as the most specific and most sensitive method of detecting doxorubicin-induced cardiotoxicity. We performed biopsies when the cumulative dose of doxorubicin reached 450 mg per square meter, since this is the conventional stopping point. Interpretation of the biopsy results is limited by the fact that only 52 percent of patients in the FDC arm and 48 percent of patients in the FDC + ICRF-187 arm consented to biopsy. We may have missed some patients with more abnormal findings since patients with major signs of clinical heart failure (New York Heart Association Grades 3 and 4) were often unable to undergo biopsy. Of the 13 patients considered to have clinical cardiotoxicity, only 5 underwent cardiac biopsies (all 5 were in the FDC arm). The biopsy scores for four of these patients were 1, 2, 2, and 2; the specimen from one patient was unevaluable. None of the scores were more than 2. Five of 11 evaluable specimens from patients in the FDC arm had a score of 2, whereas none of the 13 from patients in the FDC + ICRF-187 arm had a score of more than 1. In extensive experience with endomyocardial biopsies in patients who were receiving doxorubicin, scores of 2 or more were most likely to correlate with severe clinical cardiac failure.4 , 39 If these limitations are accepted, the biopsies show that ICRF-187 confers substantial protection.
Because not all patients underwent biopsy, we cannot provide a complete correlation between the findings at biopsy and those of clinical evaluation and the scans. Furthermore, we cannot exclude the possibility that factors other than doxorubicin increased clinical cardiac toxicity. If we include any cardiac event, using the original study criteria, there were 22 patients with at least one event in the FDC arm and 4 patients with at least one event in the FDC + ICRF-187 arm (P<0.001).
ICRF-187 did not protect completely. Clinical congestive failure developed in two patients in the FDC + ICRF-187 arm who received doses of doxorubicin of 450 and 360 mg per square meter. The clinical symptoms were mild in both patients (New York Heart Association Grade 2). In one, the nuclear scan confirmed the cardiac impairment (LVEF = 0.44). Other doses or schedules of ICRF-187 administration could perhaps result in greater protection, but higher doses would probably increase myelosuppression substantially.
Finally, the effect of ICRF-187 on the treatment of the patients is evident among the reasons for removing patients from study. Of the 39 patients removed from the FDC arm, 22 were removed because of cardiac abnormalities and 15 solely because of cardiac toxicity. In the FDC + ICRF-187 arm, only 4 patients were removed because of cardiotoxicity. Conversely, only 10 patients in the FDC arm continued to receive treatment until their disease progressed, whereas 21 in the FDC + ICRF-187 arm were able to do so.
The mechanism by which the heart is protected by ICRF-187 is not completely understood. It is possible that ICRF-187, a strong chelator of Fe+ +, prevents the generation of singlet oxygen40 by the doxorubicin: iron complex41 and inhibits intracardiac peroxidative damage. The unique sensitivity of the heart to doxorubicin may be secondary to the poor enzymatic defenses in the mammalian heart against injury due to free radicals (decreased catalase and Superoxide dismutase)42 or against doxorubicin-induced lowering of glutathione peroxidase.43 Generation of free radicals is believed to be the mechanism of doxorubicin-induced cardiac toxicity, and intra-DNA intercalation or topoisomerase II–induced DNA cleavage is considered to be the mechanism of tumor-cell killing. Free-radical-induced injury at multiple intracellular sites may also be involved.44 45 46 Our results suggest that mechanisms of doxorubicin-induced cardiotoxicity and antitumor activity are distinct. Differences in intracellular metabolism or in transport of ICRF-187 by tumor cells and normal myocardial cells could also explain these results.
Regardless of the mechanism, this study establishes that ICRF-187 protects against doxorubicin-induced cardiotoxicity. Patients who are responding to doxorubicin or who might benefit from it may safely receive higher cumulative doses of this anticancer drug.
Supported by a grant (36524) from the U.S. Public Health Service, by grants (CA-I6087 and CRC-RR-99) from the National Institutes of Health, by the Lila Motley Foundation, and by the Chemotherapy Foundation.
Presented as an abstract at a meeting of the American Society of Clinical Oncology, Atlanta, May 19, 1987, and at the First International Symposium on Organ Specific Toxicity of Anti-Cancer Drugs, Burlington, Vt., June 4–6, 1987.
We are indebted to the many members of the professional staff of the New York University Medical Center, for caring for the patients; to Drs. Marleen Meyers and Howard Hochster, for assisting in patient care; to Drs. Matthew Harris, Daniel Roses, W. Robson Grier, Alan Postel, and Fred Golomb, for surgical consultations; to our patients, for giving of themselves with great courage and good humor; to Dr. Arthur C. Fox, for reviewing the manuscript; to Margaret Nixdorf, for assisting in manuscript preparation; and to Susan Taubes, for data management.
