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Long-Term Cardiac Sequelae in Operable Breast Cancer Patients Given Adjuvant Chemotherapy With or Without Doxorubicin and Breast Irradiation

From the Istituto Nazionale Tumori, Milan, Italy.

Address reprint requests to Luca Gianni, MD, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milano, Italy; email gianni@ istitutotumori.mi.it.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To investigate long-term cardiac sequelae associated with anthracycline use in adjuvant chemotherapy of patients with early breast cancer.

PATIENTS AND METHODS: All 1,000 patients from three prospective trials of adjuvant chemotherapy containing doxorubicin (n = 637, median total dose of 294 mg/m²) or not containing the anthracycline (cyclophosphamide, methotrexate, and fluorouracil [CMF] regimen alone, n = 363) were analyzed for the relative incidence of congestive heart failure (CHF) and myocardial infarction (MI) during 14 years of follow-up. The 462 women continuously free of disease as of February 1996 were recalled, and 355 consented to undergo evaluation including 12-lead ECG and cardiac ultrasound with determination of left ventricular ejection fraction (LVEF) to assess the relative incidence of abnormalities in long-term survivors.

RESULTS: Among the 1,000 patients, there were six cases of CHF and three cases of MI. Cumulative cardiac mortality accounted for 0.4% (doxorubicin-treated = 0.6%; CMF-treated = 0). Eighteen (5%) of the 355 patients undergoing cardiac evaluation after median 11 years of follow-up presented systolic dysfunction as defined by pathologic (< 50%, n = 8) or borderline (50% to 55%, n = 10) LVEF. Systolic dysfunction was higher in doxorubicin-treated (15 of 192; 8%) than in CMF-treated patients (three of 150; 2%). Breast irradiation had a significant impact on the occurrence of early CHF (four of 116; 3%), but not on systolic dysfunctions.

CONCLUSION: At longer than 10 years of follow-up, the use of doxorubicin at a total dose commonly applied in regimens of adjuvant chemotherapy does not lead to cardiac clinical sequelae that counter-balance the benefit of treatment in patients with operable breast cancer who may be cured of their disease.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE KNOWN POTENTIAL of anthracyclines to induce chronic cardiac toxicity¹ is cause of concern that the antitumoral benefit associated with their use is counter-balanced and abrogated by severe cardiac morbidity. Such a concern is supported by findings indicating that the onset of anthracycline cardiac effects may be late (> 10 years after therapy) and yet to unfold in many asymptomatic patients after remote anthracycline use.²

The weight of late onset cardiac effects on the overall outcome of treatment in different neoplastic diseases is not well known, nor is it easy to define. In children treated with anthracyclines, occurrences of cardiac events (late arrhythmia, valvular disease, and left ventricular dysfunction) have been reported 4 to 20 years after therapy discontinuation.^3,4 In adult patients given doxorubicin with or without mediastinal irradiation, clinical or subclinical abnormalities of ventricular function have been documented.⁵

The use of anthracyclines in women with metastatic breast cancer⁶ or in adjuvant treatment of patients with operable breast cancer⁷ offers a significant therapeutic advantage. Given their relatively long survival, patients undergoing adjuvant chemotherapy with anthracyclines would seem especially suited to address the question of balance between therapeutic benefit and risk of cardiac morbidity. However, in women who underwent adjuvant chemotherapy, the estimate of late cardiotoxicity attributable to anthracyclines is difficult because of the aging of the patients and the confounding cardiac effects of intercurrent menopause, the locoregional irradiation involving the heart structure, and the presence of cardiac risk factors independent of chemotherapy. In addition, early deaths attributed to breast cancer progression may cause an underestimation of the incidence of late cardiac toxicities.

