Cancer and side effects

ALSO KNOWN AS: Concomitant events, adverse events (AEs), adverse effects, adverse drug reactions (ADRs), complications

DEFINITION: Side effects include any unintended action, reaction, effect, or change in a person’s condition that occurs as a result of medical treatment in addition to the intended action, effect, or change in condition. Medication, drug interactions, unintentional overdosage, drug allergy, vaccination, or any other procedure, therapy, or treatment can cause a concomitant event. Side effects may also be associated with diseases and conditions, nutritional or herbal supplements, comorbid conditions (those existing simultaneously with another condition), lifestyle behaviors, and medications unrelated to the treated condition.

General side effects from drugs: All drugs, whether prescription or over-the-counter (OTC), can cause side effects. These can range in duration from acute (transient) to chronic (long-term) and in intensity from mild to life-threatening. Several factors determine whether a person experiences drug-related side effects. These include individual differences in physiologic makeup. All prescription and OTC drugs have known, documented (labeled) side effects. Those of prescription drugs are listed on each medication’s package insert (PI). The PI for each marketed drug must be approved by the US Food and Drug Administration (FDA). Items that must be shown a PI include:

• comprehensive efficacy data
• pharmacokinetic
• pharmacodynamic data (information on the way the body absorbs, distributes, and metabolizes the drug)
• dosage and administration data
• safety data, including contraindications (a listing of known conditions that may preclude safe usage)
• warnings (a listing of serious side effects)
• precautions (a listing of potential concerns involving drug interactions
• laboratory test interactions
• carcinogenesis
• mutagenesis
• impairment of fertility
• pregnancy, teratogenicity
• use by nursing mothers
• pediatric use, geriatric use
• adverse reactions
• assessment of the potential for drug abuse and dependence
• signs and symptoms indicative of overdose treatment recommendations in the event of overdose

In general, the most commonly experienced drug-related side effects involve the gastrointestinal system (including anorexia, constipation, diarrhea, nausea, and vomiting). Other commonly experienced side effects involve the nervous system (including fatigue, headache, and insomnia). The Physicians’ Desk Reference (PDR), a commercially published, annually updated reference book, is a compendium of PIs. It is available to the public in original format, in layterm format, and in e-book format. An online version is also available to medical professionals.

Drug interactions: Drug-related side effects may occur due to any of the following types of interaction: one medication with another medication (a “drug-drug interaction”), one therapy with another therapy (a “concurrent therapy interaction”), and a medication with a particular food type (a “drug-food interaction”).

Drug-drug interactions. Concomitant use of certain medications can result in either a reduction of or an increase in the effects of either or both drugs, thereby increasing the incidence or severity of side effects. For example, antidiarrheal drugs taken with tranquilizers can increase the sedative effect; anticoagulants with antacids can decrease absorption of the anticoagulant and increase bleeding; diuretics with decongestants can increase hypertension; and antihistamines with antitussives (cough medications) can increase drowsiness.

Concurrent therapy interactions. Concurrent therapy interactions can occur when two or more different types of treatment are used simultaneously for the same indication (to treat the same symptom). For example, combined treatment with chemotherapy and radiation therapy, as is administered for many types of cancer, can result in a decrease in neutrophils (white blood cells) as well as other types of blood cells. When administered to those with diabetes, the resultant reduction in cell count could increase the risk of infection.

In addition to adverse drug interactions, however, a drug-drug interaction may have a positive synergistic effect. In such cases, either the efficacy of the concomitant drugs is greater than that of each drug individually, or the side effects associated with the concomitant drugs are fewer or less severe than those associated with either drug individually.

Drug-food interactions. The presence of certain types of foods in the stomach may affect the bioavailability and safety profiles of an orally administered drug by interfering with its ADMET profile. ADMET stands for the following properties:

• absorption into the circulatory system
• distribution to organs and tissues
• metabolism of the parent compound into metabolites
• excretion of the parent compound and metabolites, usually via urine and feces
• toxicity (harmfulness) of the parent compound and metabolites

For example, an enzyme in grapefruit may inhibit drug metabolism, resulting in more parent compounds in the circulatory system than would otherwise be there. This could increase the incidence or severity of side effects caused by drugs in the following drug classes: analgesics, antiarrhythmics, antibiotics, anticoagulants, anticonvulsants, antidepressants, antihypertensives, antitussives, and chemotherapy agents. Certain foods may also block drug absorption if taken within a specific interval before or after a drug dose. For example, ingesting a dairy product shortly before or after taking the antibiotic tetracycline can reduce the drug's efficacy.

