Cardiotoxicity – The What’s and Why’s

Definitions:

Cardio – related to the heart.

Toxicity – the quality, state, or relative degree of being poisonous.

Cardiotoxicity refers to the potential for certain cancer treatments, primarily chemotherapy and radiation therapy, to cause damage or dysfunction to the heart muscle and cardiovascular system. This can lead to a range of heart-related complications, some of which can be life-threatening or have long-lasting effects on a patient’s quality of life and overall health. Understanding cardiotoxicity, its causes, and preventive strategies is crucial in the management of cancer patients undergoing potentially cardiotoxic therapies.

We all recognize the signs of when someone is undergoing cancer treatment. Often they are wearing a hat or a cap as their hair has fallen out. Most look thin, underweight, tired and frankly, ill. Often these days you will see them wearing face masks as their immune system has been destroyed by the treatment. The amount their appearance might change from normal is related to the type of cancer they have and the treatment(s) being used to try and get rid of it.

Cancer is a group of diseases characterized by uncontrolled cell growth and the ability of these cells to spread to other parts of the body (metastasize). It happens because ‘something’ triggers mutations or abnormal changes in genes that control cell growth and division and tumors grow.

Tumors may be malignant (cancerous) or benign (non-cancerous). The first indication we may notice is a lump (tumor); unexplained weight loss, blood in urine, stools, coughing, headaches or anything like a sore throat that doesn’t respond to antibiotics.

A benign tumor is notable for being slow to grow, have smooth distinct borders, does not grow into surround tissue or organs and does not invade other parts of the body.

The exact cause of a benign tumor is often unknown but certain potential causes have been identified, these include environmental factors, inflammation or infection, local trauma or injury, diet, stress and genetics.

Malignant or cancerous tumors on the other hand are a totally different beast. They can grow quickly, have irregular borders and spread to other tissues or organs.

Malignant cancers can be caused by:

• Genetic factors: Certain genetic mutations or inherited gene changes can significantly increase an individual’s risk of developing specific types of cancer. For example, mutations in the BRCA1 and BRCA2 genes increase the risk of breast and ovarian cancers, while Lynch syndrome (caused by mutations in mismatch repair genes) increases the risk of colorectal and other cancers.
• Environmental exposures: Exposure to certain environmental factors, such as tobacco smoke, UV radiation, air pollution, and specific chemicals (e.g., asbestos, benzene), can damage DNA and contribute to the development of cancer.
• Lifestyle factors: Certain lifestyle choices can influence cancer risk, including:
  • Tobacco use (smoking and smokeless tobacco)
  • Excessive alcohol consumption
  • Unhealthy diet (high in processed and red meats, low in fruits and vegetables)
  • Obesity and physical inactivity
  • Certain infections (e.g., human papillomavirus, hepatitis B and C viruses)
• Age: The risk of most types of cancer increases with age, as genetic and cellular damage accumulates over time. Many cancers are more common in older adults.
• Hormonal factors: Exposure to certain hormones, such as estrogen and testosterone, can influence the development of cancers like breast, ovarian, and prostate cancers.
• Immunosuppression: People with weakened immune systems, such as those with HIV/AIDS or organ transplant recipients on immunosuppressive medications, have a higher risk of developing certain cancers.
• Chronic inflammation: Chronic inflammatory conditions, such as ulcerative colitis or Crohn’s disease, can increase the risk of developing cancers in the affected organs or tissues.

Cancer is characterized by:

• Normal cell growth and division: In a healthy body, cells grow, divide, and die in an orderly and regulated manner. This process is controlled by genes that provide instructions for cell growth and division.
• Gene mutations and cancer development: Cancer begins when a single cell undergoes a series of genetic mutations or changes that disrupt the normal processes of cell growth and division. These mutations can be inherited or acquired through exposure to carcinogens (cancer-causing agents) such as tobacco smoke, radiation, or certain chemicals.
• Uncontrolled cell growth: The mutations in cancer cells allow them to bypass the normal controls on cell growth and division. As a result, these cells continue to grow and divide uncontrollably, forming a mass of abnormal cells called a tumor.
• Characteristics of cancer cells: Cancer cells have several distinctive characteristics that set them apart from normal cells, including:
  • Sustained proliferative signaling (uncontrolled growth)
  • Evasion of growth suppressors
  • Resistance to cell death (apoptosis)
  • Enabling of replicative immortality
  • Induction of angiogenesis (formation of new blood vessels)
  • Activation of invasion and metastasis
• Cancer types and subtypes: There are over 100 different types of cancer, classified based on the tissue or organ of origin, such as breast cancer, lung cancer, prostate cancer, and leukemia (cancer of blood cells). Each cancer type can have multiple subtypes with distinct genetic profiles and characteristics.
• Cancer progression: Cancer is a progressive disease that evolves through various stages, from a localized tumor to metastatic disease, where cancer cells spread to other parts of the body. The earlier cancer is detected and treated, the better the chances of successful treatment and survival.

