27 - Side Effects of Cancer Chemotherapy | Handbook of Cancer Chemotherapy

Editors: Skeel, Roland T.

Title: Handbook of Cancer Chemotherapy, 7th Edition

> Table of Contents > Section IV - Selected Aspects of Supportive Care of Patients with Cancer > Chapter 27 - Side Effects of Cancer Chemotherapy

Chapter 27

Side Effects of Cancer Chemotherapy

Janelle M. Tipton

Systemic cancer chemotherapy agents play a valuable role in cancer treatment; however, there are undesirable effects both to normal replicating and quiescent cells. Rapidly dividing normal cells that are vulnerable to damage include cells of the bone marrow, hair follicles, and mucous membranes, and reproductive system. Other toxicities may occur that are unrelated to cell growth and are particular to individual agents. The side effects of cancer chemotherapy agents may be acute, self-limited, and mild or can be chronic, permanent, and potentially life threatening in nature. Many advances have been made in the last 10 to 15 years in the management of side effects of chemotherapy. Although much progress has been made, the management of side effects continues to be of utmost importance for the tolerability of therapy and effect on overall quality of life. The implementation of evidence-based interventions has received increased emphasis and is critical in making appropriate clinical decisions for the management of side effects.

I. Acute reactions

A. Extravasation

Extravasation is defined as the leakage or infiltration of drug into the subcutaneous tissues. Vesicant drugs that extravasate are capable of causing tissue necrosis or sloughing. Irritant drugs cause inflammation or pain at the site of extravasation. Common vesicant and irritant agents and potential antidotes are listed in Table 27.1.

Risk factors for peripheral extravasation include small, fragile veins, venipuncture technique, site of venipuncture, drug administration technique, presence of superior vena cava syndrome, peripheral neuropathy, limited vein selection due to lymph node dissection, and concurrent use of medications that may cause somnolence, altered-mental status, excessive movements, vomiting, and coughing.

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Table 27.1. Common vesicant and irritant drugs and potential antidotes

Chemotherapy Agent	Pharmacologic Antidote	Nonpharmacologic Antidote	Method of Administration
Mechlorethamine HCl	Sodium thiosulfate	None	Prepare 1/6 M solution: if 10% Na thiosulfate solution, mix 4 mL with 6 mL sterile water for injection. Through existing IV line, inject 2 mL for every 1 mL extravasated. Inject SC if needle is removed.
Cisplatin	Sodium thiosulfate	None	For large extravasations only (>20 mL of cisplatin solution with 0.5 mg/mL). Use 2 mL of 10% sodium thiosulfate solution for each 100 mg cisplatin. Administer as with mechlorethamine.
Doxorubicin	None	Topical cooling	Apply cold pad with circulating ice water, ice pack, or cryogel pack for 15 20 min at least 4 times/day for first 24 48 h. Some studies suggest benefit with 99% dimethyl sulfoxide (DMSO) 1 2 mL applied to site every 6 h.
Daunorubicin
Epirubicin
Idarubicin
Mitoxantrone
Vincristine	Hyaluronidase 150 units/1 mL SC	Warm compresses	Apply heat for 15 20 min at least 4 times/day for first 24 48 h. Hyaluronidase is instilled as multiple SC injections around extravasated area, using a small gauge needle (25 g).
Vinblastine
Vinorelbine
Etoposide	None	Warm compresses	Treatment necessary only if large amount of concentrated solution extravasates. Treat as vincristine or vinblastine extravasations.
Oxaliplatin	Case reports of use of anti-inflammatory drugs and high-dose dexamethasone.	Case reports of topical cooling, but may make neuropathy worse.
Paclitaxel (Taxol)	None	Topical cooling	Apply ice pack for 15 20 min at least 4 times/day for first 24 h