Obversely, the systemic presence of certain types of drugs may affect nutrient absorption, nutrient metabolism, or appetite. The magnitude of a drug-food effect, however, is dependent upon such variables as drug dosage and route of administration, duration of the interval between medication ingestion and food ingestion, and the age, weight, gender, and health status of the person taking the medication.

Unintentional overdosage. Toxicity can occur as the result of an accidental overdose, either from taking more than the correct dose at any one time or from taking the proper dose more often than prescribed or recommended. Side effects of acute toxicity include blurred vision, dizziness, headache, loss of muscle coordination, nausea, and vomiting. For certain antihypertensive drugs, dosages only slightly higher than the recommended therapeutic dose can cause bradycardia (slow heartbeat), hypotension, or vomiting.

Since the route of excretion for most drugs is renal (through kidney metabolism), hepatic (through liver metabolism), or both, overdosage can result in renal or hepatic toxicity. An overdose of analgesics (painkillers) is the most prevalent cause of acute hepatoxicity (liver failure) in the United States.

Toxicity can result not only from drug exposure but also from radiation exposure. Such toxicity can be minimized by limiting the volume of tissue irradiated.

Drug allergies: Certain drugs can cause allergic reactions, whereby the immune system launches a histamine response to rid the body of the drug. The resultant adverse events can range in intensity from life-threatening to mild and include anaphylactic symptoms (apnea, bronchoconstriction, cyanosis, and loss of consciousness), anxiety, confusion, diarrhea, dizziness, hives and itching, lung congestion, mouth and throat edema, nausea, rash, and tachycardia (rapid heartbeat).

Antibiotics in the penicillin family are the most common triggers for allergic reactions. Others include anticonvulsants, barbiturates, insulin, iodine (present in radiographic contrast dyes), and sulfa drugs.

Photoallergies and phototoxicities: Photoallergy and phototoxicity are two types of photosensitivity that can be caused by prescription or over-the-counter drugs. Occurrences can be either acute and isolated or chronic.

Photoallergies can occur following the topical administration of certain medications that undergo structural change when exposed to sunlight's ultraviolet wavelengths. This results in the production of antibodies that cause photosensitivity. Symptoms include an eczema-type rash a few days after treatment.

Phototoxicity can occur following topical, oral, or injected administration of certain medications. These medications absorb ultraviolet wavelengths of sunlight and then distribute them transdermally (through absorption by the skin), resulting in cell death. Symptoms occur a few days after treatment and can last up to twenty years after the treatment's cessation.

Drugs that cause photosensitivity can exacerbate existing skin conditions and may precipitate or exacerbate certain autoimmune disorders, such as lupus. The drugs that most commonly cause photosensitivity are in the following drug classes: antianxiety medications, antibiotics, anticholesterol medications, antidepressants, antiepileptic medications, antifungals, antihistamines, antihypertensives, diuretics, neuroleptic medications, nonsteroidal anti-inflammatories (NSAIDs), and vaccinations.

Side effects of chemotherapy: Chemotherapy drugs are often among the most toxic, given that their function is to destroy or otherwise mitigate tumor tissue. Hence, these agents usually have strong side effects that are managed by other drugs. Among the side effects of chemotherapy are alopecia (hair loss), anemia, anorexia, anxiety disorders, bradycardia, congestive heart failure, constipation, decreased fertility, depression, diarrhea, dyspnea (shortness of breath), fatigue, febrile neutropenia, heart arrhythmias, hypertension, incontinence, insomnia, lymphedema, mucositis (mouth sores), nausea, peripheral neuropathy (nerve damage), pulmonary infections due to a compromised immune system, renal (kidney) damage (sometimes requiring dialysis), skin and nail changes, and vomiting.

Other procedures, therapies, and treatments: Diagnostic procedures and non-drug-related therapies or treatments, such as surgery and radiation therapy, can also cause side effects.

Diagnostic procedures. Imaging procedures are among the most common diagnostic procedures. For example, a patient undergoing computed tomography (CT) scan with ingestion or injection of contrast medium may undergo a reaction to the contrast dye. Magnetic resonance imaging (MRI) may induce headache or nausea resulting from the machine's noise or injection site pain in cases where contrast is used. Nuclear scans, including positron emission tomography (PET) and single photon emission computed tomography (SPECT) scans, may cause fever or (rarely) tissue damage.

Nonpharmaceutic therapies or treatments. Side effects may also result from non-drug-related therapies or treatments, including acupuncture, blood product transfusions, hyperbaric oxygen therapy, metabolic therapy, plasmapheresis (for prevention of potential side effects), radiation therapy, surgery (including bone marrow, organ, or peripheral blood stem cell transplantation), and whole-body heat therapy. For cancer patients, toxic side effects may occur from radiation exposure, but risk is minimized by limiting the volume of tissue irradiated.