The treatments for cancer include any or a combination of surgery, chemotherapy and radiation therapy. In my own case, I was due to have surgery and then chemo and/or radiation to mop up any remaining cancerous cells but in the time it took to schedule surgery my tumor had grown so quickly that the surgeon decided he couldn’t operate and my only option was chemo and radiation.

Chemotherapy is brutal – I speak from bitter experience. Now, maybe for some the experience isn’t too bad but I’ve yet to meet anyone who didn’t suffer enormously during the process.

Chemotherapy’s one and only job is to kill dangerous, rapid growing cells and if anything else gets in its way, like normal non-cancerous cells, then so be it. Most chemotherapies aren’t that well targeted and once let loose in the body off they go to work!

Chemotherapy does tend to target fast growing cells which is fine for cancer cells but not quite so good for other harmless fast growing cells which can be found in the reproductive system, bone marrow, hair follicles, and the digestive system etc.

This means the treatment can trigger things like constipation, pain and nerve problems, diarrhea, skin changes, mood swings, mouth sores, and bruising and bleeding.

It also leads to nausea, vomiting, hair loss (not for all regimens, my hair stayed intact and in fact grows faster now that it did before!) It destroys your immune system leaving you exposed to any type of bug floating about and generally makes you feel really ill. Anti-nausea pills are prescribed but they don’t always work.

Most of these effects are short term but chemotherapy can also lead to long term health issues such as issues with fertility, early menopause, osteoporosis, nerve damage and an increased risk of developing other cancers.

The other long term issue is Cardiotoxicity. Most cancer survivors have more chance of dying from cardiac issues that from a reoccurrence of cancer.

Certain chemotherapeutic agents have well-established cardiotoxic effects, and the risk of developing heart-related complications often increases with higher cumulative doses or when combined with other cardiotoxic therapies. The cardiotoxic effects of chemotherapy have been known about for many years.

• Anthracyclines: Drugs like doxorubicin, epirubicin, and daunorubicin are among the most cardiotoxic chemotherapies. They can cause cardiomyopathy (weakening of the heart muscle), heart failure, and arrhythmias (abnormal heart rhythms). The risk of cardiotoxicity increases with higher cumulative doses of these agents.
• Targeted therapies: Drugs like trastuzumab (Herceptin), used in the treatment of breast cancer, can increase the risk of heart failure, particularly when used in combination with anthracyclines.
• Alkylating agents: Cyclophosphamide and ifosfamide have been associated with conditions like hemorrhagic myocarditis, cardiomyopathy, arrhythmias, and myocardial ischemia (reduced blood flow to the heart).
• Antimetabolites: Agents like 5-fluorouracil and capecitabine can cause ischemia, arrhythmias, and cardiomyopathy.
• Platinum compounds: Drugs like cisplatin can lead to arrhythmias, myocardial ischemia, and vascular toxicities like Raynaud’s phenomenon (episodic vascular spasm).

Cisplatin was the chemotherapy agent used during my treatment.

The mechanisms by which these chemotherapies cause cardiotoxicity can involve oxidative stress, direct cellular damage, disruption of molecular pathways, and interference with myocardial function and energy production.

Radiation therapy, also called radiotherapy, is a type of cancer treatment that uses high-energy radiation to kill cancer cells and shrink tumors. It works by damaging the DNA of cancer cells, making it difficult for them to grow and divide.

In my treatment, a high-energy beam of radiation was directed at my tumor while I was literally pinned to a treatment table by a mask that covered my head and throat and shoulders. It was impossible to move and very claustrophobic! (see the picture on the Home page!).

What could possibly go wrong?

Actually, quite a lot. Although the beam was directed at the tumor, it had to pass through me to get there. On its speed of light journey, this beam of radiation did its work on the tumor but also did a pretty good job of destroying my saliva glands, my taste buds and all the muscles in my throat which are necessary to push food down to the stomach. Apart from being excruciatingly painful after a treatment session, I also suffered radiation burns to the outside of my neck and the scars are visible today. Did I mention the carotid artery? Well, it irradiated that as well…..

Radiation therapy can expose the heart and surrounding vasculature to significant radiation doses, leading to potential cardiovascular complications.

• Coronary artery disease: Radiation exposure can accelerate the development of atherosclerosis (buildup of plaque) in the coronary arteries that supply blood to the heart muscle, increasing the risk of angina, myocardial infarction, and ischemic heart disease.
• Pericardial disease: Radiation to the pericardium (the protective sac surrounding the heart) can cause inflammation (pericarditis), pericardial effusion (fluid buildup), or pericardial constriction, impairing heart function.
• Cardiomyopathy: Direct exposure of the heart muscle (myocardium) to radiation can cause cell death and fibrosis, leading to cardiomyopathy (weakening of the heart muscle) over time, potentially progressing to heart failure.
• Valvular heart disease: Radiation can cause thickening, calcification, and dysfunction of the heart valves, particularly the mitral and aortic valves.
• Conduction abnormalities: Radiation damage to the electrical conduction system of the heart can lead to various arrhythmias (abnormal heart rhythms) like atrial fibrillation, bundle branch blocks, etc.