Source Information
From the Rita & Stanley Kaplan Cancer Center, the Departments of Medicine, Divisions of Oncology (J.L.S., M.D.G., C.W., J.W., R.B., F.M.) and Cardiology (M.R., P.S., F.F., W.S.), the Department of Radiology, Division of Nuclear Medicine (E.K., J.S.), and the Institute of Environmental Medicine Laboratory of Epidemiology and Biostatistics (N.D., A.Z.-J.), New York University Medical Center, New York; and the Ultrastructural Pathology Branch, National Heart, Lung, and Blood Institute (V.F.), Bethesda, Md. Address reprint requests to Dr. Speyer at NYU Medical Center, Old Bellevue Administration Bldg., Division of Oncology, 462 First Ave., Rm. 224, New York, NY 10016.
- References
References
1
Von Hoff
Web of Science | Medline2
Praga
Medline3
Schwartz
CrossRef | Web of Science | Medline4
Legha
Web of Science | Medline5
Speyer
CrossRef | Web of Science | Medline6
Weiss
Medline7
Gamick 8
Casazza
Medline9
Weiss
CrossRef | Web of Science | Medline10
Green M, Speyer J, Muggia F. Clinical trials with new anthracyclines in the U.S. In: Hansen HH, ed. Anthracyclines and cancer chemotherapy. Amsterdam: Excerpta Medica, 1983:112–8.
11
Myers
CrossRef | Web of Science | Medline12
Doroshow
CrossRef | Web of Science | Medline13
Herman
Medline14
Herman
Medline15
Herman 16
Perkins
CrossRef | Web of Science | Medline17
Herman
CrossRef | Web of Science | Medline18
Herman
Web of Science | Medline19
Wheeler
CrossRef | Medline20
Herman
Web of Science | Medline21
Herman
Web of Science | Medline22
Creighton
CrossRef | Web of Science | Medline23
Herman
CrossRef | Web of Science | Medline24
Woodman
Medline25
Giuliani
Medline26
Wang
CrossRef | Web of Science | Medline27
Hellmann
CrossRef | Web of Science | Medline28
Koeller
Medline29
Liesmann
CrossRef | Web of Science | Medline30
Von Hoff
Medline31
Holcenberg
Medline32
Herman
Web of Science | Medline33
Oken
CrossRef | Web of Science | Medline34
Aisner
Web of Science | Medline35
Billingham
Medline36
The Criteria Committee of the New York Heart Association. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 8th ed. Boston: Little, Brown, 1979.
37
Henderson IC. Chemotherapy for advanced disease. In: Harris JR, Hellman S, Henderson IC, et al., eds. Breast diseases. Philadelphia: J.B. Lippincott, 1987:428–79.
38
Wadler
Web of Science | Medline39
Bristow
CrossRef | Web of Science | Medline40
Myers CE. Role of iron in anthracycline action. In: Tritton T, ed. Proceedings of First International Symposium on Organ Related Toxicity. Boston: Martinus Nijhoff. 1988:17–31.
41
Myers
CrossRef | Web of Science | Medline42
Doroshow
CrossRef | Web of Science | Medline43
Revis
CrossRef | Web of Science | Medline44
Doroshow
Web of Science | Medline45
Doroshow
CrossRef | Web of Science | Medline46
Sinha
CrossRef | Web of Science | Medline
- Citing Articles (129)
Citing Articles
1
Filipa S. Carvalho, Ana Burgeiro, Rita Garcia, António J. Moreno, Rui A. Carvalho, Paulo J. Oliveira. (2013) Doxorubicin-Induced Cardiotoxicity: From Bioenergetic Failure and Cell Death to Cardiomyopathy. Medicinal Research Reviewsn/a-n/a
2
Marion Castel, Fabien Despas, Anouchka Modesto, Céline Gales, Benjamin Honton, Michel Galinier, Jean-Michel Senard, Atul Pathak. (2013) Effets indésirables cardiaques des chimiothérapies. La Presse Médicale 42:1, 26-39
3
Brian C Jensen, Howard L McLeod. (2013) Pharmacogenomics as a risk mitigation strategy for chemotherapeutic cardiotoxicity. Pharmacogenomics 14:2, 205-213
4
Eugene Oh, Harvey Chim, Hooman T. Soltanian. (2012) The effects of neoadjuvant and adjuvant chemotherapy on the surgical outcomes of breast reconstruction. Journal of Plastic, Reconstructive & Aesthetic Surgery 65:10, e267-e280
5
Thomas J. L'Ecuyer, Sanjeev Aggarwal, Jiang Ping Zhang, Richard S. Van der Heide. (2012) Effect of hypothermia on doxorubicin-induced cardiac myoblast signaling and cell death. Cardiovascular Pathology 21:2, 96-104
6
Yi Lisa Lyu, Leroy F. Liu. Doxorubicin Cardiotoxicity Revisited. In: Recent Advances in Cancer Research and Therapy. Elsevier, 2012:351-369.
7
Elvira C van Dalen, Huib N Caron, Heather O Dickinson, Leontien CM Kremer, Elvira C van Dalen. Cardioprotective interventions for cancer patients receiving anthracyclines. In: Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd, 2011.