Nutritional supplements. All vitamins and other nutritional supplements can cause side effects. Hypervitaminosis, or toxicity due to the cellular storage of an overabundance of fat-soluble vitamins (A, D, E, K), is the primary cause of nutritionally related side effects. For example, acute vitamin A toxicity can cause alopecia, blurry vision, bone calcification or inflammation. Symptoms of chronic vitamin A toxicity include alopecia, fatigue, dizziness, drowsiness, nausea, kidney damage, liver damage, elevated cholesterol, and prostate cancer. Toxic doses of mineral supplements can occur with excessive amounts of iron and zinc. Herbal supplements can cause side effects as well; dimethyl sulfoxide (DMSO), valerian, and yohimbe are only a few examples of herbals that can have toxic and sometimes life-threatening side effects. Herbal supplements can also negatively interact with prescription preparations like anesthesia, anticoagulants, and beta-blockers.

One reason that nutritional supplements can be hazardous is how they are regulated. Supplements manufacturers are not required to test them for safety or efficacy before marketing them. Unless a manufacturer makes specific claims that a supplement can treat, cure, or prevent a particular disease, that manufacturer does not need to prove to the FDA that those claims are true. They are also not required to provide quality assurance that the supplement contains what the label states or provide quality control to ensure it is contaminant-free.

Diseases and conditions: Having a specific disease or condition may predispose an individual to experience side effects. Moreover, disease-related physiologic changes may cause pharmacodynamic anomalies and result in a reduction in drug efficacy or an increase in the incidence of drug-related adverse events.

Cancer's side effects include bone metastasis, resulting in pain, fracture, and resultant hypercalcemia due to calcium from damaged bone being released into the bloodstream. Chronic lymphocytic leukemia causes immune system alterations, resulting in lysis (dissolution) of red blood cells. Retinoblastoma results in glaucoma, eye pain, and vision loss.

A comorbid condition, a concurrent condition that is unrelated to the primary disease, may also predispose an individual to experience side effects and precipitate disease-related physiologic changes that may cause pharmacodynamic anomalies and result in a reduction in drug efficacy or an increase in the incidence of drug-related adverse events. In the case of cancer, a variety of comorbidities have side effects that mitigate treatment.

Some comorbid conditions may predate the primary disease, while others develop after the onset of the primary disease. For example, cancer treatment may be compromised by comorbidities such as compromised cardiac or lung function (which makes the patient a poor surgical risk and a poor risk for concomitant chemotherapy and radiation therapy); Alzheimer's disease (which makes the patient a poor risk for brain irradiation to counteract brain metastasis); and diabetes, hypertension, renal problems, or congestive heart failure (all of which interfere with the healing process). Cancers that affect comorbid conditions, on the other hand, include small-cell lung cancer (SCLC), which may cause Lambert-Eaton syndrome (LEMS) and resultant muscle weakness.

Special populations: Drug therapy used by subpopulations of geriatric, pediatric, and adult females requires increased vigilance given the possibility of increased incidence of drug side effects at dosages that would otherwise be considered therapeutic.

Geriatric populations. Clinically significant age-associated differences in a drug's efficacy or safety profiles can occur in the elderly, who tend to take more medications. This increases the potential for drug reactions and drug-drug interactions. Older adults also have a decreased metabolic rate, which increases both a drug's mean residence time in the body and the resultant potential for toxicity. Often, these drug-related side effects, which can include fatigue, weight loss, and loss of balance, are attributed to natural aging changes. They can also signal signs or symptoms of underlying diseases and an existing or newly acquired medical condition rather than the drugs themselves. Therefore, dosing based on body weight and metabolic rate is essential for the elderly population.

Pediatric populations. Drug-related side effects are of great concern regarding those in the pediatric population, in which drugs can have a significant impact on growth, development, and maturation at many levels: behavioral, cognitive, immunological, physiological (organ systems), physical, sexual, and skeletomuscular.

Additional concerns include the possibility of teratogenicity (genetic mutations) or reductions in body weight gain. Also of concern is the possibility that, because of differences in developing systems as opposed to mature adult systems, drug-related adverse events or drug interactions may not be immediately identifiable but rather may manifest at a later stage of growth, development, or maturation.

