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Preventing Chemotherapy Toxicities And Other Issues On Drugs Used In Oncology
Dr. Robert Ignoffo, PharmD, Clinical Professor, UCSF, Zoe Ngo, PharmD &Julie Schwenka, PharmD, UCSF,

Nausea and Vomiting
Mouth Sores
Diarrhea
Constipation
Low White Blood Counts (Neutropenia)
Low Platelet Counts (Thrombocytopenia)
Low Red Blood Count (Anemia)
Bladder or Urinary toxicity from Chemotherapy
Hypersensitivity Reactions from Chemotherapy
Dermatologic (skin) Reactions from Chemotherapy
Fertility Effects of Chemotherapy
Cardiac (heart) toxicity from Chemotherapy


Nausea and Vomiting
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Nausea and vomiting are common side effects of chemotherapy drugs that are used to treat cancer. Some chemotherapy drugs are worse offenders than others are. In most cases, patients will be given anti-vomiting (antiemetics) and anti-nausea medication prior to the administration of chemotherapy. Some of the commonly used antiemetics are listed in the chart below. As you can see, these drugs may also have some side effects of their own. Several antiemetics are available by prescription for use at home in the event that nausea or vomiting are persistent.

Drug Name Usual Dose Side Effects Cost
Compazine (prochlorperazine) 10 mg orally every 8 hours as needed Sleepiness, dystonic reactions, lockjaw $0.20/tablet
Lorazepam (Ativan) 0.5 to 1 mg orally every 4 to 6 hrs as needed Sleepiness, confusion $0.50/1 mg tablet
Ondansetron (Zofran) 4 to 8 mg orally 2 to 3 times daily Headache, constipation $15.00/8 mg tablet
Granisetron (Kytril) 1 mg orally twice a day or 2 mg once daily Headache, constipation $35.00/1 mg tablet
Dolasetron (Anzemet) 100 mg orally once daily Headache, constipation $20.00/100 mg tablet
Dronabinol (Marinol) 2.5 to 5 mg orally four times daily Sleepiness, appetite stimulation, confusion $1.00/tablet
Dexamethasone 4 to 8 mg orally twice daily with meals Insomnia, stomach upset $0.50/tablet
Metoclopramide (Reglan) 10 to 20 mg orally four times daily Diarrhea, anxiety, sleepiness $0.60/tablet

Delayed nausea and vomiting can occur after cisplatin, carboplatin, and cyclophosphamide chemotherapy. The most effective antinausea medications for delayed nausea and vomiting are Reglan and dexamethasone. However, these drugs have more side effects than the setrons (ondansetron, granisetron, and dolasetron). A setron should be used after Reglan and dexamethasone has been tried. If effective a setron may be used as a preventative therapy during the next cycle of chemotherapy.


Mouth Sores
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The mouth and digestive tract are composed of cells (mucosa) that are more sensitive to chemotherapy. Thus, during or after chemotherapy or radiation therapy, a cancer patient may present with some sort of mouth problem, ranging from dryness to ulcers. These mouth problems may be related to the cancer itself, but more are often due to chemotherapy or other medication. Three to ten days following chemotherapy, patients may experience a burning sensation, followed by ulcers. When ulceration develops, treatment is mostly supportive until the cells regenerate themselves, which takes about 7 to 14 days. This can impact on oral comfort and nutrition, but adequate care can minimize these effects.

Prevention Basic mouth hygiene is of primary importance, and should be initiated before chemotherapy starts. Patients should brush their teeth 3 to 4 times a day with a soft toothbrush or sponge and use floss. Patients at high risk (those receiving 5-FU or methotrexate) should rinse their mouth frequently with salt water, baking soda or chlorhexidine following chemotherapy.

Treatment. Once mouth sores developed, analgesics and anesthetics can be employed. Xylocaine is a local anesthetic available as a gel or spray used to decrease pain, but has a short duration of action. It should not be used prior to meals, as it can cause choking. Protective agents (sucralfate, kaopectate) are also used to cover ulcers and decrease irritation. It is important to stay away from irritant substances like peroxide as they way worsen the ulcers. Topical steroids should not be used as they may facilitate infections. In addition, patients should not eat spicy, hot, acidic or coarse foods or juice. Preference should be put on soft moist foods.