8
Douglas B. Sawyer, Chang-seng Liang, Wilson S. Colucci. Oxidative and Nitrosative Stress in Heart Failure. In: Heart Failure: A Companion to Braunwald's Heart Disease. Elsevier, 2011:185-197.
9
Michael S. Ewer, Steven M. Ewer. (2010) Cardiotoxicity of anticancer treatments: what the cardiologist needs to know. Nature Reviews Cardiology 7:10, 564-575
10
Katherine A Janeway, Holcombe E Grier. (2010) Sequelae of osteosarcoma medical therapy: a review of rare acute toxicities and late effects. The Lancet Oncology 11:7, 670-678
11
Elvira C van Dalen, Huib N Caron, Heather O Dickinson, Leontien CM Kremer, Elvira C van Dalen. Cardioprotective interventions for cancer patients receiving anthracyclines. In: Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd, 2008.
12
Laurel Steinherz. (2008) Early Breast Cancer Therapy and Cardiovascular Injury. Journal of the American College of Cardiology 51:12, 1235
13
James L. Speyer, Boris Kobrinsky, Michael S. Ewer. Cardiac Effects of Cancer Therapy. In: Abeloff's Clinical Oncology. Elsevier, 2008:983-998.
14
Yan-Fei Xin, Guo-Liang Zhou, Min Shen, Yun-Xiang Chen, Shu-Peng Liu, Guo-Chan Chen, Hao Chen, Zhen-Qiang You, Yao-Xian Xuan. (2007) Angelica sinensis: A Novel Adjunct to Prevent Doxorubicin-Induced Chronic Cardiotoxicity. Basic & Clinical Pharmacology & Toxicology 101:6, 421-426
15
Tamar Safra. (2007) Chemotherapeutics and cardiac toxicity: treatment considerations and management strategies. Community Oncology 4:9, 540-548
16
William P. Hogle. (2007) Cytoprotective Agents Used in the Treatment of Patients With Cancer. Seminars in Oncology Nursing 23:3, 213-224
17
Genzou Takemura, Hisayoshi Fujiwara. (2007) Doxorubicin-Induced Cardiomyopathy. Progress in Cardiovascular Diseases 49:5, 330-352
18
Chemotherapeutic Agents and Thalidomide. In: Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose. Elsevier, 2007:927-941.
19
Ei Ikegami, Ryuji Fukazawa, Masaru Kanbe, Miki Watanabe, Masanori Abe, Makoto Watanabe, Mitsuhiro Kamisago, Miharu Hajikano, Yasuhiro Katsube, Shunichi Ogawa. (2007) Edaravone, a Potent Free Radical Scavenger, Prevents Anthracycline-Induced Myocardial Cell Death. Circulation Journal 71:11, 1815-1820
20
Maurizio Civelli, Daniela Cardinale, Alessandro Martinoni, Giuseppina Lamantia, Nicola Colombo, Alessandro Colombo, Sara Gandini, Giovanni Martinelli, Cesare Fiorentini, Carlo M. Cipolla. (2006) Early reduction in left ventricular contractile reserve detected by dobutamine stress echo predicts high-dose chemotherapy-induced cardiac toxicity. International Journal of Cardiology 111:1, 120-126
21
I.K. Mohan, K.V. Kumar, M.U.R. Naidu, M. Khan, C. Sundaram. (2006) Protective effect of CardiPro against doxorubicin-induced cardiotoxicity in mice. Phytomedicine 13:4, 222-229
22
Mahmood Khan, Saradhadevi Varadharaj, Jagdish C Shobha, Madireddi U Naidu, Narasimham L Parinandi, Vijay Kumar Kutala, Periannan Kuppusamy. (2006) C-Phycocyanin Ameliorates Doxorubicin-Induced Oxidative Stress and Apoptosis in Adult Rat Cardiomyocytes. Journal of Cardiovascular Pharmacology 47:1, 9-20
23
Annette Frost, Daniela Gmehling, Marc Azemar, Clemens Unger, Klaus Mross. (2006) Treatment of Anthracycline Extravasation with Dexrazoxane – Clinical Experience. Onkologie 29:7, 314-318
24
Mahmood Khan, Jagdish Chandra Shobha, Iyyapu Krishna Mohan, Madireddi Umamaheswara Rao Naidu, Challa Sundaram, Shashi Singh, Periannan Kuppusamy, Vijay Kumar Kutala. (2005) Protective effect ofSpirulina against doxorubicin-induced cardiotoxicity. Phytotherapy Research 19:12, 1030-1037
25
Marcelo G. Paiva, Antônio S. Petrilli, Valdir A. Moisés, Carla Renata Donato Macedo, Cristiana Tanaka, Orlando Campos. (2005) Cardioprotective effect of dexrazoxane during treatment with doxorubicin: A study using low-dose dobutamine stress echocardiography. Pediatric Blood & Cancer 45:7, 902-908
26
Eileen M. Hoke, Caroline A. Maylock, Emily Shacter. (2005) Desferal inhibits breast tumor growth and does not interfere with the tumoricidal activity of doxorubicin. Free Radical Biology and Medicine 39:3, 403-411
27
EC van Dalen, HN Caron, HO Dickinson, LCM Kremer, Elvira van Dalen. Cardioprotective interventions for cancer patients receiving anthracyclines. In: The Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd, 2005.