Women. The risk of drug-related side effects is sometimes gender-dependent. Hormonal differences, including cyclic hormonal variations as well as physiologic differences, may cause women to be at greater risk for side effects than men. The tendency for women both to weigh less and to have a higher percentage of body fat also predisposes them to the possibility of additional side effects related to toxicity. Concerning body fat, a certain amount of drug is often stored in adipose tissue for later release, resulting in a drug present systemically that exceeds the intended therapeutic dose, given the cumulative effect of the administered dose combined with the release of the previously stored drug. Another concern for women is the possibility of impairment of fertility and the possibility of maternal or fetal risk during pregnancy. Therefore, dosing by body weight is an essential consideration in managing a drug's safety margin for women.

Lifestyle: Lifestyle choices can either increase or decrease the likelihood of the incidence of adverse events. Moreover, Certain lifestyle choices are associated with negative and positive side effects. An example of the latter is caffeine consumption. Positive effects include bronchodilation (an effective asthma treatment), decreased fatigue, and increased alertness. Adverse effects can include dizziness, impaired fine motor control, increased excretion of calcium (contributing to osteoporosis), increased respiratory rate, insomnia, and tachycardia.

Negative lifestyle choices include smoking and alcohol or narcotic consumption. The negative side effects associated with smoking include:

• Cardiopulmonary adverse events.
• Increased incidence of certain forms of cancer.
• Increased incidence of complications following breast reconstruction surgery.

Adverse effects associated with alcohol or narcotic consumption include hypertension and hepatic adverse events, including an increased risk of acute liver failure resulting from acetaminophen hepatotoxicity.

Healthy eating habits, optimal weight maintenance, and regular exercise are positive lifestyle choices. The positive side effects of these choices may include an overall improvement in general health, a decrease in blood pressure, a decrease in cholesterol levels (LDL and triglycerides), a reduction in heart attack risk, and a reduction in stroke risk.

Beneficial side effects: Although the term "side effects" has an inherently negative connotation, not all side effects are undesirable, unwanted, or harmful to one's health. In certain instances, a side effect can be desirable. In addition to beneficial side effects from positive lifestyle choices, unintended beneficial side effects have been associated with certain drugs. This often results in their off-label (unindicated) use for their efficacy in treating conditions for which they were not originally developed. Examples include aspirin, which, in addition to being used as an analgesic, has a beneficial side effect as an anticoagulant in helping to prevent heart attacks. Similarly, DMSO (approved for treatment of interstitial cystitis) can improve the efficacy of certain chemotherapy drugs, and tamoxifen (used to treat breast cancer) may help prevent breast cancer and also decrease blood cholesterol levels. It should be noted, however, that these drugs can be associated with negative side effects as well.

In the mid-2020s, new cancer treatments offered patients innovative treatment options. Such drugs included Herceptin, which was proven effective against breast cancer. These treatments provided targeted therapies, which contrasted with chemotherapy, which destroys both healthy and cancerous tissues. Another such drug is Enhertu, which was also used to treat tumors. Despite the efficacy and promise demonstrated by new treatments, these also could result in adverse side effects such as intolerable nausea and fatigue. Nonetheless, targeted treatments offer the potential to eliminate cancerous growths while sparing patients the ill effects of treatments, which could likewise be debilitating.

Bibliography

Cukier, Daniel, et al. Coping with Chemotherapy and Radiation Therapy. 4th ed. New York, McGraw, 2004.

Dicato, Mario. Side Effects of Medical Cancer Therapy: Prevention and Treatment. New York, Springer, 2013.

Galloway, D. “Treating Patients with Cancer Requires Looking beyond the Tumor.” OncoLog, vol. 49, no. 7/8, 2004.

Kelvin, Joanne, and Leslie Tyson. One Hundred Questions and Answers about Cancer Symptoms and Cancer Treatment Side Effects. 2nd ed. Sudbury, Jones, 2011.

"Late and Long-term Effects of Cancer." American Cancer Society, 29 May 2024, www.cancer.org/cancer/survivorship/long-term-health-concerns/long-term-side-effects-of-cancer.html. Accessed 26 June 2024.

Madhusoodanan, Jyoti. "These Cancers Were beyond Treatment—but Might Not Be Anymore." Scientific American, 1 Mar. 2024, www.scientificamerican.com/article/a-new-type-of-cancer-drug-shrinks-hard-to-treat-tumors. Accessed 25 Jun. 2024.

Physician’s Desk Reference, 2014. 68th ed. Montvale, PDR, 2013.

"Side Effects of Cancer Treatment." National Cancer Institute, www.cancer.gov/about-cancer/treatment/side-effects. Accessed 26 June 2024.

"Side Effects of Cancer Treatment." U.S. Centers for Disease Control and Prevention, 6 Feb. 2024, www.cdc.gov/cancer-survivors/patients/side-effects-of-treatment.html. Accessed 26 June 2024.