Drug name Usual dose Side Effects Cost
Saline mouthwash 10-30 mL swish and swallow every 2 to 6 hours Few None
Baking soda mouthwash 1/2 tsp. salt plus 1/2 tsp. baking soda in a cup of warm water, rinse every 3 or 4 hours Few None
Chlorhexidine (Peridex) Rinse every 4 hours Taste, color, teeth staining $
Betadine mouthwash Diluted with water 50-50 10 cc 3 times a day and as needed applied locally or swish Iodine allergy, color, teeth staining $
Xylocaine GEL: 5 to 15 mL every 4 hours SPRAY: 1 spray every 4 hours Possible systemic effect Choking if taken before meals $$
Sucralfate or kaopectate 10 to 30 mL every 2 to 6 hours, swish and spit Taste $$

Damage to the mucosa can facilitate some infections, such as candida or herpes simplex virus infections. Appropriate treatment should be started. Thrush can be treated with topical antifungals, such as clotrimazole or nystatin. When infection is more severe, oral ketoconazole, fluconazole, or intravenous amphotericin may be used.

Drug Name Usual dose Side effects Cost
Clotrimazole troches (Mycelex) Place troche in mouth 4 to 5 times a day, for 7 to 14 days Well tolerated, taste $$
Nystatin suspension 1 teaspoonful every 4 to 6 hours, swish and swallow Well tolerated, irritation $$
Fluconazole (Diflucan) 100mg every day Nausea, vomiting, itching $$$
Amphotericin B Intravenous dose varies Headache, fever, chills. $$
Amphotericin B mouthwash 10mg swish and swallow every day Taste $$$

Dry mouth (xerostomia) can occur in certain patients and can be easily treated with drinking fluids, sodas, sucking ice chips, eating fresh fruits or chewing gum. Preparation containing alcohol or glycerin should not be used because they may irritate or aggravate dryness. Artificial saliva (MoiStir, Artisial) is commercially available and can be useful in some patients. Dryness should not be overlooked, as it may predispose to ulcers and infections.


Diarrhea
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Several anti-cancer drugs can damage the digestive tract, at times leading to diarrhea. Specific drugs particularly associated with diarrhea are 5-FU, methotrexate, cytarabine, capecitabine and irinotecan. Because it is difficult to predict which patients will develop diarrhea, prevention is not an effective management strategy and antidiarrheal therapy is the mainstay of treatment. In addition, adequate fluid intake is critical in order to prevent dehydration. Drinking water, soup or non-caffeinated beverage is adequate in mild diarrhea, and oral fluid replacement preparation (such as Gatorade) is preferable in moderate losses. Intravenous fluid support might be required in a severe case of dehydration. Diarrhea can be controlled with Lomotil or Imodium, unless the diarrhea is caused by infection.

Drug name Usual dose Side effects Cost
Water, broth, soda 8 to 10 glasses daily No coffee or caffeine-containing liquids, as they can worsen diarrhea Minimal
Rehydration formulas As indicated Well tolerated $$
Loperamide (Imodium) 2 capsules followed by 1 capsule after each loose stool, up to 8 capsules per day Sedation, drowsiness $$
Lomotil 1 or 2 tablets 3 to 4 times per day Nervousness, drowsiness $$

Diarrhea caused by irinotecan is treated in a different manner. If diarrhea occurs less than 24 hours after the infusion, atropine is given to control the symptoms. For late-onset diarrhea (more than 24 hours after infusion), the patient should take 2 caplets of loperamide (4mg) after the first episode of loose stools, followed by one caplet (2mg) every 2 hours until diarrhea-free for 12 hours. During nighttime, the patient should take 2 caplets (4mg) every 4 hours. This regimen is tailored for irinotecan-treated patients and should ot be used in others, unless indicated otherwise.


Constipation
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Constipation may be due to a number of drugs used in the management of patients with cancer, including narcotic analgesics (painkillers), vinca chemotherapy drugs vincristine (Oncovin), vinblastine (Velban), and vinorelbine (Navelbine), and calcium-contained antacids (Tums). Patients administered any of the above drugs should be given a bowel regimen in order to maintain normal bowel functioning.

Narcotic analgesics administered by any route (oral, topical, or injectable) may cause substantial decrease in bowel movements by inhibiting the nerves in the gastrointestinal tract. Drugs such as oral morphine (MS Contin), oral oxycodone (Oxycontin), fentanyl (Duragesic) topical patch or injectable morphine, hydrocodone (Dilaudid) have been implicated. The vinca chemotherapy drugs frequently cause constipation beginning within 7 days of therapy. Elderly patients are particularly susceptible to constipation from both narcotics and vincas.

