The clinical use of anthracyclines like doxorubicin and daunorubicin can be viewed as a sort of double-edged sword. On the one hand, anthracyclines play an undisputed key role in the treatment of many neoplastic diseases; on the other hand, chronic administration of anthracyclines induces cardiomyopathy and congestive heart failure usually refractory to common medications. Second-generation analogs like epirubicin or idarubicin exhibit improvements in their therapeutic index, but the risk of inducing cardiomyopathy is not abated. It is because of their janus behavior (activity in tumors vis-a-vis toxicity in cardiomyocytes) that anthracyclines continue to attract the interest of preclinical and clinical investigations despite their longer-than-40-year record of longevity. Here we review recent progresses that may serve as a framework for reappraising the activity and toxicity of anthracyclines on basic and clinical pharmacology grounds. We review 1) new aspects of anthracycline-induced DNA damage in cancer cells; 2) the role of iron and free radicals as causative factors of apoptosis or other forms of cardiac damage; 3) molecular mechanisms of cardiotoxic synergism between anthracyclines and other anticancer agents; 4) the pharmacologic rationale and clinical recommendations for using cardioprotectants while not interfering with tumor response; 5) the development of tumor-targeted anthracycline formulations; and 6) the designing of third-generation analogs and their assessment in preclinical or clinical settings. An overview of these issues confirms that anthracyclines remain "evergreen" drugs with broad clinical indications but have still an improvable therapeutic index.

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Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

Although there has been considerable progress in reducing cancer incidence in the United States, the number of cancer survivors continues to increase due to the aging and growth of the population and improvements in survival rates. As a result, it is increasingly important to understand the unique medical and psychosocial needs of survivors and be aware of resources that can assist patients, caregivers, and health care providers in navigating the various phases of cancer survivorship. To highlight the challenges and opportunities to serve these survivors, the American Cancer Society and the National Cancer Institute estimated the prevalence of cancer survivors on January 1, 2012 and January 1, 2022, by cancer site. Data from Surveillance, Epidemiology, and End Results (SEER) registries were used to describe median age and stage at diagnosis and survival; data from the National Cancer Data Base and the SEER-Medicare Database were used to describe patterns of cancer treatment. An estimated 13.7 million Americans with a history of cancer were alive on January 1, 2012, and by January 1, 2022, that number will increase to nearly 18 million. The 3 most prevalent cancers among males are prostate (43%), colorectal (9%), and melanoma of the skin (7%), and those among females are breast (41%), uterine corpus (8%), and colorectal (8%). This article summarizes common cancer treatments, survival rates, and posttreatment concerns and introduces the new National Cancer Survivorship Resource Center, which has engaged more than 100 volunteer survivorship experts nationwide to develop tools for cancer survivors, caregivers, health care professionals, advocates, and policy makers.

https://onlinelibrary.wiley.com/doi/pdf/10.3322/caac.21149

Cancer treatment and survivorship statistics, 2012

2-D
: two-dimensional
3-D
: three-dimensional
5-FU
: 5-fluorouracil
ACE
: angiotensin-converting enzyme
ARB
: angiotensin II receptor blocker
ASE
: American Society of Echocardiography
BNP
: B-type natriuretic peptide
CABG
: coronary artery bypass graft
CAD
: coronary artery

/pdf/2016-esc-position-paper-on-cancer-treatments-and-1bzyne0xi3.pdf

2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines

Doxorubicin (Adriamycin) has been used in oncologic practice since the late 1960s. It held promise as a powerful drug in the fight against cancer. The tumors most commonly responding to doxorubicin when it is given as a single agent or in combination with other antitumor agents include breast and esophageal carcinomas; osteosarcoma, Kaposi's sarcoma, and soft-tissue sarcomas; and Hodgkin's and non-Hodgkin's lymphomas. Other cancers that are less responsive to doxorubicin but that are still treated with the drug because of its overall benefits include gastric, liver, bile-duct, pancreatic, and endometrial carcinomas. However, reports of fatal cardiotoxic effects of doxorubicin have . . .

Doxorubicin-Induced Cardiomyopathy

No abstract available
Keywords: European Society of Cardiology; arrhythmias; cancer therapy; cardio-oncology; cardiotoxicity; chemotherapy; early detection; ischaemia; myocardial dysfunction; surveillance.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ejhf.654

2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC)

Objective. —To assess the cardiac status of long-term survivors of pediatric malignancies who received chemotherapy, including anthracyclines. Design and Method. —Patients were evaluated by echocardiogram from 4 to 20 years (median, 7 years) after completion of anthracyclines, with prospective and retrospective analysis. Patients. —The consecutive sample of 201 patients had received a total anthracycline dose of 200 to 1275 mg/m2(median, 450 mg/m2), and 51 patients had mediastinal radiotherapy. Main Outcome Measures. —The overall incidence and severity of abnormal systolic cardiac function were determined for the entire cohort. Risk factors of total anthracycline dose, mediastinal radiotherapy, age during treatment, and length of follow-up were examined. Results. —Twenty-three percent (47/201) of the cohort had abnormal cardiac function on noninvasive testing at long-term follow-up. Correlation between total cumulative dose, length of follow-up, and mediastinal irradiation with incidence of abnormalities was significant. Fifty-six patients were followed up for 10 years or more (median, 12 years), with a median anthracycline dose of 495 mg/m2, Thirty-eight percent (21/56) of these patients, compared with 18% (26/145) of patients evaluated after less than 10 years, had abnormal findings. Sixty-three percent of patients followed up for 10 years or more after receiving 500 mg/m2or more of anthracyclines had abnormal findings. Nine of 201 patients had late symptoms, including cardiac failure and dysrhythmia, and three patients died suddenly. Microscopic examination of the myocardium on biopsy and autopsy revealed fibrosis. Conclusion. —The 23% incidence of late cardiac abnormalities warrants continued evaluation of patients after anthracyclines to guide patient care and the design of future chemotherapeutic protocols. (JAMA. 1991;266:1672-1677)

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=JAMA&articleId=392085&pdfFileName=jama_266_12_036.pdf

Cardiac toxicity 4 to 20 years after completing anthracycline therapy.

Five children, aged 16 to 38 months, were found to have serum alkaline phosphatase levels seven to 30 times the upper limit of the reference range. Studies suggested a skeletal origin for the enzyme. No other abnormalities or explanations for the unusual enzyme levels were found. The enzyme levels returned to the reference range. A retrospective review of the records of 74 children with lymphoblastic leukemia, who were 2 to 4 years of age at diagnosis, disclosed only four cases of transient, isolated serum alkaline phosphatase elevation similar in degree to those described herein. The review covered 661 patient-years of follow-up and 2,417 enzyme measurements. Benign, transient hyperphosphatasemia is a rarely recognized clinical entity. Awareness of this condition should curtail the extensive evaluation that may follow the detection of such an abnormality. ( JAMA 1984;252:3289-3292)

M. L. Murphy

Papers

Cardiac toxicity 4 to 20 years after completing anthracycline therapy.

Transient, Marked, Unexplained Elevation of Serum Alkaline Phosphatase