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The incidence of extravasation for vesicant chemotherapy is recorded as 1% to 6% in the literature for peripheral chemotherapy. Extravasation may also occur with central venous catheters. Potential causes for central venous catheter extravasation include backflow secondary to fibrin sheath or thrombosis in the central venous catheter, needle dislodgement from a venous access port, central venous catheter damage, breakage, or separation, and displacement or migration of the catheter from the vein.
Common signs and symptoms of extravasation are pain or burning at the IV site, redness, swelling, inability to obtain a blood return, and change in the quality of the infusion. Any of these complaints or observations should be considered a symptom of extravasation until proved otherwise.
Procedures to manage peripheral extravasation are imperative to have in place, including guidelines or orders for extravasation management of vesicant and irritant agents before administration. If an extravasation is suspected, the following actions should be taken:
- Stop administration of the chemotherapy agent.
- Leave the needle/catheter in place and immobilize the extremity.
- Attempt to aspirate any residual drug in the tubing, needle, or suspected extravasation site.
- Notify the physician.
- Administer the appropriate antidote, as shown in Table 27.1. This may include instillation of a drug antidote or application of heat or cold to the site. Of note, hyaluronidase was not commercially available from²001 to late 2004. It is now available as Amphadase (hyaluronidase injection, Amphastar Pharmaceuticals, Rancho Cucamonga, CA).
- Provide the patient and/or caregiver with instructions, including the need to elevate the site for 48 hours and the continuation of antidote measures as appropriate.
- Discuss the need for further intervention with the physician, and photograph if indicated.
- Document extravasation occurrence according to institutional guidelines.
- Continued monitoring of extravasation site at 24 hours, 1 week, 2 weeks, and additionally as guideline recommends. Secondary complications such as infection and pain may occur. Follow-up photographs at these periods, if possible, are helpful in monitoring extent of injury and progress in healing.
Procedures for central extravasation are also critically important to follow, as extravasation of chemotherapeutic agents in the upper torso or neck area is difficult to manage and may result in extensive defects, requiring reconstructive surgery. Extreme caution should be taken by nurses administering chemotherapy by this route. Procedures followed in central extravasation are similar to peripheral extravasation. Assessment of lack of blood return, patient reports in changes of sensation, pain, burning, or
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swelling at the central venous catheter site or chest warrant immediate discontinuation of chemotherapy. Prompt administration of the appropriate antidote is recommended, but if the extravasation has been extensive, the actions may not prevent damage. Collaboration with the physician regarding the need for further studies to identify the cause of the extravasation will be necessary as well as other decisions for future plans for venous access.

B. Hypersensitivity and anaphylaxis

Specific drugs with the potential for hypersensitivity with or without an anaphylactic response should be administered under constant supervision of a competent and experienced nurse and with a physician readily available, preferably during the daytime. Important preassessment data to be documented include the patient's allergy history, though this information may not predict an allergic reaction to chemotherapy. Other risk factors include previous exposure to the agent and failure to administer effective prophylactic medications. Drugs with the highest risk of immediate hypersensitivity reactions are asparaginase, murine monoclonal antibodies (e.g., ibritumomab tiuxetan), the taxanes (paclitaxel and docetaxel), and platinum compounds (cisplatin, carboplatin, oxaliplatin). Drugs with a low to moderate risk include the anthracyclines, bleomycin, IV melphalan, etoposide, and humanized (e.g., trastuzumab) or chimeric (e.g., rituximab) monoclonal antibodies. Test doses or skin tests may be performed if there is an increased suspicion for hypersensitivity. In specific occasions, this is generally done with carboplatin, bleomycin and asparaginase. A skin testing protocol for carboplatin skin testing is shown in Table 27.2.

Type 1 hypersensitivity reactions are the most common chemotherapy-induced type of reactions. These reactions characteristically occur within 1 hour of receiving the drug; however, with paclitaxel, the hypersensitivity reactions often occur within the first 10 minutes of the start of the infusion. Common manifestations of a type 1 reaction

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include urticaria, respiratory distress, bronchospasm, hypotension, angioedema, flushing, chest and back pain, and anxiety. With appropriate premedication, the incidence of the hypersensitivity reactions has markedly decreased with paclitaxel. Commonly used premedications include dexamethasone, diphenhydramine, and an H2-histamine antagonist such as cimetidine, ranitidine, or famotidine. Emergency equipment should be immediately accessible, including oxygen, an Ambu respiratory assist bag, and suction equipment. The following parenteral drugs should also be stocked in the treatment area: epinephrine 1:1,000 or 1:10,000 solution, diphenhydramine 25 to 50 mg, methylprednisolone 125 mg, and dexamethasone 20 mg. The development of a clinical guideline for hypersensitivity reactions, with or without true anaphylaxis, may be helpful in preparing for a potential reaction, reducing delays in response time to a reaction, and standardizing the management of a reaction with standing orders. Table 27.3 provides a sample preprinted/standing order for the management of hypersensitivity and anaphylactic reactions.