28
Nicholas J. Robert, Charles L. Vogel, I. Craig Henderson, Joseph A. Sparano, Melvin R. Moore, Paula Silverman, Beth A. Overmoyer, Charles L. Shapiro, John W. Park, Gail T. Colbern, Eric P. Winer, Alberto A. Gabizon. (2004) The role of the liposomal anthracyclines and other systemic therapies in the management of advanced breast cancer. Seminars in Oncology 31, 106-146
29
Lipshultz , Steven E. , Rifai , Nader , Dalton , Virginia M. , Levy , Donna E. , Silverman , Lewis B. , Lipsitz , Stuart R. , Colan , Steven D. , Asselin , Barbara L. , Barr , Ronald D. , Clavell , Luis A. , Hurwitz , Craig A. , Moghrabi , Albert , Samson , Yvan , Schorin , Marshall A. , Gelber , Richard D. , Sallan , Stephen E. , . (2004) The Effect of Dexrazoxane on Myocardial Injury in Doxorubicin-Treated Children with Acute Lymphoblastic Leukemia. New England Journal of Medicine 351:2, 145-153
Free Full Text30
Kirsten J.M Schimmel, Dick J Richel, Renée B.A van den Brink, Henk-Jan Guchelaar. (2004) Cardiotoxicity of cytotoxic drugs. Cancer Treatment Reviews 30:2, 181-191
31
Srigiridhar Kotamraju, Shasi V. Kalivendi, Eugene Konorev, Christopher R. Chitambar, Joy Joseph, B. Kalyanaraman. Oxidant-Induced Iron Signaling in Doxorubicin-Mediated Apoptosis. Elsevier, 2004:362-382.
32
Maria Theodoulou, Andrew D Seidman. (2003) Cardiac effects of adjuvant therapy for early breastcancer. Seminars in Oncology 30:6, 730-739
33
Diane M.F Savarese, Gayle Savy, Linda Vahdat, Paul E Wischmeyer, Barbara Corey. (2003) Prevention of chemotherapy and radiation toxicity with glutamine. Cancer Treatment Reviews 29:6, 501-513
34
M.I. Gharib, A.K. Burnett. (2002) Chemotherapy-induced cardiotoxicity: current practice and prospects of prophylaxis. European Journal of Heart Failure 4:3, 235-242
35
Evert L de Beer, Antonio E Bottone, Maartje C van Rijk, Jolanda van der Velden, Emile E Voest. (2002) Dexrazoxane pre-treatment protects skinned rat cardiac trabeculae against delayed doxorubicin-induced impairment of crossbridge kinetics. British Journal of Pharmacology 135:7, 1707-1714
36
Michael P Kosty, James E Herndon, Nicholas J Vogelzang, Hedy L Kindler, Mark R Green. (2001) High-dose doxorubicin, dexrazoxane, and GM-CSF in malignant mesothelioma: a phase II study—Cancer and Leukemia Group B 9631. Lung Cancer 34:2, 289-295
37
K.B Chakrabarti, J.W Hopewell, D Wilding, P.N Plowman. (2001) Modification of doxorubicin-induced cardiotoxicity. European Journal of Cancer 37:11, 1435-1442
38
M. Verrill. (2001) Anthracyclines in breast cancer: therapy and issues of toxicity. The Breast 10, 8-15
39
P. Schmid, K. Possinger. (2001) Liposomal anthracyclines for improved cardiac tolerability. The Breast 10, 22-27
40
Evert L De Beer, Antonio E Bottone, Emile E Voest. (2001) Doxorubicin and mechanical performance of cardiac trabeculae after acute and chronic treatment: a review. European Journal of Pharmacology 415:1, 1-11
41
Terrence W. Doyle, Dolatrai M. Vyas. Chemotherapeutics, Anticancer. In: Kirk-Othmer Encyclopedia of Chemical Technology. John Wiley & Sons, Inc., 2000.