Despite these apparent difficulties, a recent retrospective evaluation of breast cancer patients given adjuvant cyclophosphamide and doxorubicin (45 mg/m² per cycle) revealed that, compared with the general female population, high total doses of the anthracycline (10 cycles) were associated with a three- to four-fold increase in risk of cardiac events, especially when high-dose volumes of cardiac irradiation were also delivered.⁸

Given the important bearing that knowledge of long-term treatment-related morbidity has on therapeutic decision making, in the present study we show the findings of the cardiac effects observed during follow-up of 1,000 patients who entered three prospective clinical trials performed at the Istituto Nazionale Tumori of Milano in the 1980s. Treatment consisted of adjuvant chemotherapy with or without doxorubicin and with or without breast irradiation. These data have been combined with the analysis of a direct clinical and instrumental cardiac assessment performed in 355 women who represent a subset of patients who were continuously free of recurrence for a median of 11 years after adjuvant systemic treatment. The study allows for a more direct estimate of the risk of late cardiac toxicity associated with anthracycline use in a population of adult women potentially cured of their neoplastic disease.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
From January 1980 to July 1995, three different randomized adjuvant programs, based on the extension of nodal involvement at surgery, were carried out at the Istituto Nazionale Tumori. The details on study designs and drug therapy have been reported elsewhere.^9-11 Briefly, patients with node-negative and estrogen receptor–negative tumors were randomly allocated to receive intravenous (IV) cyclophosphamide, methotrexate, and fluorouracil (CMF) for 12 courses every 3 weeks (45 women) versus no systemic treatment.⁹ Patients with limited nodal extension (< four positive nodes) received the every-3-weeks IV CMF regimen for 12 courses (275 women) versus the same drug combination for eight courses followed by four doses of doxorubicin 75 mg/m² every 3 weeks (277 women).¹⁰ Finally, patients with four or more positive nodes were all given four doses of doxorubicin either in a sequential fashion (201 women), with the anthracycline given front-line and followed by eight courses of IV CMF, or in an alternating schedule (202 women) of CMF and doxorubicin.¹¹ All but two patients subjected to breast-conserving surgery received irradiation to the remaining portion of the breast (50 Gy using opposing tangential fields plus a boost of 10 Gy in 4 to 6 weeks to be started within 6 to 8 weeks from surgery), which was delivered concurrently with adjuvant chemotherapy. Irradiation to other regions (eg, axilla, internal mammary nodes, chest wall) was not allowed, regardless of the extent of breast surgery.

Before entry into the three different protocols, patients were subjected to baseline examination to confirm eligibility criteria. Regarding cardiac events, patients with a history of congestive heart failure, myocardial infarction, or cardiomyopathy were considered ineligible, but patients presenting with other risk factors (such as high blood pressure or dyslipidemia, for instance) were not excluded.^9-11 All patients were continuously followed-up in the outpatient clinic of the Division of Medical Oncology A, both for detection of breast cancer relapse and occurrence of treatment complications. Cardiac monitoring required physical examination and recording of ECG findings once a year or whenever indicated by the clinical situation.

The medical records of 1,000 patients given adjuvant chemotherapy and followed-up for a median of 14 years (range, 9 to 17 years) as of December 1998 were reviewed for the development of cardiac events from the time of randomization to the most recent follow-up examination or death. Overall, a total of 363 women received CMF alone, either because of random allocation (320 patients) or for refusal to start doxorubicin or disease progression while on CMF (43 patients); 637 patients received both CMF and doxorubicin.

Subset Analysis and Criteria of Evaluation
From February 1996 to December 1998, all patients alive in first continuous clinical remission were requested to undergo an evaluation of the cardiac status that included history, physical examination, 12-lead ECG registration, and cardiac heart ultrasound with the determination of left ventricular ejection fraction (LVEF).

All patients were evaluated at the Division of Cardiology of our institute by the same team of physicians. ECG abnormalities were conventionally assessed. In particular, ST-T alterations were considered of aspecific significance in the absence of a positive history for ischemic heart disease, ventricular hypertrophy, or treatment with digitalis.

Patients underwent standard M-mode, two-dimensional, and Doppler echocardiography using a commercially available equipment (ATL Ultramark 9 [Advanced Technology Laboratories, Seattle, WA] with a 2.5-Mhz transducer). The left ventricular internal dimensions and wall thickness were measured from bidimensional guided M-mode recordings according to the recommendations of the American Society of Echocardiography.¹² Left ventricular enlargement was defined as an end-diastolic diameter exceeding 3.2 cm/m² of body-surface area.

LVEF was calculated according to Teichholz’s formula in patients with normal ventricles or in those with diffuse hypokinesis.¹³ In patients with inadequate parasternal views or in those with regional wall motion abnormalities, the monoplane or biplane area-length methods were used, respectively. Values of LVEF less than 50% were considered as clearly abnormal, whereas values between 50% and 55% were classified as borderline. The definition of systolic dysfunction was applied to all cases with abnormal and borderline LVEF.

