Chemotherapy Side Effects and Syndromes

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Original Editors -Alisha Dye & Monica Toole Students from Bellarmine University's Pathophysiology of Complex Patient Problems project.

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Definition/Description

     Chemotherapy is the use of medicines or drugs to treat a disease, such as cancer. This treatment is often just called “chemo.” Two other medical terms used to describe cancer chemotherapy are antineoplastic (meaning anti-cancer) therapy and cytotoxic (cell-killing) therapy. Chemotherapy differs from surgery or radiation in that it’s almost always used as a systemic treatment. This means the drugs travel throughout the body to reach cancer cells wherever they are. Chemo can kill cancer cells that have metastasized or spread to parts of the body far away from the primary (original) tumor.   

     The first drug used for cancer chemotherapy did not start out as a medicine. Mustard gas was used as a chemical warfare agent during World War I and was studied further during World War II. During a military operation in World War II, a group of people were accidentally exposed to mustard gas and were later found to have very low white blood cell counts. Doctors reasoned that something that damaged the rapidly growing white blood cells might have a similar effect on cancer. So, in the 1940s, several patients with advanced lymphomas (cancers of certain white blood cells) were given the drug by vein, rather than by breathing the irritating gas. Their improvement, although temporary, was remarkable. That experience led researchers to look for other substances that might have similar effects against cancer. As a result, many other drugs have been developed. 

     Depending on the type of cancer, its stage, and where you are in the treatment process, the goal of chemo is to: cure the cancer, keep the cancer from spreading, slow the cancer’s growth, kill cancer cells that may have spread to other parts of the body, and relieve symptoms caused by cancer.

Prevalence

File:Cancer map.jpg

 Systemic chemotherapy plays a major role in the management of the 60% of malignancies that are not curable by regional modalities.

Characteristics/Clinical Presentation

Side Effetct	Clinical Presntation
Anemia	Fatigue, dizziness, paleness, shortness of breath, weakness or racing heart
Fatigue	Mild tiredness or feeling completely wiped out that doesn’t get better with rest/sleep
Pain	Burning, numbness, tingling (most often in the fingers or toes), headaches, muscle pains, or stomach pains
Hair Loss	Mild or severe hair loss on arms, legs, face or scalp
Decreased CBC	Unexpected bruising, red/pink urine, bloody BM, nose/gum bleeding, or dizziness
Infection	Fever, chills, sweating, loose stools, sore throat, or abdominal pain
Nausea/Vomiting	Usually lasts several hours after treatment
Constipation	No BM in 2 or more days
Diarrhea	2 or more loose stools in 4 hours
Mouth/Gum/Throat Problems	Sores, dryness, bleeding, or irritation
Nerve/Muslce Problems	Loss of balance, clumsiness, jaw pain, hearing loss, vision changes, stomach pain, or constipation
Skin/Nail Changes	Color changes, redness, itching, peeling, dryness, rashes or acne
Bladder/Kidney Problems	Pain when urinating, frequent urination, bloody urine, fever or chills

Associated Co-morbidities

     The most common per-existing condition observed in all patients with cancer is hypertension. Diabetes is the second most prevalent pre-existing condition in middle-aged patients, while a previous solid tumor is the second most common pre-existing condition in patients 74 years of age or older.

Other comorbidities that may occur with cancer include:

Obesity
Digestive system disease
Arthritis
Dementia
Thrombotic events and conditions
Depression and other psychiatric illnesses
Chronic obstructive pulmonary disease (COPD) and other pulmonary conditions
Osteoporosis

Medications

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 are used to treat many different cancers, including leukemia, lymphoma, Hodgkin disease, multiple myeloma, and sarcoma, as well as 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: Nitrogen mustards, Nitrosoureas, Alkyl sulfonates, Triazines, and Ethylenimines.

 2. Antimetabolites: 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, cancers of the breast, ovary, and the intestinal tract, as well as other types of cancer. Examples of antimetabolites include: 5-fluorouracil, 6-mercaptopurine, Capecitabine, Cladribine, Clofarabine, Cytarabine, Floxuridine, Fludarabine, Gemcitabine, Hydroxyurea, Methotrexate, Pemetrexed, Pentostatin, and Thioguanine.

3. Anthracyclines: There are anti-tumor antibiotics that interfere with enzymes involved in DNA replication. These drugs work in all phases of the cell cycle. They are widely used for a variety of cancers. A major consideration when giving these drugs is that they can permanently damage the heart if given in high doses. For this reason, lifetime dose limits are often placed on these drugs. Examples of anthracyclines include: Daunorubicin, Doxorubicin, Epirubicin and Idarubicin.

4. Mitoxantrone: This anti-tumor antibiotic is similar to doxorubicin in many ways, including the potential for damaging the heart. This drug also acts as a topoisomerase II inhibitor (see below), 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 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 to treat many different types of cancer including breast, lung, myelomas, lymphomas, and leukemias. These drugs are known for their potential to cause peripheral nerve damage, which can be a dose-limiting side effect. Examples of mitotic inhibitors include: Taxanes,Epothilones, Vinca alkaloids, and Estramustine.

