Chemotherapy Side Effects and Syndromes

Original Editors -from Bellarmine University's Pathophysiology of Complex Patient Problems project.

Top Contributors - Alisha Dye, Jasmine Athanasakes, Kim Jackson, Elaine Lonnemann, Lucinda hampton, Admin, Evan Thomas, Vidya Acharya, 127.0.0.1, Wendy Walker and WikiSysop  

Definition/Description

Chemotherapy refers to treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.

• Chemotherapy may be given by mouth, injection, or infusion, or on the skin, depending on the type and stage of the cancer being treated.
• It is a systemic treatment.
• It may be given alone or with other treatments, such as surgery, radiation therapy, or Immunotherapy.

Chemotherapy is associated with a range of adverse effects e.g., nausea, vomiting, increased risk of infection (see immunocomprimised client), and impaired growth of healthy cells, and with some agents, an increased risk of secondary neoplasms.

• Systemic chemotherapy plays a major role in the management of the 60% of malignancies that are not curable by regional modalities. It can significantly delay and interfere with cancer treatment because the presence of chemotherapy-induced side effects can warrant a dose reduction, or a delay or cessation in treatment.

General Side Effects

Chemotherapy damages rapidly growing tissues, but can also be neurotoxic and lead to peripheral neuropathy.

1. Gastrointestinal mucosa: mucositis - Inflammation of the mucous membranes lining the digestive tract from the mouth to the anus. Mucositis is a common side effect of chemotherapy and of radiotherapy that involves any part of the digestive tract. Mucositis affects the rapidly dividing mucosal cells that line the mouth, throat, stomach, and intestines (all normally have a short lifespan). If a therapy destroys these cells, they may not be replaced right away, resulting in mucositis. A person with mucositis may have raw sores (ulcers) in the mouth and throat and feel like he or she has a sunburn in the throat.
2. Hematopoiesis (myelosuppression)
   • Granulocytopenia and lymphocytopenia (increased risk of infection)
   • Thrombocytopenia (increased bleeding risk)
   • Anemia (fatigue)
3. Hair follicles: hair loss
4. Chemotherapy-induced peripheral neuropathy
   • Pain, burning, tingling, and loss of sensation in the distal extremities that spread from the hands and feet.
   • Typically spreads in a “stocking-glove pattern”
   • Causative agents include platinum-based medications (e.g., cisplatin), taxanes (e.g., paclitaxel), and vinca alkaloids (e.g., vincristine).
5. Centrally induced vomiting
6. Gonadal damage

Chemotherapy Agents

1. 
   Alkylating agents: These directly damage DNA to prevent the cancer cell from reproducing. These agents work in all phases of the cell cycle. Alkylating agents commonly treat leukemia, lymphoma, Hodgkin disease, multiple myeloma, sarcoma, and cancers of the lung, breast, and ovary. Because these drugs damage DNA, they can cause long-term damage to the bone marrow. There are different classes of alkylating agents, including: Oxaliplatin, Nitrogen mustards, Nitrosoureas, Alkyl Sulfonates, Triazines, and Ethylenimines.
2. Antimetabolites: This is a class of drugs that interfere with DNA and RNA growth by substituting for the normal building blocks of RNA and DNA. They are commonly used to treat leukemias, breast and ovary cancers. Examples include: Capecitabine, Cladribine, Clofarabine, Cytarabine, Floxuridine, Fludarabine, Gemcitabine, Hydroxyurea, Methotrexate, Pemetrexed, Pentostatin, and Thioguanine.
3. Anthracyclines: These anti-tumor antibiotics interfere with enzymes involved in DNA replication and are used for a variety of cancers. These drugs work in all phases of the cell cycle. A major consideration when giving these drugs is that they can permanently damage the heart if given in high doses. Because of this, lifetime dose limits are often placed on these drugs. Examples include: Daunorubicin, Doxorubicin, Epirubicin and Idarubicin.
4. Mitoxantrone: This anti-tumor antibiotic also interferes with enzymes involved in DNA replication. This drug also has potential for damaging the heart and can lead to treatment-related leukemia. Mitoxantrone is used to treat prostate cancer, breast cancer, lymphoma, and leukemia.
5. Topoisomerase inhibitors: These drugs interfere with enzymes called topoisomerases, which help separate the strands of DNA so they can be copied. They are used to treat certain leukemias, as well as lung, ovarian, gastrointestinal, and other cancers. Examples include: Topotecan, Airinotecan, Etoposide and Teniposide.
6. Mitotic inhibitors: These medications are often plant alkaloids and other compounds derived from natural products. They can stop mitosis or inhibit enzymes from making proteins needed for cell reproduction. They are used for breast and lung cancer, myelomas, lymphomas, and leukemias. These drugs are known for their potential to cause peripheral nerve damage. Examples include: Taxanes, Epothilones, Vinca alkaloids, and Estramustine.
7. Corticosteroids: Steroids are hormone-like drugs that are useful in treating cancer including lymphoma, leukemias, and multiple myeloma. Corticosteroids are also commonly used as anti-emetics to help prevent nausea and vomiting caused by chemotherapy. They are also used before chemotherapy to help prevent severe allergic reactions. When a corticosteroid is used to prevent vomiting or allergic reactions, it’s not considered chemotherapy. Examples include: Prednisone, Methylprednisolone, and Dexamethasone.