Using color-flow mapping, mild regurgitations from mitral and aortic valves in patients with structurally normal hearts were not considered as events, whereas the other cases were classified as valvular disease. The diagnosis of hypertensive cardiopathy was formulated in the presence of a history of abnormal blood pressure and echographic findings of left ventricular hypertrophy and/or septal thickening. Isolated septal hypertrophy in the absence of positive history for arterial hypertension was evaluated separately.

	RESULTS

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Findings in the Total Case Series
Congestive heart failure was recorded in a total of six patients of the entire case series of 1,000 women (0.6%). All six patients had received doxorubicin (six of 637; 1%) with (4 of 116 or 3%) or without (2 of 521 or 0.4%, P = .012) left breast irradiation. Regarding total doses of doxorubicin delivered, only 26 women received between 75 and 150 mg/m², mainly because of refusal to continue treatment with the anthracycline. In only one of these patients (3.8%), doxorubicin was discontinued because of congestive heart failure after the second dose of the drug (total 150 mg/m²). All of the remaining five patients who developed congestive heart failure completed the four planned doses of the anthracycline (total doses of 294, 297, 297, 303, and 303 mg/m²) for a total incidence of 1.3% or five of 392 patients.

Four cases had been reported in a previous evaluation,¹⁴ and in all patients, cardiac disease developed during or within 1 month from the end of chemotherapy. Two women aged 67 and 61 years died of cardiac failure 32 and 86 months later, respectively. One patient who fully recovered from congestive heart failure developed a poorly differentiated endometrioid cancer of the ovary (stage III, grade 3) 67 months later at the age of 50 years; bilateral ovariosalpingectomy and hysterectomy was performed, followed by IV carboplatin for seven cycles and, subsequently, intraperitoneal fluorouracil for five cycles. She eventually died as a result of progressive ovarian cancer more than 10 years after the diagnosis of cardiac disease. Another patient developed congestive heart failure at the age of 38 years, and 11 years later she presented with systolic dysfunction due to a borderline (52%) LVEF value. The two additional cases recently documented (see below) presented with LVEF of less than 50% and cardiac dilatation.

Acute myocardial infarction was recorded in three patients, all treated with CMF alone (0.8%) but none with left breast irradiation. Two patients, mentioned below, were alive 3 and 8 years after infarction. The remaining patient developed bone metastases 5 months after infarction and died of progressive breast cancer 6 years later.

Cumulative rates of causes of death at a median overall follow-up of 14 years for the entire case series are reported in Table 1. Overall, breast cancer relapse represented the first cause of death, with a cumulative rate of 36.7%. It was more frequent in the doxorubicin-containing regimen (41.5%), because approximately 63% of the patients given the anthracycline were at high risk (> three positive axillary nodes) for breast cancer relapse, whereas CMF alone chemotherapy was delivered only in patients with intermediate prognosis.

Other causes of death not attributed to malignant disease included embolism (six patients) and suicide (four women).

Characteristics and Clinical Findings of Subset Analysis
As of February 1996, a total of 462 women were continuously free of disease for a median of 11 years (range, 6.0 to 14.6 years). Of these, 355 consented to undergo cardiac evaluation to assess potential iatrogenic toxicity. Locoregional and systemic treatments given to the patients at the diagnosis of breast cancer are described in Table 2. IV CMF every 3 weeks for a median of 8 courses (range, six to 12 courses) was administered to all patients. A total of 200 women (56%) also received doxorubicin for a median cumulative dose of 294 mg/m² (range, 75 to 308 mg/m²). Main patient characteristics are reported in Table 3. The median age was 47 years (range, 26 to 69 years) at entry into the therapeutic protocols and 58 years (range, 38 to 80 years) at the time of cardiac assessment.

At the time of the present evaluation, a history of congestive heart failure that developed at 6, 65, and 93 months from starting adjuvant chemotherapy was reported in three patients (0.8%), all treated with doxorubicin (1.5%). Acute myocardial infarction was recorded in two women given CMF 57 and 130 months from the start of chemotherapy.