7. Corticosteroids: Steroids are natural hormones and hormone-like drugs that are useful in treating some types of cancer (lymphoma, leukemias, and multiple myeloma), as well as other illnesses. When these drugs are used to kill cancer cells or slow their growth, they are considered chemotherapy drugs. Corticosteroids are also commonly used as anti-emetics to help prevent nausea and vomiting caused by chemotherapy. They are used before chemotherapy to help prevent severe allergic reactions (hypersensitivity reactions), too. When a corticosteroid is used to prevent vomiting or allergic reactions, it’s not considered chemotherapy. Examples include: prednisone, methylprednisolone, and dexamethasone.

Diagnostic Tests/Lab Tests/Lab Values

Complete Blood Counts

CBCs are routinely performed during chemotherapy and other cancer treatments to check the number of each type of blood cell circulating in the body. This test is also called a hemogram.

Red blood cells (RBC)
Men: 4.5 to 6.2 million per drop
Women: 4.2 to 5.4 million per drop

White blood cells
Men and Women: 3,700 to 10,000 per drop
Lowest level at which someone is safe from infection: 1,000

Platelets
Men and Women: 150,000 to 450,000 per drop
Lowest level at which someone's blood can still clot normally: 100,000
Level at which there's a risk of spontaneous bleeding: 50,000
Level at which bleeding can become life-threatening: 5,000

OnPART

This diagnostic test was designed to determine an individual’s risk of developing side effects associated with chemotherapy based on their genomic profile. The preliminary results of a clinical study of OnPART were recently reported by the company at the annual meeting of the Multinational Association of Supportive Care in Cancer. In this study, OnPART correctly identified patients at risk for chemotherapy-induced diarrhea (CID) with an accuracy of 96.7%. This diagnostic test is expected to be commercially available in 2014.

Etiology/Causes

None.

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, vessles and the pericardium. Risk factors for cardiotoxicity include pre-existing cardiac disease, the use of concurrent chemotherapy agents, older than 70, female, and current or previous radiation therapy involving the mediastinum.

Renal System
Several chemotherapy drugs can cause either acute or chronic renal failure. Common chemotherapy drugs used to treat numerous types of cancers are often a cause of renal tubular and glomerular damage. Most commonly, there medications cause: proximal tubular abnormality, haemorrhagic cystitis, microangiopathic haemolytic anaemia and renal failure.

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

Gastrointestinal
Gastrointestinal toxicity is common after administration of most chemotherapy drugs and includes nausea and vomiting, mucositis, diarrhea and dehydration. In these cases, it is important that fluid and electrolytes are replinished.

Medical Management (current best evidence)

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Physical Therapy Management (current best evidence)

It is extremely important to take a client history of current therapy dosages and to monitor the hematologic values in clients receiving these treatment modalities. Current guidelines recommend that individuals that undergo chemotherapy should not exercise within two hours of the treatment because increases in circulation may change the effects of the treatment. The suggested two hour delay is reasonable given the half- life of most chemotherapeutic agents.

• Strength
• Balance
• Endurance
• Range of motion
• Coordination
• Quality of life 

Platelet count	<50,000/ml
Hemoglobin	<10 g/dl
WBC	<3,000/ml; >10,000 with fever
Absolute granulocytes	<500/ml

Alternative/Holistic Management (current best evidence)

Acupuncture: Studies show acupuncture may be helpful in relieving nausea and may also help relieve certain types of pain in people receiving chemotherapy. 

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.

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.

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

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.

Differential Diagnosis

None

Case Reports/ Case Studies

Inoperable pancreatic adenocarcinoma rendered complete remission by high-intensity focused ultrasound concurrent with gemcitabine-capecitabine chemotherapy: Case report and topic review.

Lau P, Zheng S, NG W, YU S. Inoperable pancreatic adenocarcinoma rendered complete remission by high-intensity focused ultrasound concurrent with gemcitabine-capecitabine chemotherapy: Case report and topic review. Journal Of Digestive Diseases [serial online]. January 2012;13(1):60-64. Available from: Academic Search Premier, Ipswich, MA. Accessed April 2, 2013.

Thalidomide Combined with Neoadjuvant Chemotherapy in Angiosarcoma of the Breast with Complete Pathologic Response: Case Report and Review of Literature.

Alvarado-Miranda A, Bacon-Fonseca L, Lara-Medina Fernando ,, Maldonado-Martínez H, Arce-Salinas C. Thalidomide Combined with Neoadjuvant Chemotherapy in Angiosarcoma of the Breast with Complete Pathologic Response: Case Report and Review of Literature. Breast Care [serial online]. March 2013;8(1):74-76. Available from: CINAHL, Ipswich, MA. Accessed April 2, 2013.

Caffeine-potentiated chemotherapy for clear cell sarcoma: a report of five cases.

Karita M, Tsuchiya H, Yamamoto N, Shirai T, Hayashi K, Nishida H. Caffeine-potentiated chemotherapy for clear cell sarcoma: a report of five cases. International Journal Of Clinical Oncology [serial online]. February 2013;18(1):33-37. Available from: Academic Search Premier, Ipswich, MA. Accessed April 2, 2013.

Resources

 American Cancer Society  

Cancer Care

OncoLink 

Recent Related Research (from Pubmed)

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References

see adding references tutorial.