Table 27.2. Sample carboplatin skin testing protocol

All patients receiving their sixth and each subsequent doses of carboplatin will have skin test dosing.
Patients receive an intradermal injection of 0.02 mL of an undiluted aliquot from the carboplatin preparation planned for subsequent infusion. This dose is then diluted in 50 mL of 0.9% normal saline.
Following the intradermal injection, the injection site is examined at 5, 15, and 30 min.
A positive skin test is a wheal of 5 mm in diameter, with surrounding redness. A strongly positive skin test was one with 1 cm in diameter. If a patient develops a positive skin test, the physician is notified.
If the skin test is negative, the patient is then pretreated for the carboplatin with antiemetics, dexamethasone, diphenhydramine, and famotidine. Thirty minutes after the premedications are given, the carboplatin is given.

Retreatment and rechallenge of patients who have experienced paclitaxel-associated hypersensitivity reactions are supported in the literature. If rechallenge is considered, paclitaxel should be administered in the appropriate setting where immediate emergency situations may be handled. The decision to reinstitute paclitaxel should be based on the clinical importance of using the drug in

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the particular disease setting. Patients have been successfully retreated within hours to days of the initial paclitaxel reactions at full doses.

Table 27.3. Sample standing orders for hypersensitivity reactions to chemotherapy agents

Have the following medications available:
1. Diphenhydramine (Benadryl) 50 mg IV
2. Methylprednisolone (Solu-Medrol) 125 mg IV or equivalent hydrocortisone
3. Epinephrine (1:10,000) 10 mL single-dose vial (or 1 mL of 1:1,000, 1-mg vial)
If signs/symptoms of hypersensitivity occur (such as urticaria [hives], respiratory distress, bronchospasm, hypotension, angioedema, flushing, chest /back pain, anxiety), stop infusion of chemotherapy/biotherapy agent.
Maintain IV access with IVF normal saline at 200 mL /h until blood pressure stabilizes.
Administer oxygen at 2 4 L /min and measure pulse oximetry.
Administer methylprednisolone 125 mg IVP.
Administer diphenhydramine (Benadryl) 50 mg IVP.
Monitor blood pressure, pulse, and oxygen saturation continuously.
Notify physician immediately for further orders.
If symptoms do not resolve or if they worsen, administer epinephrine as directed by physician.
Initiate a code if airway patency is not maintained or cardiopulmonary arrest occurs.

IVF, intravenous fluid.

Reinstitution of paclitaxel after experiencing a hypersensitivity reaction includes immediate discontinuation of the paclitaxel infusionat the onset of symptoms and rapid administration of additional diphenhydramine and methylprednisolone. Following stabilization of the patient and waiting approximately for 30 minutes, the paclitaxel infusion is reinitiated, with initial infusion rates of 10% to 25% of the total infusion rate. If tolerated, the rate can be gradually increased over the next several hours. Nursing care would also include vital signs every 5 minutes or continuous observation for the first 15 minutes, then every 15 minutes through the first hour, then hourly until the infusion is completed. An alternative is to pretreat the patient for 24 hours with dexamethasone 10 mg three times orally and to restart the infusion at the rate indicated earlier on the second day.
Desensitization approaches. Rechallenge after a severe hypersensitivity reaction of the second episode of hypersensitivity reaction to paclitaxel and carboplatin are documented in the literature; however, planning for the desensitization is necessary. Regimens including dexamethasone 20 mg orally at 36 and 12 hours before chemotherapy and on the morning of chemotherapy have been studied. A full 30minutes before the chemotherapy, other IV premedications such as dexamethasone 20 mg, diphenhydramine 50 mg, and H2-histamine antagonist are given. For paclitaxel, the desensitization procedure continues with the administration of a test dose of 2 mg in 100 mL of normal saline over 30 minutes. If there is no reaction, 10 mg in 100 mL of normal saline is given over 30 minutes, followed by the remaining full dose in 500 mL of normal saline over 3 hours if still no reaction. If a reaction is experienced, the usual diphenhydramine and methylprednisolone medications are given.