ECG Findings
Pathologic ECG findings were documented in 80 patients (23%). Aspecific alterations of ST-T trait were reported in 12% of the patients, whereas two cases (0.5%) presented with signs of a previous myocardial infarction. Other findings were consistent with conduction disturbances (4%), left ventricular hypertrophy (4.5%), and arrhythmia (2%). In particular, arrhythmias were observed in seven patients, four of whom were treated previously with the anthracycline. The distribution of these pathologic findings seemed unrelated to the local and systemic treatments applied at the diagnosis of breast cancer, as shown in Fig 1.

View larger version (35K): [in this window] [in a new window]   Fig 1. Abnormal ECG findings according to systemic treatment. &U25A8;, CMF plus doxorubicin; , CMF.

Cardiac dilatation was present in all patients with abnormal LVEF, whereas it was recorded for only one woman with borderline values. Cardiac dilatation was also recorded in three additional patients. Two of them had other abnormal findings (ischemic and valvular disease), whereas in the third woman, cardiac dilatation was classified as idiopathic. Regional wall motion abnormalities, with LVEF greater than 55%, were reported in six women, half of them treated with the anthracycline.

	DISCUSSION

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Doxorubicin was introduced into clinical use more than a quarter of a century ago,¹⁶ but reports on long-term cardiac events in adult patients treated with this drug are still scanty. This may be due to different reasons. The first reports on the efficacy of doxorubicin were in patients with widespread cancer or highly aggressive malignancies, and survivorship was often poor. Consequently, only relatively few patients survived long enough to experience potential late cardiac events. In addition, patients undergoing anthracycline therapy were never stratified according to preexisting cardiac risk factors, so that cardiac events could not be attributed to treatment in an unbiased way. Finally, cardiac surveillance, when applied, was often based on techniques (eg, ECG monitoring) of uncertain value and sensitivity to detect anthracycline-dependent effects.

Patients with breast cancer have been indicated as especially suitable for studying the potential late cardiac effects of anthracyclines, because their sensitivity to this class of drugs and their survival would have allowed for prolonged clinical observation and adequate risk assessement.^17-19 Regimens of adjuvant systemic therapy that include anthracyclines would seem ideal in that respect. However, the introduction of doxorubicin into adjuvant therapy of breast cancer was not combined with prospective monitoring of the cardiac function in any major trial, so the vast majority of data on the sequelae of anthracycline use are based on retrospective evaluations.⁸

In the analysis of 1,000 patients presented in this report, we matched the data that emerged during the clinical follow-up of the trials with those gathered by ad hoc clinical and instrumental cardiac assessment of 355 women who were continuously free of disease.

In the overall 1,000 patients, the incidence of major cardiac events (congestive heart failure and acute myocardial infarction) remained low (approximately 1%) at a median follow-up of 14 years from the commencement of anticancer therapy. Congestive heart failure occurred only when doxorubicin, planned to be delivered at a total dose of 300 mg/m², was part of the chemotherapy regimen (six cases in 637 women; 1%). Irradiation to the remaining portion of the left breast represented an additional risk factor (four cases in 116 patients; 3%), especially when congestive heart failure developed during chemotherapy treatment or within 1 month from its discontinuation (three of four patients). Despite adequate medical treatment, congestive heart failure was fatal in two patients.

Doxorubicin-related congestive heart failure has been reported to occur during treatment or within 10 months from anthracycline discontinuation.¹ In our case series, four cases were documented during this period of time, but two additional cases were recorded 4.5 and 7 years after chemotherapy discontinuation, underscoring the risk of long-term cardiac toxicity in doxorubicin-treated patients. Similar findings were also observed by Shapiro et al,⁸ who, in a series of breast cancer patients given doxorubicin, reported that a high risk of cardiac events was observed up to 10 years after treatment. Regarding irradiation, it is important to re-emphasize that, in our patient sample, the internal mammary nodes were not purposely irradiated and standard tangential fields were delivered only to the remaining portion of the breast after conservative surgery. Such a limited program of irradiation has little or no cardiotoxic potential of its own according to recent reports.¹⁷ However, it could have exposed the heart to moderate dose volumes in left-sided tumors¹⁹ and contributed to increasing the damage to the myocardium. Acute myocardial infarction was recorded in three patients, but its occurrence was unrelated to both drug and locoregional treatment.