Any patients started on these drugs should also be taking adequate fluids and fruits (prunes or raisins) to stimulate bowel functioning. In addition, a stimulant laxative such as senokot or dulcolax along with a stool softener (Colace) should be taken concurrently with narcotics. If senokot is ineffective, a prescription medication may be required such as lactulose or an over-the-counter solution of citrate of magnesia. The usual doses of medications to prevent and treat constipation are shown in the table below.

Drug name Usual dose Side effects Cost
Senokot 2 tablet twice daily until regular bowel functioning then 1 tab/day Stomach upset $
Colace 2 capsules (100mg each) twice daily None $
Dulcolax 1 or 2 tablets daily until regular bowel functioning then 1 tab/day Stomach upset $
Lactulose 15 to 30 ml two to three times daily to induce bowel functioning Diarrhea (excessive dose); flatulence $
Miralax 17 grams (1 tablespoon) per day Nausea, bloating, cramping. $


Low White Blood Counts (Neutropenia)
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In the process of destroying cancer cells, chemotherapy can also cause damage to other rapidly dividing cells, such as the bone marrow cells. Bone marrow is responsible for producing red blood cells (RBCs), white blood cells (WBCs) and platelets. The reduced activity of the bone marrow is named myelosuppression. Blood components will decrease after chemotherapy, but at different speeds. White blood cells will be affected more rapidly, because of their shortest life span. White blood cells are the soldiers defending the human body against infections, so a low number is associated with increased infections. Your doctor will follow the number of white blood cells (counts) throughout your cancer treatments. White blood cells will reach their lowest number 10 to 14 days after the end of chemotherapy. The lowest number is also known as the nadir. White blood cells will recover within 3 to 4 weeks, except for some drugs that can cause a slower decrease and a longer recovery, such as the nitrosoureas or mitomycin C. There are two methods of measuring your number of cells. The first one is by counting the total number of WBC, which is preferably over 3,000/mm³. The other method is to calculate the Absolute Neutrophil Count (ANC), which should be over 1,500/mm³ to reduce the risk of infections. If the WBC count or ANC does not come back fast enough, your doctor may decide to hold the next cycle of chemotherapy until your blood count are sufficient.

In order to speed up the recovery and the activity of your WBCs, drugs such as colony-stimulating factors (CSFs) can be administered. Two CSFs are used in the United States to increase the WBC count, G-CSF (Neupogen) and GM-CSF (Leukine). They are given according to the weight of the patient and the level of bone marrow recovery. GCSF is given by subcutaneous injection every day for about 1 week after chemotherapy. Patient experiencing bone pain (usually in the sternum or hips) may take acetaminophen or a non-steroidal analgesic (ibuprofen, naproxen) if necessary.

Drug name Usual dose Side effects Cost
G-CSF (Filgastrim, Neupogen) 5mcg/kg/day SQ for 7 to 10 days rounded to:
300 mcg if < 75kg
480 mcg if >75 kg
Until ANC>1,000
Nausea, fever, bone pain $$$$
GM-CSF (Sargramostim, Leukine) 250 mcg/m² SQ or IV for 14 day Fever, flushing, hypotension, rigors, bone pain. $$$$


Low Platelet Counts (Thrombocytopenia)
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Your doctors will periodically monitor all of your blood counts. One of the blood counts is of the platelets. A normal value ranges from 150,000 to 300,000 per ml of blood. Low blood counts including a low platelet count can occasionally occur after receiving a lot of chemotherapy or radiation therapy. Thrombocytopenia, a very low platelet count (< 20,000/ml of blood) can result in bleeding from the nose, gums, urinary tract, or gastrointestinal tract. The usual time for a low platelet to occur is 10 to 21 days after chemotherapy, but any bleeding at any time should be reported immediately to your doctors. In order to keep the risk of having any bleeding during chemotherapy, it is best to avoid drugs that can affect the functioning of platelets. Such drugs include aspirin, ibuprofen (Advil), naprosyn (Aleve). If your platelet level is very low, you may be prescribed a platelet transfusion. In patients who have a low trend to thrombocytopenia, a drug called Neumega may be prescribed to prevent further fall in the platelet counts.