Medications to Treat Chemotherapy-Induced Side Effects

1. Chemoprotectants: Designed to reduce toxicity of chemotherapy drugs and repair DNA while not reducing the effectiveness of the chemotherapy drug. Amofistine is the most common medication. Studies have investigated its effect on taxanes and pathlitaxel and have shown that amofistine has no effect on sensory and motor neurotoxic symptoms. Leukovorin is another drug designed to counteract the effects of the chemotherapy drug methotrexate.
2. Vitamins and Minerals:
   • Vitamin E - Vitamin E is an antioxidant (see free radicals) and is used to protect against several side effects of cisplatin and cytotoxic drugs such as numbness, tingling, burning, or pain. Research studies show Vitamin E decreases these neurotoxic symptoms.
   • Calcium and Magnesium Infusions - Designed to prevent neurotoxicity side effects associated with oxaliplatin. Studies have shown that they effectively reduce pseudolaryngospasm, neuropathy and other neurotoxic symptoms.
3. Tricyclic Antidepressants: Have analgesic effects to treat chemotherapy related pain. Mixed evidence that they may decrease paresthesias.
4. Anticonvulsants: Carbamazepine most common. Small studies have shown that it decreases or eliminates CIPN.
5. Glutamine: Used to treat symptoms of paclitaxel. Research shows that glutamine reduces side effects of chemotherapy, particularly dysesthesias in the fingers and toes, weakness, and loss of vibratory sensation.
6. Glutathione: Used to treat symptoms of platinum compounds. Shown through research to reduce CIPN. It has also been shown to improve mood and decrease depression. However a side effect of glutathione is weight gain.
7. Capsaicin ointment: Found to significantly decrease hypoesthesia from diabetic neuropathy. May cause allergic reaction in a small percentage of people. It's effects on CIPN have not been studied.
8. Chinese Herbal Medicines: Low level evidence that these medicines reduce nausea and vomiting and improve leukopenia and immune system function.

Systemic Involvement

Respiratory System
Patients receiving chemotherapy are at risk for developing infection, metastatic disease, pulmonary embolism, or drug-induced pulmonary toxicity. Chemo drugs commonly cause pulmonary toxicity but many other drugs may also have an association. Initial presentation can be hard to detect because the patient may be asymptomatic and changes on chest X-ray may be minimal. However, patients may complain of a dry cough or increasing breathlessness with exercise. Due to the immunosuppressant effects of chemotherapy drugs, patients may also present with infections such as pneumonia.

Cardiovascular System
Cardiac toxicity due to chemotherapy is common and may be life threatening or cause significant morbidities. Common symptoms include hypotension, hypertension, arrhythmias, myocardial infarction, congestive cardiac failure, cardiomyopathy, myocarditis, and pericarditis, leading to pericardial effusion and cardiac tamponade. Cardiac toxicity can be immediate or delayed after completion of the course of chemotherapy.

Chemotherapy drugs tend to damage myocytes, cardiac valves, vessels and the pericardium. Risk factors for cardiotoxicity include pre-existing cardiac disease, the use of concurrent chemotherapy agents, older than the age of 70, female, and current or previous radiation therapy involving the mediastinum.

Renal System
Several chemotherapy drugs can cause acute or chronic renal failure. Common chemotherapy drugs are often a cause of renal tubular and glomerular damage. Most commonly, these medications cause: proximal tubular abnormality, hemorrhagic cystitis, microangiopathic hemolytic anemia and renal failure.