The subset of patients who underwent cardiac assessment offers a valuable opportunity to assess the impact of doxorubicin use in a population of patients who may be cured of their cancer and were subjected to a total dose of the anthracycline similar to that currently applied in many programs of adjuvant systemic therapy of breast cancer. In this group, cardiac function was assessed after a minimum of 6 years from starting adjuvant therapy. Systolic dysfunction was observed in 18 women (5%), occurred more frequently in doxorubicin-treated patients (8% v 2%; P = .032), but it was not significantly associated with left breast irradiation (9% v 7%). Importantly, 16 of the 18 patients with systolic dysfunction were asymptomatic, thus the clinical significance of the findings is uncertain. All 16 patients are presently under cardiologic monitoring to assess the possible development to overt major cardiac events.

The value of asymptomatic cardiac alterations in patients treated with doxorubicin is little known. Abnormal left ventricular systolic function was also reported to occur in two case series of children and young adults^3,4 at a long-term follow-up after anthracycline treatment for a variety of malignancies. By contrast, no attempt at investigating these events was performed on breast cancer patients in the series of Shapiro et al,⁸ where echocardiographic findings were reported only in patients with congestive heart failure or myocardial infarction.

A comparison between the findings recorded in children and young adults and our own results is difficult for many reasons. First of all, the median age of our patient subset was 47 years (range, 26 to 69 years) when treatment with doxorubicin was started, and the maximum cumulative dose delivered was 308 mg/m². Besides young age, the delivered doses of different anthracyclines, including daunorubicin hydrochloride, ranged between 200 and 1,275 mg/m² in the series of Steinherz et al,⁴ and the dose of doxorubicin was in the range of 45 to 550 mg/m² in the series of Lipshultz et al.³

The problem of doxorubicin-induced cardiac events remains a complex one. Our present report has both advantages and limitations. Our entire case series consists of 1,000 women who were all continuously followed-up in the outpatient clinic of the Division of Medical Oncology A, allowing for consistent criteria of evaluation and reporting. However, the trials were not designed to specifically address the problem of cardiac morbidity of administered therapies. Criteria of eligibility at entry into the therapeutic protocols required only a negative history of major cardiac diseases, but no in-depth examinations were required to assess cardiac function. In addition, follow-up examinations similarly did not require routine echographic monitoring but relied only on ECG findings, unless individual clinical situation suggested additional investigations. Because of this clinical monitoring, we decided to identify major cardiac events as congestive heart failure and acute myocardial infarction because they were more likely to be recorded in all patients and less apt to be biased by differential surveillance. Both the rates of incidence (approximately 1%) and mortality (0.4%) caused by these events are very low, especially when compared with the findings reported in other series,⁸ but our treatment program did not include high total doses of doxorubicin and irradiation was delivered to the breast only.

The value of the overall assessment in the 1,000 patients is strengthened by the consideration that the direct assessment of cardiac function in the subset of patients continuously free of disease for median 11 years did not cause a substantial shift in the number of cases with major cardiac problems. In these patients, the role of aging and of cardiac risk factors preexisting or independent of anthracycline use could not be explored, and the recorded asymptomatic alterations may still be due to doxorubicin therapy and could evolve to clinical symptoms. However, the low incidence of effects and events is reassuring that doxorubicin use was safe in the vast majority of patients, even after 11 years of follow-up from chemotherapy discontinuation.

In conclusion, the use of doxorubicin in regimens of systemic adjuvant therapy has undoubtedly contributed to further reduce the risk of disease relapse and death.⁷ The findings of the present report suggest that the risk of major cardiac events does not outweigh the benefits achieved. It is plausible that a more accurate patient selection, the administration of breast irradiation after and not concurrently with anthracyclines, as it is now current practice, and the accurate use of radiotherapy techniques could further reduce the risk of major cardiac disease. Meanwhile, we think that the findings of our study are relevant to appropriate decision making in treatment selection: at the dose of doxorubicin commonly used in adjuvant chemotherapy of breast cancer, the chance of inducing cardiac effects is low compared with the risk of decreasing the potential of cure without anthracyclines.

	NOTES

 
Presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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3. Lipshultz SE, Colan SD, Gelber R, et al: Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 324: 808-815, 1991[Abstract]

4. Steinherz LJ, Steinherz PG, Tan CTC, et al: Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 266: 1672-1677, 1991[Abstract/Free Full Text]

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Submitted June 5, 2000; accepted August 3, 2000.

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