Low Red Blood Count (Anemia)
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Your doctors will periodically monitor all of your blood counts. One of the blood counts is of the red blood cells. Cancer and its treatment with chemotherapy or radiation can depress the number of red blood cells to a low level and eventually produce tiredness, lack of energy, and anemia. A normal value of red blood cells produces a hematocrit of nearly 40 or a hemoglobin of 14 to 15. Symptoms of anemia appear when the hematocrit falls below 30 or the hemoglobin is less than 9. If you have severe symptoms of anemia, you may be prescribed a red blood cell transfusion. A trend toward anemia may be prevented with the early initiation of a weekly injection of epoetin alfa (Procrit). The usual therapy for anemia is outlined below.

Drug or Therapy Usual dose Side effects Cost
Red blood Cell 1 unit for each 3 HCT points below normal Intravenously Hypersensitivity reactions, hepatitis $250/unit
Procrit (Epoetin Alfa) 40,000 units per week subcutaneously Hypertension $150 to 300 per injection


Bladder or Urinary toxicity from Chemotherapy
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Two chemotherapy drugs are associated with toxic side effects to the bladder and ureter. Both cyclophosphamide and ifosfamide can irritate the bladder and ureter leading to a condition called cystitis, which can occur in up to 10% of patients receiving intermittent or chronic low dose cyclophosphamide and 40% receiving cyclophoshamide in a high dose bone marrow transplant program. Cystitis is manifested as urinary burning or bleeding after several cycles of chemotherapy. Prevention of cystitis is achieved through frequent voiding and vigorous hydration. A patient receiving either of these drugs will be instructed on a method to prevent cystitis from being a problem. Adequate fluids, either taken orally or intravenously, dilute the urine such that the offending metabolites of these drugs will not damage the lining of the bladder or ureters. For ifosfamide a uroprotectant drug called MESNA will be given concurrently along with good hydration. The regimens to protect from cystitis are shown below. Treatment of hemorrhagic cystitis may require bladder irrigation with saline or formalin.

Drug name Therapy to prevent cystitis Uroprotectant Comments
Cyclophosphamide 8 glasses (8 ounces) over the 24 hours after administration of the drug. Mesna not required MESNA may be used when very high doses of cyclophosphamide are used as in Bone Marrow Transplant programs
Ifosfamide 8 glasses (8 ounces) over the 24 hours after administration of the drug. Mesna is required. MESNA 20% of the Ifosfamide dose given IV just prior to ifosfamide and then 4 and 8 hours given IV or orally. OR MESNA 90% mixed with Ifosfamide given continuously IV Mesna should be continued for 12-24 hours after the completion of ifosfamide therapy


Hypersensitivity Reactions from Chemotherapy
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Chemotherapy can cause some type of allergic reactions, better classified as hypersensitivity reactions (HSR).

Drug Type of Reaction and Treatment Frequency Premedication
Paclitaxel (Taxol) Type I. Severe HSRs include shortness of breath, wheezing, hives and itching, and low blood pressure, which occur within minutes after treatment usually after the 1st or 2nd dose. Most reactions resolve completely after stopping treatment and occasionally after treatment with diphenhydramine, fluids and dexamethasone. The drug may be restarted as a slower infusion rate and gradually increased after given premedications. 2-3% with premedication 1. Dexamethasone 20 mg orally 12 and 6 hours before treatment and 20 mg IV just before administration 2. Ranitidine 150 mg or cimetidine 300 mg IV 30 minutes prior to administration. 3. Diphenhyramine 50 mg orally and IV in the same schedule as dexamethasone.
Docetaxel (Taxotere) Type I. Most HSRs are minor and characterized by flushing, chest tightness, and low back pain. A major HSR is characterized by shortness of breath, wheezing, and low blood pressure usually occurring in the 1st 2 cycles and within minutes of starting the infusion. Discontinue treatment with docetaxel and administer diphenhydramine 50 mg IV and dexamethasone 10 mg IV. After resolution of symptoms, docetaxel may be restarted at a slower infusion rate. 2-3% with premedication 1. Dexamethasone 8 mg orally twice daily for 5 days starting 1 day prior to docetaxel. 2. (optional) #2 and #3 as above)
Etoposide (VP-16) Type I. HSRs can occur and manifest as chills, fever, shortness of breath, low blood pressure or wheezing. The drug should be stopped and the reaction treated with dexamethasone, diphenhydramine, and epinephrine (if necessary). For mild reactions, the infusion may be restarted at a slower infusion rate along with IV fluids and gradually increased with blood pressure monitoring. 0.7 to 2% None
Bleomycin Type I. HSRs from Bleomycin can occur from the 1st dose on, especially in patients with lymphoma. These reactions manifest as chills, fever, shortness of breath, low blood pressure or wheezing. The drug should be stopped and the reaction treated with dexamethasone, diphenhydramine, and epinephrine (if necessary). 1 % Test dose of 0.5 to 1 unit should be given to all patients prior to the 1st dose of bleomycin