Nervous System
Chemotherapy can damage any part of the nervous system. Chemotherapy agents can cause neurotoxicity, peripheral neuropathy, muscle pain, cranial neuropathy, seizures or exacerbate pre-existing neurological conditions. There are also effects on the autonomic nervous system, which can cause orthostatic hypotension. In high-doses some drugs may induce acute encephalopathy, causing confusion, seizures, hemiparesis, and coma. It is important that physical therapists conduct a full neurological examination to detect any neurological damage.

Gastrointestinal
Gastrointestinal toxicity is a common side effect of most chemotherapy drugs. Signs and symptoms of gastrointestinal toxicity includes: nausea and vomiting, mucositis, diarrhea and dehydration. It is important that fluid and electrolytes are replenished before and after exercise.

Medical Management

Cycle

Chemotherapy is generally given at regular intervals called cycles. A chemotherapy cycle may involve a dose of one or more drugs followed by several days or weeks without treatment. This gives normal cells time to recover from the drug’s side effects. Sometimes, doses may be given several days in a row, or every other day for several days, followed by a period of rest. Some drugs work best when given continuously over a set number of days.

Cycle considerations include:

• Minimizing side effects
• Number of drugs being used
• Type of cancer
• Stage of cancer
• Health status
• Goals of treatment.

Physical Therapy Management

• NB Important to take a client history of current chemotherapy dosages and to monitor the hematologic values in clients receiving physical therapy.
• A Systematic Review of Clinical Practice Guidelines suggests therapeutic physical exercises effectively alleviate the several adverse effects (pain, restricted mobility, fatigue, edema, mood) caused by breast cancer treatment.
• Current guidelines recommend that individuals undergoing chemotherapy should not exercise within two hours of their treatment because the increase in blood circulation during exercise may change the effects of the chemotherapy treatment. The suggested two hour delay is reasonable given the half-life of most chemotherapeutic agents.
  

Exercise Precautions for the Current Cancer Patient
(Box 9-5 from Pathology: Implications for the Physical Therapist)

• Fever
• Extreme or unsual fatigue
• Unusual muscular weakness
• Irregular heart beat, chest palpitations, chest pain
• Sudden onset of dyspnea
• Leg pain or cramps
• Unusual joint pain
• Recent or new-onset back, neck, or bone pain
• Unusual bruising, nosebleeds, or bleeding from any other body opening
• Sudden onset of nausea during exercise
• Rapid weight gain or weight loss
• Severe diarrhea or vomiting
• Disorientation, confusion, dizziness, or lightheadedness
• Blurred vision or other visual disturbances
• Skin pallor or unusual skin rash

Contact physician about any of these symptoms.

Specific Exercise Precautions for the Cancer Survivor Post-treatment

• Severe Anaemia, medical eval necessary
• Compromised immune function / bone marrow transplantation; Should avoid public gyms for about 1 year
• Medical approval needed to expose irradiated skin to chlorine
• Indwelling catheters: infection precautions, avoid resistance training so catheter won’t be dislodged
• Stationary bike may be better than treadmill for patients with poor balance, gait disturbances, or peripheral neuropathies
  

Physical Therapy Implications

Strength:

• A Longitudinal Pilot Study in patients with head and neck cancer (HNC) undergoing seven weeks of chemo-radiotherapy (CRT) showed a clinically significant increase in the incidence of probable sarcopenia and a considerable decline in handgrip strength, skeletal muscle mass and Timed Up and Go performance.
• Research has shown that resistance training has been shown to improve strength in people with neuropathy from causes other than chemotherapy.
• Some moderate-level studies have also shown that resistance training may reverse muscle atrophy caused from peripheral neuropathy.

Pain and Sensation:

• Pain and sensation deficits were shown to be effectively treated by long-wave diathermy and interferential currents after long periods of treatment (>30 weeks).
• TENS is shown to improve numbness, lancinating pain, allodynia, prickling sensations, and allodynia in people with diabetic neuropathy.
• High frequency muscle stimulation has also been shown to improve diabetic neuropathy symptoms such as numbness, burning, paresthesia, and dysesthesia..

Balance:

• Yoga, Tai Chi, Otago balance program are all options

Endurance:

• Endurance training program (low to moderate levels of aerobic exercise) improve physical performance and temperament while reducing mental stress and fatigue when undergoing chemotherapy.
• Walking over a flat ground or pedal on a cycloergometer as well as aquanastics (water exercises) improve cardiovascular fitness following chemotherapy.

Range of motion:

• Stretching exercises improve eg functional reach in people with peripheral neuropathy.

Cognition:

• Studies have shown a positive relationship between increased physical activity and improved mental activity.

