2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

The drug has been approved in treatment of many types of
cancer (e.g., colorectal, lung, and breast cancers). Hypertension
is the adverse event correlated most strongly to bevacizumab,
with an incidence ranging from 16% to 47%. 29 From
the results of prospective trials, it seems that higher doses
of bevacizumab result in higher incidence of hypertension.
However, the exact dose that causes hypertension is not
known. 30 This effect appears to be dose dependent, but the
exact dose that causes hypertension is not known. Given in
combination with sorafenib, the incidence of hypertension
was 67%. 31 This is because VEGF/VEGFR signaling affects
the adaptive response of the heart to blood pressure stress.
In addition, signal pressure is inhibited, which leads to
heart failure. The incidence of ischemic heart disease and
arterial thromboembolic events is as high as 3.3%. 30 Approved
for the treatment of patients with metastatic renal
cancer, the TKIs sunitinib and sorafenib are multikinases
inhibitors. Sunitinib is also used in the treatment of gastrointestinal
stromal tumors, and sorafenib is used in the
treatment of advanced hepatocellular carcinoma. They are
inhibitors of growth factor receptors, the most important of
which are VEGF, platelet-derived growth factor, the stem
cell factor KIT receptor, and the Von Hippel-Lindau
hypoxia-inducible gene pathway. Furthermore, sorafenib
also affects the RAS-RAF-MEK-ERK pathway by inhibiting
the intracellular kinases RAF and BRAF. This inhibition
substantially affects tumor angiogenesis and/or cell proliferation.
These kinases also play an important role in the
maintenance of the normal function of the vascular system.
Therefore, inhibition may also lead to dysfunction in the
cardiovascular system. An observational single-center study
Author’s Disclosure of Potential Conflicts of Interest
Author
Marianne Ryberg*
*No relevant relationships to disclose.
Employment or
Leadership
Positions
Consultant or
Advisory Role
1. Albini A, Pennesi G, Donatelli F, et al. Cardiotoxicity of Anticancer
drugs: The need for Cardio-Oncological Prevention. J Natl Cancer Inst.
2010;102(1):14-25.
2. Carver JR, Shapiro CL, Ng A, et al. American Society of Clinical
Oncology Clinical Evidence Review on the Ongoing Care of Adult Cancer
Survivors: Cardiac and Pulmonary Late Effect. J Clin Oncol. 2007;25:3991-
4008.
3. Minotti G, SalvatorelliE, Menna P. Pharmacological Foundations of
Cardio-Oncology. J Pharmacol Exp Ther. 2010;334:2-8.
4. von Hoff DD, Layard MW, Basa P, et al. Risk Factors for Doxorubicininduced
congestive heart failure. Ann Intern Med. 1970;91:710-717.
5. Ryberg M, Nielsen D, Cortese G, et al. New insight to epirubicin cardiac
toxicity. Competing risks analysis of 1097 breast cancer patients. J Natl
Cancer Inst. 2008;100:1-10.
6. Swain SM, Whaley FS, Ewer MS. Congestive Heart Failure in Patients
Treated with Doxorubicin. A retrospective Analysis of Three Trials. Cancer.
2003;97:2869-2879.
7. Blanco JG, Leisenring WM, Gonzalez-Covarrubias VM, et al. Genetic
Polymorphisms in the carbonyl reductase 3 gene CBR3 and the NAD(P)H:
Quinone Oxioreductase 1 gene NQO1 in patients who developed anthracycline-related
congestive heart failure after childhood cancer. Cancer. 2008;
112:2789-2895.
8. Zhou S, Palmeira CM, Wallace KB. Doxorubicin-induced persistent
oxidative stress to cardiac myocytes. Toxicol Lett. 2011;121:151-157.
9. Minotti G, Menna P, Salvatorelli E, et al. Anthracyclines: Molecular
advances and pharmacologic development in antitumor activity and cardiotoxicity.
Pharmacol Rev. 2004;56:185-229.
558
analyzed 86 patients who received TKI treatment for metastatic
renal carcinoma and found that 18% had experienced
life-threatening cardiovascular events. The cancer therapy
was interrupted and treatment of the cardiovascular symptoms
was initiated, after which all patients were able to
continue treatment. This highlights the reversibility of cardiac
symptoms and the importance of cardiac monitoring
and intervention for these patients. 32
The previously mentioned inhibitors are only the beginning
of a new era, in which many more are in development
for the treatment of cancer and other diseases. As a result,
developing preclinical systems that can detect whether a
potential drug is cardiotoxic is imperative. It is equally
important that clinical trials be designed to assess the risk
of cardiotoxicity, if there is any suspicion of it during
preclinical trials.
Conclusion
The reason why cardiovascular symptoms develop during
and after the treatment of cancer depends on the treatment
modality and on the patient’s general status. As a result,
increasing physician knowledge about the various treatment
regimens and their short- and long-term effects on the heart
is crucial. Furthermore, as many heart diseases are treatable,
close collaboration between cardiologists and oncologists
is imperative. The number of new therapies available
for treating patients with cancer will continue to grow,
which is why cataloging and updating side effects, including
long-term side effects, are essential to keeping individual
specialists abreast of the newest treatment developments.
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Ownership Honoraria
REFERENCES
Research
Funding
Expert
Testimony
MARIANNE RYBERG
Other
Remuneration
10. Wallace KB. Adriamycin-induced interference with cardiac mitochondrial
calcium homeostasis. Cardiovasc Toxicol. 2007;7:101-107.
11. De Angelis A, Piegari E, Cappetta D, et al. Anthracycline cardiomyopathy
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