Dermatologic Reactions from Chemotherapy
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Chemotherapy can cause several skin reactions. Vesicant drugs (nitrogen mustard, vincristine, etoposide, doxorubicin and other) can cause local skin reactions when injected but precautions and antidotes can minimize these reactions. Liposomal doxurubicin can also cause skin reactions. Specific drugs (bleomycin, paclitaxel) have the potential of causing allergic reactions. This can be minimized with adequate anti-allergic medications taken before chemotherapy. Patients receiving tretinoin can experience redness, dryness, itching and increase sensitivity to sunlight, thus should take adequate precautions. Finally, the Hand-foot syndrome is a painful redness, irritation and fissuration of the hands and soles seen with fluorouracil and capecitabine. Treatment of this syndrome is mainly support and moisturizing of the affected regions with creams and emolients.


Fertility Effects of Chemotherapy
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Today, many young patients are cured of cancer after receiving chemotherapy. However, alterations in gonadal (reproductive) function are now recognized as a common complication of cancer chemotherapy. Women may experience premature gonadal failure, menopause, sterility and even osteoporosis (from estrogen deprivation). Men may have low sperm count and infertility. Other issues concerning cancer survivors are risks of complications of pregnancy, birth defects, and malignancy in their offspring.

Although many questions remain to be answered, your doctors will provide counseling and use newer strategies to prevent gonadal complications from chemotherapy. One approach is to use alternative hormonal therapies or preservation of sperm or eggs for future use.

Chemotherapy (especially cyclophosphamide) given to boys before or during puberty has resulted in 1% and 67% gonadal dysfunction, respectively. MOPP chemotherapy used in Hodgkin's inhibits virtually 90% of sperm function in men. Gonadal damage after puberty is usually assessed by analyzing the seminal fluid. The effects of various chemotherapy regimens on male spermatogenesis are shown in the table below. It appears that the major drugs that cause gonadal dysfunction are the alkylating agents such as cyclophosphamide, thiotepa, nitrogen mustard, and chlorambucil. For patients in whom fertility is spared, the outcome of pregnancies has not shown a higher incidence of congenital anomalies, spontaneous abortion, or neonatal mortality. There are fewer studies of fathers surviving cancer. In men with germ cell tumors, there has not been an excess of congenital anomalies and chromosomal abnormalities in their offspring. In addition, there was no difference in growth maturation. In pregnancy, fetal exposure to multidrug chemotherapy has been associated with minimal risk when chemotherapy was after the first trimester.

Disease Regimen % Low Sperm Count
Hodgkin's MOPP 85%
Hodgkin's ABVD 0
Testes Cancer Cisplatin, vinblastine, bleomycin 14-28%
Sarcoma Doxorubicin + Cyclophosphamide 65%

Disease Regimen % Amenorrhea
Ovarian Cancer Cisplatin, Vincristine, methotrexate, etoposide, actinomycin D 6%
Breast Cancer CMF 85%
Breast Cancer Cyclophosphamide 83%
Breast Cancer FU 9%
Hodgkin's MOPP 24%
Hodgkin's COPP 57%
Hodgkin's ABVD 0

Modified from M Perry. Chemotherapy Source Book. Williams and Wilkins. 2nd Edit 1997, pg. 813-832



Cardiac (heart) toxicity from Chemotherapy
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Some chemotherapy drugs, such as doxorubicin and daunorubicin or radiation therapy to the chest can cause adverse reactions on the heart. The effects (cardiac congestion, decreased exercise tolerance) are generally seen with prolong treatment, but can also occur faster. Your doctor may record an echo of your heart before and throughout the treatment. In case of damage to the heart, the drug may be stopped or modified. One other medication (Dexrazoxane) can be given to minimize the effects of chemotherapy on the heart muscle. Another way to decrease the adverse effect of chemotherapy is to give doxorubicin in a liposomal format.



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First appeared June 12, 2000 updated July 8, 2007