II. Nausea and vomiting

Patients who are about to begin chemotherapy are often concerned and apprehensive about nausea and vomiting. Nausea and vomiting can be distressing enough to the patient to cause extreme physiologic and psychological discomfort, culminating in withdrawal from therapy. With the advent of more effective antiemetic regimens in the last 15 years, many improvements in the prevention and control of nausea and vomiting have led to a better quality of life for patients receiving chemotherapy. The goal of therapy is to prevent the three phases of nausea and vomiting: that which occurs before treatment is administered (anticipatory), that which follows within the first 24 hours after treatment (acute), and that which occurs more than 24 hours after treatment (delayed). It is also important to assess nausea and vomiting separately because they are different events and may have different causes. Factors related to the chemotherapy that can affect the likelihood and severity of symptoms include the specific agents used, the doses of the drugs, and the schedule and route of administration. Other

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patient characteristics that may effect emesis include history of poor emetic control, history of alcoholism, age, gender, and history of motion sickness.

A. Emetic potential of the drug

To plan an effective approach to control nausea and vomiting, the chemotherapeutic agents are grouped according to their emetic potential (Table 27.4). This type of categorization is helpful in making decisions regarding possible antiemetics to be used and how aggressive the antiemetic regimen should be for patients receiving chemotherapy for the first time or in subsequent treatments. It is important to select appropriate antiemetics from the various antiemetic classes, and not to under treat the patient for nausea and vomiting in the initial chemotherapy cycle. Failure to control nausea and/or vomiting may result in a conditioned response and subsequent anticipatory nausea and vomiting.

B. Antiemetic drugs

Agents that have been effective in preventing and treating nausea and vomiting (Table 27.5) come from various pharmacologic classes. They work by different mechanisms that may relate to the pathophysiologic processes causing nausea and vomiting. For many years, the mainstays of antiemetic therapy have been agents that block dopamine receptors. These agents have been somewhat effective but have limited value for highly emetogenic agents and, in escalating doses, have caused problematic side effects. Within the last 15 years, it was discovered that agents that block predominately the serotonin (5-hydroxytryptamine) subtype 3 (5-HT3) receptors, rather than the dopamine receptors, have greater efficacy in the prevention of nausea and vomiting. More recent research indicates that the tachykinins, including a peptide called substance P, play an important role in emesis. Substance P binds to the neurokinin type 1 (NK-1) receptor. Thus, the NK-1-receptor antagonists are now validated in their role in inhibiting nausea and vomiting with moderately and highly emetogenic chemotherapy. OralNK-1-receptor antagonists are thought to improve acute nausea and vomiting associated with chemotherapy when combined with standard regimens (i.e., dexamethasone and 5-HT3 receptor antagonists) and to have additional effect during the period of delayed nausea and vomiting, alone or in combination with dexamethasone.

C. Combination antiemetic therapy

Several antiemetic regimens are effective, but their design should be based on two general principles:

Combinations of antiemetics are more effective than single agents. It is common to use two or more antiemetics to prevent or manage nausea and vomiting.
Preemptive treatment and scheduled administration are more effective than reactive therapy to prevent nausea and vomiting early in therapy and to manage potential delayed nausea and vomiting in the days following treatment.

Table 27.6 shows examples of antiemetic regimens that may be used when the chemotherapy has a high, moderate, and low emetic potential.

D. Nonpharmacologic interventions

Patients who are likely to experience or who have experienced anticipatory

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nausea and vomiting related to chemotherapy may benefit from the use of nonpharmacologic interventions in addition to the pharmacologic agents taken. The use of acupuncture, acupressure, guided imagery, music therapy, and progressive muscle relaxation are often effective in preventing nausea and vomiting. Many of these are forms of distraction that assist patients in maintaining a feeling of control over their treatment effects. Massage therapy, hypnosis, exercise, and acustimulation with wristband devices have insufficient data, and further studies are needed to support their use as interventions. With increasing attention to complementary therapies, it is hoped that more clinical studies will determine their value in patient care. Patients who are able to have little or no nausea and vomiting with their first chemotherapy treatment often assert that positive thinking is helpful as well. Patients may also prepare for their chemotherapy treatments by eating foods that do not have offensive odors or spicy taste. Clear liquids, foods served at room temperature, soda crackers, and carbonated beverages are sometimes good suggestions. Following chemotherapy, smaller, more frequent meals are less likely to promote the development of nausea and vomiting.

