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. Carcinogenic factors of chemotherapy and radiation can directly cause it, but it may take months or years to develop. Roughly 10% of cancer survivors are estimated to develop secondary cancer related to their primary cancer treatment.

Chemotherapy and radiation treatment are well known for their high toxicity and potential to cause severe side effects during treatment. However, treatment also increases the risk of developing other disorders later in life, such as high blood pressure, heart disease, osteoporosis, renal failure, and secondary cancers. Many secondary cancers, such as basal or squamous cell carcinoma, are often treated easily. Others, however, are more serious and can be fatal, such as acute leukemia. Let’s talk about these more severe 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 four main types of leukemia:

• Acute Myeloid Leukemia,
• Chronic Myeloid Leukemia,
• Acute Lymphocytic Leukemia
• Chronic Lymphocytic Leukemia.

Myeloid means cancer starts in immature red blood cells, white blood cells, or platelets. Lymphocytic means beginning in the bone marrow's immature lymphocytes (a type of white blood cell). Acute means that cancer develops quickly. Chronic means it grows slowly, and a person may not experience early symptoms. These early symptoms may be vague and may mimic other medical conditions. Routine blood testing usually diagnoses chronic leukemia.

The most common chemotherapy-induced cancer is Acute Myeloid Leukemia (AML). Typically, there is a long latency period, meaning cancer will generally 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 five times more likely to develop AML than the average population. Several risk factors contribute to the potential of developing AML and specific chemotherapy agents.

Let’s now look at those risk factors and keep in mind that these risk factors do not directly cause cancer. They 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 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 battling other diseases 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:  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 exposed to arsenic, or hairdressers are more exposed to toxic hair dyes than the general population).
5. Genetics: This gets complicated, so we wanted to break it down. Research shows 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 five and 7, if a patient has monosomy (only one) or is missing part of or all of chromosomes 5 or 7, this can also be described as complex karyotype or complex marrow cytogenetics.

Other genetic issues that can predispose someone are:

• The presence of mutations in p53, a crucial tumor suppressor gene responsible for maintaining genetic stability by preventing genome mutations, is a significant indicator of the development of 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:
• Cowden’s Disease 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.
• 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.
• 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, of a particular gene. For example, some people have the -187 Ser allele for the NQO1 gene; these people are more at risk.

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

Researchers suggest that specific agents in radiation and chemotherapy are also associated with increased risk, for example, alkylating agents (nitrogen mustard, cyclophosphamide, procarbazine), topoisomerase inhibitors, vinca alkaloids (vincristine, vinblastine), and anthracycline agents (like doxorubicin). Studies show these agents are more carcinogenic, though not all to the same degree. Further research is needed to 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. Proton therapy for cancer offers the benefit of treating tumors located near or in critical areas of the body, such as the brain, spine, and chest.

Proton therapy allows doctors to deliver high-dose radiation more selectively. Studies have shown that it provides 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, damaging nearby tissues. Proton therapy targets cancer cells with a “pencil beam,” providing more precision and less “exit dose,” reducing overall toxicity and minimizing side effects, which helps 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 used for pediatric patients who can’t tolerate radiation or chemotherapy and for those 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 studying proton therapy to determine whether it is a better option for treating some types of cancer and to find ways to make it more available and affordable for patients.

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