42
Daniela Cardinale, Maria Teresa Sandri, Alessandro Martinoni, Alessio Tricca LabTech, Maurizio Civelli, Giuseppina Lamantia, Saverio Cinieri, Giovanni Martinelli, Carlo M Cipolla, Cesare Fiorentini. (2000) Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy. Journal of the American College of Cardiology 36:2, 517-522
43
Arshia Noori, Joann Lindenfeld, Eugene Wolfel, Debbie Ferguson, Michael R. Bristow, Brian D. Lowes. (2000) β-Blockade in adriamycin-induced cardiomyopathy. Journal of Cardiac Failure 6:2, 115-119
44
A.J. Birtle. (2000) Anthracyclines and Cardiotoxicity. Clinical Oncology 12:3, 146-152
45
Charles H. Cha, Gregory D. Kennedy, John E. Niederhuber. (1999) METASTATIC BREAST CANCER. Surgical Clinics of North America 79:5, 1117-1143
46
, Jens Büntzel. (1999) Erfahrungen mit Natriumselenit in der Behandlung von akuten und späten Nebenwirkungen der Radiochemotherapie von Kopf-Hals-Karzinomen. Medizinische Klinik 94:S3, 49-53
47
YiHong Cao, Richard Kennedy, V.Suzanne Klimberg. (1999) Glutamine Protects against Doxorubicin-Induced Cardiotoxicity. Journal of Surgical Research 85:1, 178-182
48
Bo S Andersson, Staffan Eksborg, Ricardo F Vidal, Monica Sundberg, Magdalena Carlberg. (1999) Anthraquinone-induced cell injury: acute toxicity of carminomycin, epirubicin, idarubicin and mitoxantrone in isolated cardiomyocytes. Toxicology 135:1, 11-20
49
Koichi Sugimoto, Makoto Sasaki, Kenji Tamayose, Kazuo Oshimi. (1999) Inhibition of p34cdc2 dephosphorylation in DNA damage- and topoisomerase II inactivation-induced G2 arrests in HL-60 cells. British Journal of Haematology 105:3, 720-729
50
Johannes Feenstra, Diederick E Grobbee, Willem J Remme, Bruno H.Ch Stricker. (1999) Drug-induced heart failure. Journal of the American College of Cardiology 33:5, 1152-1162
51
H. Rosing, W. W. Ten Bokkel Huinink, R. Gijn, R. F. M. Rombouts, A. Bult, J. H. Beijnen. (1999) Comparative open, randomized, cross-over bioequivalence study of two intravenous dexrazoxane formulations (Cardioxane® and ICRF-187) in patients with advanced breast cancer, treated with 5-fluorouracil-doxorubicin-cyclophosphamide (FDC). European Journal of Drug Metabolism and Pharmacokinetics 24:1, 69-77
52
Ronald Bukowski. (1999) Cytoprotection in the treatment of pediatric cancer: Review of current strategies in adults and their application to children. Medical and Pediatric Oncology 32:2, 124-134
53
Khaled A. Tolba, Efthymios N. Deliargyris. (1999) Cardiotoxicity of Cancer Therapy. Cancer Investigation 17:6, 408-422
54
Günter Weiss, Mark Loyevsky, Victor R. Gordeuk. (1999) Dexrazoxane (ICRF-187). General Pharmacology: The Vascular System 32:1, 155-158
55
Timothy J. Woodlock, Robin Lifton, Michael DiSalle. (1998) Coincident acute myelogenous leukemia and ischemic heart disease: Use of the cardioprotectant dexrazoxane during induction chemotherapy. American Journal of Hematology 59:3, 246-248
56
G. Falcone, W. Filippelli, B. Mazzarella, R. Tufano, P. Mastronardi, A. Filippelli, L. Berrino, F. Rossi. (1998) Cardiotoxicity of doxorubicin: Effects of 21-aminosteroids. Life Sciences 63:17, 1525-1532
57
Susan Goodin, Robert S. DiPaola. (1998) Strategies for using cytoprotective agents to improve outcomes associated with cancer chemotherapy. Disease Management and Clinical Outcomes 1:5, 155-160
58
Joseph Swafford, Harry R. Gibbs. (1998) CARDIAC COMPLICATIONS OF CANCER TREATMENT. Anesthesiology Clinics of North America 16:3, 597-604
59
Richard F. Stevens, Ian M. Hann, Keith Wheatley, Richard G. Gray, . (1998) Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukaemia: results of the United Kingdom Medical Research Council's 10th AML trial. British Journal of Haematology 101:1, 130-140
60
Henk van den Berg, Jószef Zsiros, Anita Veneberg, Nardi J. Schutten, Wilma Kroes, Rosalyn M. Slater, Henk Behrendt. (1998) Favorable outcome after 1-year treatment of childhood T-cell lymphoma/T-cell acute lymphoblastic leukemia. Medical and Pediatric Oncology 30:1, 46-51
61
Laurel J Steinherz, Leonard H Wexler. (1998) The prevention of anthracycline cardiomyopathy. Progress in Pediatric Cardiology 8:3, 97-108
62
Henri Faure, Mireille Mousseau, Jean Cadet, Catherine Guimier, Michelle Tripier, Hassan Hida, Alain Favier. (1998) Urine 8-Oxo-7, 8-Dihydro-2′-Deoxyguanosine vs. 5–(Hydroxymethyl) Uracil as DNA Oxidation Marker in Adriamycin-Treated Patients. Free Radical Research 28:4, 377-382
63
