Radiation and Chemotherapy Induced Secondary Malignancies

Radiation and Chemotherapy Induced Secondary Malignancies

Chemotherapy and radiation are an integral part of cancer treatment; more than half of all cancer patients will undergo one or both therapies. With significant advances in radiation and chemotherapy, the number of long-term cancer survivors has dramatically increased over the years. However, there is a growing concern about radiation and chemotherapy-induced secondary malignancies.

Secondary malignancy means cancer that develops entirely separately from primary cancer due to chemotherapy and or radiation. It may take months or years to develop but is directly caused by the carcinogenic factors of chemotherapy and radiation. It is estimated that roughly 10% of cancer survivors will develop secondary cancer related to their primary cancer treatment.

It is well known that chemotherapy and radiation treatment are highly toxic and may cause severe side effects while on treatment. However, treatment is also linked to a higher risk of developing other disorders later in life, for example, high blood pressure, heart disease, osteoporosis, renal failure, and secondary cancers. Many of the secondary cancers are skin cancers, such as basal cell or squamous cell carcinoma, which can be treated easily. Others, however, are more serious and can be fatal, such as acute leukemia. Let’s talk about these more serious cancers, but first, we need to discuss what leukemia means.

 What is Leukemia?

Leukemia is a cancer that develops in the blood cells.

There are 4 main types of leukemia: Acute Myeloid Leukemia, Chronic Myeloid Leukemia, Acute Lymphocytic Leukemia, and Chronic Lymphocytic Leukemia. Myeloid means that cancer starts in immature red blood cells, white blood cells, or platelets. Lymphocytic means that it starts in immature lymphocytes (a type of white blood cell) in the bone marrow. Acute means that cancer develops quickly. Chronic means that it develops more slowly and a person may not experience early symptoms. These early symptoms may be vague and may mimic other medical conditions. Chronic leukemia is usually diagnosed after routine blood testing.

The most common chemotherapy-induced cancer is Acute Myeloid Leukemia (AML). Typically, there is a long latency period, meaning cancer will typically start to develop 5-10 years after the initial chemotherapy or radiation treatment. Linda S. Sutton, MD, says that “developing secondary cancer from cancer treatment is a relatively rare occurrence.” However, chemotherapy patients are 5 times more likely to develop AML than the normal population. There are several risk factors that contribute to the potential of developing AML, as well as certain chemotherapy agents.

Let’s now take a look at what those risk factors are and keep in mind that these risk factors do not directly cause cancer, they simply predispose a person to be more at risk:

1. Age: survivors of pediatric malignancies are more at risk, possibly due to genotoxic injury to stem cells, which are more active in kids. It can possibly be due to longer latency, which is a quality of chemo-induced cancer. Also, the older you are when you become a “survivor” of cancer, the more likely you will develop secondary cancer related to treatment.
2. Gender: females, especially those with primary breast cancer, are at higher risk due to the increased radio-sensitivity of breast tissue and organ-specific genetic factors- BRCA1 and BRCA2 genes.
3. Comorbidities: a person that is also battling other diseases when undergoing chemotherapy and radiation, the simultaneous presence of 2 chronic diseases. For example, someone with breast cancer may also be struggling with depression, causing this person to be at higher risk.
4. Environmental factors also play a role, smoking cigarettes, alcohol consumption, high stress, chronic inflammation, UV light exposure, GMOs in food and foods with higher levels of preservatives, environmental chemicals like pollution, obesity, exposure to asbestos, hormone levels, certain types of jobs (ex: electricians are more exposed to arsenic, or hairdressers are more exposed to toxic hair dyes than the general population).
5. Genetics also seems to play a big role. This gets a little complicated, so we wanted to break it down. Research is showing that over 90% of all therapy-induced leukemia cases, are due to complex clonal chromosomal abnormalities, meaning there is a missing or extra chromosome or a structural abnormality of a chromosome. Specifically, with chromosomes 5 and or 7, if a patient has monosomy (only one) or they are missing part of or all of the chromosomes 5 or 7. This can also be described as complex karyotype or complex marrow cytogenetics.

Other genetic issues that can predispose someone are:

• Mutations in p53 (tumor suppressor gene responsible for conserving genetic stability by preventing genome mutations) lead to Li-Fraumeni syndrome.
• Germline mutations in the Rb gene lead to familial retinoblastoma, which causes cancer that rapidly develops from the immature cells of a retina.
• Dysregulated RAS and RAS effector kinase signaling lead to:

1. Cowden’s Disease which is an autosomal dominant inherited condition characterized by benign overgrowths called hematomas as well as an increased lifetime risk of breast, thyroid, uterine, and other cancers.
2. Tuberous Sclerosis is a rare multisystem genetic disease that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs, and skin.
3. Neurofibromatosis is a condition that causes tumors to form in the brain, spinal cord, and nerves.

• If someone has a family history of cancer, usually a first or second-degree relative.
• Some patients carry different gene alleles. An allele is a different form of a certain gene. For example, some people carry the -187 Ser allele for the NQO1 gene, these people have been found to be more at risk.

Some people have conditions other than cancer, and radiation is used for treatment. For example, rheumatologic or dermatologic conditions and infectious diseases are sometimes treated with radiation therapy. This therapy will cause an increased risk of developing cancer in the future due to the mutagenesis of normal tissue.

It is suggested that certain agents in radiation and chemotherapy are associated with increased risk too, for example, alkylating agents (nitrogen mustard, cyclophosphamide, procarbazine), topoisomerase inhibitors, vinca alkaloids (vincristine, vinblastine), and anthracycline agents (like doxorubicin). These agents are shown to be more carcinogenic, although not all to the same degree, and more study is needed in this field to really determine the leukemogenic potency of individual drugs.

So, what is the solution? Doctors and scientists consider proton therapy a better option for many patients.

Proton therapy is radiation therapy that uses protons (positively charged atomic particles) to treat cancer. Protons cause less damage to healthy cells than other forms of radiation therapy, such as X-rays. The benefits of proton therapy for cancer are that it can be used to treat tumors near or in critical areas of the body, such as the brain, spine, and chest.

Proton therapy allows doctors to more selectively deliver high-dose radiation and has been shown to deliver higher cure rates than traditional radiation treatment even in some of the most challenging situations. Radiation is more local than chemotherapy however, the x-rays continue to deposit radiation as they exit the body, therefore, damaging nearby tissues. Proton therapy targets cancer cells with a “pencil beam” providing more precision and less “exit dose”, so not only does it reduce overall toxicity but also minimizes side effects which help to maintain quality of life during treatment.

Proton therapy has been shown to reduce the possibility of developing radiation and chemotherapy induced secondary malignancies. by 66%. It is already indicated for pediatric patients that can’t tolerate radiation or chemotherapy, and in patients with eye or brain tumors, or tumors in the spinal cord or brain stem where radiation poses an unacceptable risk.

The National Cancer Institute (NCI) is currently studying proton therapy to see if it is a better option for treating some types of cancer. The NCI is also studying ways to make proton therapy more available and affordable for patients.

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