Coordination and Sensation (Neuropathy):

• Physical therapy treatment can consist of a warm up, and recovery through neuroproprioceptive facilitation (PNF) in order to improve muscle tone and postural stability which can improve proprioception for the patient with CIPN.
• Dan and Boca published some advice on,

          - activities for improving balance: sensory stimulation, surfaces with different textures

          - activities for developing coordination: adapted ball game with coordination of visual and kinesthetic aspects for LEs

Quality of life

• Physical therapy treatment has been incorporated into a 12 month study by for breast cancer survivors to increase QOL. Jung et al. suggests Reiki ( a Japanese stress reducing technique) to decrease pain and improve QOL of the CIPN patient.

Assistive Devices

• There are no research studies about the use of assistive devices with patients with cancer. However there are some for the effects of a cane and orthotic for patients with diabetic neuropathy. These patients found that the cane and orthotic helped with injury prevention. They were not found to have an effect on the peripheral neuropathy. Patients with cancer are often referred to physical therapy to be fitted with an assistive device, orthotic, or splint to improve balance and proper alignment of the lower extremity.

Education

• Energy conservation
• Integumentary education, especially foot care
• Infection education
• Signs and symptoms of chemo-induced side effects, particularly CIPN
• Increased fall risk due to loss of LE sensation. Teach patients to use vision to prevent falls.
• Managing risks for ischemic and thermal injuries due to sensation losses
• Strategies to manage complications of autonomic neuropathy (ex. postural hypotension, constipation, urinary retention) such as dangling legs before standing, standing slowly, a high fiber diet, and hydration

More on Energy Conservation

• Schedule most demanding tasks at time where energy it at its peak
• Alternate strenuous and easy tasks
• Plan frequent rest points
• Avoid working to the point of fatigue
• Avoid extra trips
• Delegate tasks to others
• Keep items in easy places to reach
• Minimize carrying objects, can use a wheeled cart
• Daily stretching
• Brief increments of activity (5 min even)

Other Management Strategies

Acupuncture: Studies show acupuncture may be helpful in relieving nausea and may also help relieve certain types of pain in people receiving chemotherapy. Also shown to improve gait and balance, as well as decrease the required dosage of analgesic drugs. In one study, these improvements were sustained for 6 months and no adverse effects were seen. Not shown to have an effect on neuropathy or vibration sensation.

Aromatherapy: Aromatherapy uses fragrant oils to provide a calming sensation which may be helpful in relieving nausea, pain and stress. 

Biofeedback: Biofeedback may be helpful in relieving pain in people with cancer.

Behavioral Therapy: Systemic desensitization has been found to significantly decrease anticipatory N&V before chemotherapy treatments.

Exercise: Exercise may help you manage signs and symptoms during and after cancer treatment. Gentle exercise, such as walking or swimming, may help relieve fatigue and stress and help you sleep better.

Hypnosis: Hypnosis may be helpful for people with cancer who are experiencing anxiety, pain and stress. It may also help prevent anticipatory nausea and vomiting that can occur if chemotherapy has made you sick in the past.

Massage therapy: Studies have found massage can be helpful in relieving pain in people with cancer. It may also help relieve anxiety, fatigue and stress.

Meditation: Meditation may help people with cancer by relieving anxiety and stress.

Music therapy: Music therapy may help relieve pain and control nausea and vomiting.

Pulsed Infrared Light Therapy: Also called anodyne therapy. Machine delivers infrared light to foot with neuropathy (CIPN has not been studied but other forms of neuropathy have) and stimulates nitric oxide production to improve circulation. Shown to improve sensation, neuropathic symptoms and pain in most patients, excluding those with very advanced neuropathy scores.

Relaxation techniques: Relaxation techniques may be helpful in relieving anxiety and fatigue and they may also help people with cancer sleep better.

Spinal Cord Stimulation: Not yet recommended for practice due to lack of research and high surgical risks and costs. The surgery involves placing electric leads into the involved section of the spinal cord or nerve roots to transmit energy that blocks the pain through the gate-control theory. One case study of 2 patients who underwent the surgery showed that they had improved pain, sensation, gait, and flexibility afterwards. They were also able to decrease their analgesic dosage.

Tai chi: Practicing tai chi may help relieve stress.

Yoga: Yoga may provide some stress relief for people with cancer. Yoga has also been shown to improve sleep and reduce fatigue.

Some alternative treatments have been shown to work well together but more research is needed for conclusive evidence.  

Videos

• Patient's Perspective on Chemotherapy-Induced Side Effects