Julia Calzas, Pilar Lianes, Hernán Cortés-Funes. (1998) Corazón y neoplasias. Revista Española de Cardiología 51:4, 314-331
64
Lewis B. Silverman, Thomas W. McLean, Richard D. Gelber, Mia J. Donnelly, D. Gary Gilliland, Nancy J. Tarbell, Stephen E. Sallan. (1997) Intensified therapy for infants with acute lymphoblastic leukemia. Cancer 80:12, 2285-2295
65
William H. Frishman, Henry C.M. Yee, Deborah Keefe, Helen M. Sung, Linda L. Liu, Avi I. Einzig, Janice Dutcher. (1997) Cardiovascular toxicity with cancer chemotherapy. Current Problems in Cancer 21:6, 301-360
66
Robert J Boucek. (1997) Mechanisms for anthracycline-induced cardiomyopathy: clinical and laboratory correlations. Progress in Pediatric Cardiology 8:2, 59-70
67
Atsuyoshi Maeda, Masaaki Honda, Takehiko Kuramochi, Koichi Tanaka, Toshikazu Takabatake. (1997) AN ANGIOTENSIN-CONVERTING ENZYME INHIBITOR PROTECTS AGAINST DOXORUBICIN-INDUCED IMPAIRMENT OF CALCIUM HANDLING IN NEONATAL RAT CARDIAC MYOCYTES. Clinical and Experimental Pharmacology and Physiology 24:9-10, 720-726
68
N.I. Weijl, F.J. Cleton, S. Osanto. (1997) Free radicals and antioxidants in chemotherapyinduced toxicity. Cancer Treatment Reviews 23:4, 209-240
69
Gunter Weiss, Stefan Kastner, Jeremy Brock, Josef Thaler, Kurt Grünewald. (1997) Modulation of transferrin receptor expression by dexrazoxane (ICRF-187) via activation of iron regulatory protein. Biochemical Pharmacology 53:10, 1419-1424
70
P.- F. CONTE, A. ROMANINI, I. BRUNETTI, P. GIANNESSI, A. FANUCCHI, A. GADDUCCI. (1997) Ovarian cancer in elderly women. International Journal of Gynecological Cancer 7:s1, 23-26
71
E. Cameron, S.D. Heys, D. Bruce, O. Eremin, A.W. Hutcheon, P.H. Whiting. (1997) Combination chemotherapy and renal enzyme and protein excretion in patients with breast cancer. The Breast 6:1, 26-30
72
Julie Blatt. (1997) Editorial: ICRF-187 As a Cardioprotectant in Children Treated with Anthracyclines. Pediatric Hematology-Oncology 14:3, iii-vi
73
A. Schiavetti, M. A. Castello, P. Versacci, G. Varrasso, A. Padula, F. Ventriglia, B. Werner, V. Colloridi. (1997) Use of ICRF-187 for Prevention of Anthracycline Cardiotoxicity in Children: Preliminary Results. Pediatric Hematology-Oncology 14:3, 213-222
74
D. Schuler, E. Horváth, R. Koós, P. Kajtár, I. Zimonyi, I. Virág, P. Masát, M. Garami, J. D. Borsi. (1997) Safety of Dexrazoxane in Children with All Undergoing Anthracycline Therapy: Preliminary Results of a Prospective Pilot Study. Pediatric Hematology-Oncology 14:1, 93-94
75
O.I. Aruoma. (1996) Peroxyl radical scavenging activity of the antihypertensive drug carvedilol. Toxicology in Vitro 10:5, 625-629
76
Vittorina Zagonel, Lucia Fratino, Cosimo Sacco, Roberta Babare, Simon Spazzapan, Valter Gattei, Salvatore Improta, Antonio Pinto. (1996) Reducing chemotherapy-associated toxicity in elderly cancer patients. Cancer Treatment Reviews 22:3, 223-244
77
Paul Pouna, Simone Bonoron-Adèle, Gérard Gouverneur, Liliane Tariosse, Pierre Besse, Jacques Robert. (1996) Development of the model of rat isolated perfused heart for the evaluation of anthracycline cardiotoxicity and its circumvention. British Journal of Pharmacology 117:7, 1593-1599
78
Norishi Ueda, Radhakrishna Baliga, Sudhir V Shah. (1996) Role of ‘catalytic’ iron in an animal model of minimal change nephrotic syndrome. Kidney International 49:2, 370-373
79
R.T. Dorr, K. Lagel, S. McLean. (1996) Cardioprotection of rat heart myocytes with amifostine (Ethyol®) and its free thiol, WR-1065, in vitro. European Journal of Cancer 32, S21-S25
80
F Pein, G Vassal, C Sakiroglu, M.F Tournade, J Lemerle. (1995) Aspects pédiatriques de la toxicité cardiaque des anthracyclines et implications pratiques pour sa prévention. Archives de Pédiatrie 2:10, 988-999
81
Elizabeth A. Lowenthal, John T. Carpenter. (1995) The use of anthracyclines in the adjuvant treatment of breast cancer. Cancer Treatment Reviews 21:3, 199-214
82
Shujia J. Pan, Alan B. Combs. (1995) Effects of pharmacological interventions on emetine cardiotoxicity in isolated perfused rat hearts. Toxicology 97:1-3, 93-104
83
G.J. Kontoghiorghes, E.D. Weinberg. (1995) Iron: Mammalian defense systems, mechanisms of disease, and chelation therapy approaches. Blood Reviews 9:1, 33-45
84
(1995) Abstracts. Cancer Investigation 13:s1, 1-61
85
Chaim Hershko. (1994) 11 Control of disease by selective iron depletion: a novel therapeutic strategy utilizing iron chelators. Baillière's Clinical Haematology 7:4, 965-1000