The risk of radiation-induced cardiotoxicity depends on factors like the total radiation dose received by the heart, the volume of heart exposed, the radiation techniques used (e.g., intensity-modulated radiation therapy can better spare the heart), and the presence of other cardiovascular risk factors.

Given the potential for serious cardiovascular complications, implementing strategies to prevent, detect, and manage cardiotoxicity is crucial in cancer care. These involve:

• Baseline cardiac assessment: Before initiating potentially cardiotoxic cancer treatments, patients should undergo a comprehensive baseline evaluation of their cardiovascular health, including assessments like echocardiography, electrocardiograms, and cardiac biomarker testing. This helps identify individuals at higher risk and guides appropriate monitoring and preventive measures.
• Cardiac monitoring: Regular monitoring of cardiac function through various tests (e.g., echocardiography, biomarkers) should be performed during and after completion of cardiotoxic therapies. Early detection of subclinical changes can prompt timely interventions.
• Cardioprotective strategies: There are several approaches that may help mitigate the risk of cardiotoxicity, including:
  • Dexrazoxane: A cardioprotective agent that can be used in conjunction with anthracyclines to reduce the risk of heart failure.
  • Liposomal formulations: Certain chemotherapies, like liposomal doxorubicin, may have a lower risk of cardiotoxicity compared to conventional formulations.
  • Dose optimization: Adjusting chemotherapy doses or radiation fields to minimize cardiac exposure while maintaining therapeutic efficacy.
  • Cardiac medication: Prophylactic use of medications like ACE inhibitors, beta-blockers, or statins may help protect the heart in high-risk patients.

In order to effectively manage cardiotoxicity the following are deemed necessary:

• Cardiac rehabilitation: Implementing cardiac rehabilitation programs, including exercise training and lifestyle modifications, can help improve cardiovascular health and potentially mitigate the long-term effects of cardiotoxicity.
• Multidisciplinary approach: Effective management of cardiotoxicity requires close collaboration between oncologists, cardiologists, radiation oncologists, and other healthcare professionals in a multidisciplinary setting. This team-based approach ensures comprehensive evaluation, monitoring, and coordinated care for patients at risk of cardiotoxicity.
• Research and surveillance: Ongoing research into novel cardioprotective agents, advanced radiation techniques, and long-term surveillance of cancer survivors is essential to further improve our understanding and management of cardiotoxicity.

In conclusion, cardiotoxicity is a significant concern in cancer treatment, with both chemotherapies and radiation therapy having the potential to cause heart-related complications. By understanding the causes, implementing preventive strategies, and adopting a multidisciplinary approach to monitoring and management, doctors can strive to minimize the cardiovascular risks associated with these life-saving cancer therapies and improve overall outcomes for patients.

Over the past 20 years, there have been the establishment of dedicated cardio-oncology clinics and programs have emerged across North America, Europe, South America, Asia, South Africa, and Australia; however, many of these clinics are in academic centers or large cities, where there is more infrastructure support, and most clinics are led by cardiologists.

Outside the academic centers and large cities where many are treated, myself included, the dangers of cardiotoxicity and risk assessments are largely ignored.

The cardiology community has fully embraced gaining a better understanding of the impact of modern cancer therapies on cardiovascular health in patients with cancer.

In contrast, cardio-oncology (the meeting point of cardiology and oncology) among the oncology community has a very limited reach. Only a handful of oncologists in North America or globally have an academic interest in cardio-oncology, and there is little presence at international meetings such as ASCO (American Society of Clinical Oncology) or ESMO (European Society for Medical Oncology). A true partnership requires all parties to work together to improve the care of patients. This can only be accomplished with the input and leadership of oncologists, cardiologists, and allied health-care professionals. Position papers and guidelines are of little value if they are not endorsed or implemented by all members of the multidisciplinary team.

The net result is that today, in 2024, many cancer patients who survive chemo and radiation therapy will ultimately die from cardiovascular issues.

Despite collapsing and having to have my heart stopped and restarted, the Atrial Fibrillation (now at 35%), the massively reduced Left Ventricle Ejection Fraction, the need to have a Pacemaker/Defibrillator implanted and in the next week or so a Watchman implant in my heart to stop potentially fatal blood clots and death by stroke, never once have I had a cardiac assessment prior to or during cancer treatment and never once has the issue of cardiotoxicity been mentioned – until I chose to do so.

I will be starting a course of cardiac rehabilitation in the coming weeks. It is noteworthy that it was my GP who suggested it and not one of my other specialist doctors (Cardio or Oncology)….go figure!

How many more will die before what everybody knows needs to be done, is done, to improve the long term survival rate of cancer patients?