Table 27.4. Emetogenic potential for commonly used chemotherapeutic agents^a

Highly Emetogenic Agents ( 75% Potential for Nausea, Vomiting, or Both)	Moderately Emetogenic Agents (50% 75% Potential for Nausea, Vomiting, or Both)	Mildly Emetogenic Agents (25% 50% Potential for Nausea, Vomiting, or Both)
Carmustine	Carboplatin	Asparaginase
Cisplatin (>40 mg/m²)	Cisplatin (<40 mg/m²)	Bleomycin
Cyclophosphamide (>1 g/m²)	Cyclophosphamide	Busulfan
Cyclophosphamide (>1 g/m²)	(200 mg/m²to 1 g/m²)	Capecitabine
Cytarabine (>1 g/m²)	Cytarabine	Bevacizumab
Dacarbazine (days 1 and 2)	(200 mg/m²to 1 g/m²)	Bortezomib (Velcade)
Dacarbazine (days 1 and 2)	Daunorubicin	Cetuximab
Dactinomycin	Doxorubicin (<60 mg/m²)	Cladribine
Doxorubicin (>60 mg/m²)	Etoposide	Cyclophosphamide
Epirubicin	Gemcitabine	(<200 mg/m²)
Ifosfamide (>1.2 g/m²)	Idarubicin	Cytarabine (<200 mg/m²)
Mechlorethamine	Ifosfamide (<1.2 g/m²)	Docetaxel
Methotrexate (>1 g/m²)	Irinotecan	Fludarabine
Mitomycin (>15 mg/m²)	Methotrexate (50 mg/m²to 1 g/m²)	Fluorouracil
Oxaliplatin	Methotrexate (50 mg/m²to 1 g/m²)	Hydroxyurea
Streptozocin	Mitomycin (<15 mg/m²)	Imatinib
	Mitoxantrone	Liposomal doxorubicin
	Procarbazine	Melphalan
	Topotecan	Methotrexate (<50 mg/m²)
	Vinorelbine	Paclitaxel
		Pemetrexed
		Rituximab
		Temozolomide
		Thioguanine or mercaptopurine (6-MP)
		Vinblastine
		Thiotepa
		Trastuzumab
		Vinblastine
		Vincristine
^aHigh-dose therapy requiring progenitor cell support is not included in this table.

Table 27.5. Agents used for chemotherapy-induced nausea and vomiting

Agent	Route of Administration	Dose	Comments
Phenothiazines
Prochlorperazine (Compazine)	PO	10 mg every 4 6 h	Some EPS; potential for postural hypotension when given IV
	PO (sustained release)	15 30 mg every 12 h
	IM or IV	2 10 mg every 4 6 h
	PR	25 mg every 12 h
Thiethylperazine (Torecan)	PO, IM, or PR	10 mg every 6 8 h	Some EPS
Trimethobenzamide (Tigan)	PO	250 mg every 4 6 h	Some EPS
Trimethobenzamide (Tigan)	IM or PR	200 mg every 4 6 h	Some EPS
Butyrophenones
Haloperidol (Haldol)	IM, PO, or IV	2 5 mg every 2 4 h	Some EPS
Droperidol (Inapsine)	IV or IM	0.5 2.5 mg every 4 h	Causes sedation, cardiac arrhythmias, EPS, hypotension. Not recommended.
Substituted benzamide
Metoclopramide (Reglan)	PO or IV	10 40 mg q.i.d. to 1- to 2-mg/kg dose at 2-h intervals	EPS common in higher doses that should be given with diphenhydramine; EPS worse with younger patients; may have diarrhea in higher doses
Benzodiazepines
Lorazepam (Ativan)	PO, SL, or IV	1 2 mg every 4 6 h 0.5 2 mg every 4 6 h	Causes sedation, amnesia, and confusion
Corticosteroids
Dexamethasone (Decadron)	IV	4 20 mg (10 20 mg x 1), otherwise every 4 6 h	Potential for agitation, delirium
Dexamethasone (Decadron)	PO	4 8 mg every 4 h	Potential for agitation, delirium
Serotonin (5-HT3) antagonists
Ondansetron (Zofran)	IV	8 32 mg x 1 0.15 mg/kg, every 4 h x 3	For highly emetogenic chemotherapy; lower doses effective for less emetogenic regimens
Ondansetron (Zofran)	PO	8 mg b.i.d.
Granisetron (Kytril)	IV	1 mg x 1	Similar to ondansetron
Granisetron (Kytril)	PO	1 2 mg x 1	Similar to ondansetron
Dolasetron (Anzemet)	IV or PO	100 mg before chemotherapy	Similar to above
Palonosetron (Aloxi)	IV	0.25 mg IV (single dose only)	Similar to above
Cannabinoids
Dronabinol (Marinol)	PO	2.5 10 mg every 4 6 h	Causes sedation, may be habit forming, a controlled substance
NK-1 Receptor Antagonists
Aprepitant (Emend)	PO	Tri- pack: 125 mg 30 min before chemotherapy day 1, then 80 mg daily on days 2 and 3
EPS, extrapyramidal symptoms.