86
Jan de Jong, Birgitta C.P. Hüsken, Bob Beekman, Wim J.F. van der Vijgh, Aalt Bast. (1994) Radical formation by metal complexes of anthracyclines and their metabolites. Is there a relation with cardiotoxicity?. European Journal of Pharmaceutical Sciences 2:3, 229-237
87
Jun Zhang, Eugene H. Herman, Victor J. Ferrans. (1994) Effects of ICRF-186 [(l)1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] on the toxicity of doxorubicin in spontaneously hypertensive rats. Toxicology 92:1-3, 179-192
88
Brian B. Hasinoff. (1994) An HPLC and spectrophotometric study of the hydrolysis of ICRF-187 (dexrazoxane, (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane) and its one-ring opened intermediates. International Journal of Pharmaceutics 107:1, 67-76
89
Michael S. Ewer, Mohamed K. Ali, Harry R. Gibbs, Joseph Swafford, Kristi L. Graff, Ayten Cangir, Norman Jaffe, Mohinder K. Thapar. (1994) Cardiac Diastolic Function in Pediatric Patients Receiving Doxorubicin. Acta Oncologica 33:6, 645-649
90
E. H. Herman, Jun Zhang, Victor J. Ferrans. (1994) Comparison of the protective effects of desferrioxamine and ICRF-187 against doxorubicin-induced toxicity in spontaneously hypertensive rats. Cancer Chemotherapy and Pharmacology 35:2, 93-100
91
B. B. Hasinoff, S. Venkataram, M. Singh, T. I. Kuschak. (1994) Metabolism of the cardioprotective agents dexrazoxane (ICRF-187) and levrazoxane (ICRF-186) by the isolated hepatocyte. Xenobiotica 24:10, 977-987
92
Brian B. Hasinoff. (1994) Pharmacodynamics of the hydrolysis-activation of the cardioprotective agent (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane. Journal of Pharmaceutical Sciences 83:1, 64-67
93
Joan L. Buss, Brian B. Hasinoff. (1993) The one-ring open hydrolysis product intermediates of the cardioprotective agent ICRF-187 (dexrazoxane) displace iron from iron-anthracycline complexes. Agents and Actions 40:1-2, 86-95
94
B. B. Hasinoff, S. V. Kala. (1993) The removal of metal ions from transferrin, ferritin and ceruloplasmin by the cardioprotective agent ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] and its hydrolysis product ADR-925. Agents and Actions 39:1-2, 72-81
95
Carin Thomas, Glenn F. Vile, Christine C. Winterbourn. (1993) The hydrolysis product of ICRF-187 promotes iron-catalysed hydroxyl radical production via the Fenton reaction. Biochemical Pharmacology 45:10, 1967-1972
96
Lynn Ann Meister, Anna T. Meadows. (1993) Late effects of childhood cancer therapy. Current Problems in Pediatrics 23:3, 102-131
97
Norbertus C. Robben, Andrew W. Pippas, Joseph O. Moore. (1993) The syndrome of 5-fluorouracil cardiotoxicity. An elusive cardiopathy. Cancer 71:2, 493-509
98
David T. Rossi, Barbara A. Phillips, John R. Baldwin, Prem K. Narang. (1993) Improved methodology for subnanogram quantitation of doxorubicin and its 13-hydroxy metabolite in biological fluids by liquid chromatography. Analytica Chimica Acta 271:1, 59-68
99
Russell L. Basser, Michael D. Green. (1993) Strategies for prevention of anthracycline cardiotoxicity. Cancer Treatment Reviews 19:1, 57-77
100
Giorgio Minotti. (1992) The role of an endogenous nonheme iron in microsomal redox reactions. Archives of Biochemistry and Biophysics 297:2, 189-198
101
Y. Fukuda, E.H. Herman, V.J. Ferrans. (1992) Effect of ICRF-187 on the pulmonary damage induced by hyperoxia in the rat. Toxicology 74:2-3, 185-202
102
Eugene D. Weinberg. (1992) Roles of iron in neoplasia. Biological Trace Element Research 34:2, 123-140
103
(1992) Childhood cancer, anthracyclines, and the heart. The Lancet 339:8806, 1388-1389
104
Debra Wujcik. (1992) Current research in side effects of high-dose chemotherapy. Seminars in Oncology Nursing 8:2, 102-112
105
Annette Galassi. (1992) The next generation: New chemotherapy agents for the 1990s. Seminars in Oncology Nursing 8:2, 83-94
106
Franco M. Muggia. (1992) Managing breast cancer in an outpatient setting. Breast Cancer Research and Treatment 21:1, 27-34
107
De Juran Richardson. (1992) Withdrawal censoring and the sequential logrank procedure. Statistics in Medicine 11:10, 1359-1366
108
John F. Forbes. (1992) Long-Term Effects of Adjuvant Chemotherapy in Breast Cancer. Acta Oncologica 31:2, 243-250
109
(1992) Abstracts. Cancer Investigation 10:s1, 1-41
110
Richard B. Silverman. DNA. In: The Organic Chemistry of Drug Design and Drug Action. Elsevier, 1992:220-276.
111
Klaus Mross. (1991) New anthracycline derivatives: What for?. European Journal of Cancer and Clinical Oncology 27:12, 1542-1544
112
Thomas G. Burke, Terry D. Lee, Josephus van Balgooy, James H. Doroshow. (1991) Characterization of the aqueous decomposition products of (+)1,2-bis(3,5-dioxopiperazinyl-1-yl)-propane (ICRF-187) by liquid chromatographic and mass spectral analysis. Journal of Pharmaceutical Sciences 80:4, 338-340
113
Doroshow , James H. , . (1991) Doxorubicin-Induced Cardiac Toxicity. New England Journal of Medicine 324:12, 843-845
Full Text114
Franco M. Muggia, Michael D. Green. (1991) New anthracycline antitumor antibiotics. Critical Reviews in Oncology/Hematology 11:1, 43-64
115
J. Koning, P. Palmer, C.R. Franks, D.E. Mulder, J.L. Speyer, M.D. Green, K. Hellmann. (1991) Cardioxane—ICRF-187 towards anticancer drug specificity through selective toxicity reduction. Cancer Treatment Reviews 18:1, 1-19
116
Eugene H. Herman, Victor J. Ferrans. (1990) Examination of the potential long-lasting protective effect of ICRF-187 against anthracycline-induced chronic cardiomyopathy. Cancer Treatment Reviews 17:2-3, 155-160
117
B. B. Hasinoff. (1990) The iron(III) and copper(II) complexes of adriamycin promote the hydrolysis of the cardioprotective agent ICRF-187 ((+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane). Agents and Actions 29:3-4, 374-381
118
James H. Doroshow, Steven Akman, Fong-Fong Chu, Steven Esworthy. (1990) Role of the glutathione-glutathione peroxidase cycle in the cytotoxicity of the anticancer quinones. Pharmacology & Therapeutics 47:3, 359-370
119
Ronald H. Blum, Christina Walsh, Michael D. Green, James L. Speyer. (1990) Modulation of the Effect of Anthracycline Efficacy and Toxicity by ICRF-187. Cancer Investigation 8:2, 267-268
120
Michael D. Green, Peggy Alderton, Janet Gross, Franco M. Muggia, James L. Speyer. (1990) Evidence of the selective alteration of anthracycline activity due to modulation by ICRF-187 (ADR-529). Pharmacology & Therapeutics 48:1, 61-69
121
Nigel Bailey, George Blackledge. Cytostatics and immunosuppressive drugs. Elsevier, 1990:397-420.
122
A. Francine Tryka. (1989) ICRF 187 and polyhydroxyphenyl derivatives fail to protect against bleomycin induced lung injury. Toxicology 59:2, 127-138
123
Victor J. Ferrans. (1989) Pathologic anatomy of the dilated cardiomyopathies. The American Journal of Cardiology 64:6, C9-C11
124
D.Y. Wang, H. Hamed, C.I. Mockridge, I.S. Fentiman. (1989) Radioimmunoassayable insulin-like growth factor-I in human breast cyst fluid. European Journal of Cancer and Clinical Oncology 25:5, 867-872
125
Stefan S. Bielack, Rudolf Erttmann, Kurt Winkler, Günther Landbeck. (1989) Doxorubicin: Effect of different schedules on toxicity and anti-tumor efficacy. European Journal of Cancer and Clinical Oncology 25:5, 873-882
126
(1989) ICRF-187 and Doxorubicin-Induced Cardiac Toxicity. New England Journal of Medicine 320:6, 399-400
Full Text127
Brian B. Hasinoff, John P. Davey, Peter J. O'brien. (1989) The Adriamycin (doxorubicin)-induced inactivation of cytochrome c oxidase depends on the presence of iron or copper. Xenobiotica 19:2, 231-241
128
Brian B. Hasinoff. (1989) Self-reduction of the iron(III)-doxorubicin complex. Free Radical Biology and Medicine 7:6, 583-593
129
A. Herbay, B. Dörken, G. Mall, M. Körbling. (1988) Cardiac damage in autologous bone marrow transplant patients: An autopsy study. Klinische Wochenschrift 66:23, 1175-1181