Table 27.6. Examples of antiemetic regimens for prevention and management of chemotherapy-induced nausea and vomiting

Level 1: patients receiving a mildly emetogenic agent

Dexamethasone 8 10 mg PO/IV before chemotherapy

With or without

Prochlorperazine 10 mg PO before chemotherapy, then 10 mg PO every 4 6 h p.r.n., or

Lorazepam 1 mg PO every 4 6 h p.r.n., or both

Level 2: patients receiving a moderately emetogenic agent or patients receiving a mildly emetogenic agent who have failed to respond to or are intolerant of at least two level 1 regimens

Aprepitant 125 mg PO before chemotherapy day 1, then 80 mg PO daily on days 2 and 3, and

Palonosetron^a 0.25 mg IV before chemotherapy, and

Dexamethasone 10 12 mg IV/PO before chemotherapy, then 8 mg PO daily on days 2 4

With or without

Lorazepam 1 mg PO or IV before q4 6 h p.r.n., or

Prochlorperazine 10 mg PO q4 6 h p.r.n., or both

Level 3: patients receiving a highly emetogenic agent or patients receiving two or more moderately emetogenic agents or patients who have failed a level 2 regimen

Aprepitant 125 mg PO before chemotherapy on day 1, then 80 mg PO daily on days 2 and 3, and

Palonosetron^b 0.25 mg IV before chemotherapy, and

Dexamethasone 10 12 mg PO/IV before chemotherapy, then 8 mg PO on days 2 4, and

Lorazepam 1 mg PO or IV before chemotherapy, then q4 6 h p.r.n.

In addition, for delayed nausea and vomiting:

Metoclopramide 40 mg PO q6 h x 4 days, with

Dexamethasone 4 mg PO q6 h x 3 days, then 4 mg PO q12 h x 1 day (if not given already with Aprepitant)

Give antiemetics 20 30 min before chemotherapy when using the IV route and 1 h before chemotherapy when using the PO route. Given in this manner, oral medication is usually as effective as the same medication IV, and the cost is considerably less.

^aAlternatives (5-HT3): ondansetron 10 mg IVx1 before chemotherapy, or dolasetron 100 mg PO or IV, or granisetron 1 mg PO or IV before chemotherapy.
^bAlternatives (5-HT3 antagonists): ondansetron 32 mg IV before chemotherapy; dolasetron 100 mg PO or IV, or granisetron 1 mg PO or IV before chemotherapy.

E. Herbal remedies: ginger

There have long been anecdotally based recommendations for the use of ginger to help prevent and minimize chemotherapy-induced nausea and vomiting. Few randomized controlled trials have been done to evaluate ginger as an intervention in this patient population. Although early studies show safety and little toxicity, it is difficult to recommend the use of ginger because of the lack of evidence, particularly with respect to dosages and schedules.

III. Other short-term complications related to cancer chemotherapy

A. Stomatitis and other oral complications

The oral mucosa is vulnerable to the effects of chemotherapy and radiotherapy because of its rapid growth and cell turnover rate. Radiotherapy also interferes with the production of saliva and may increase oral complications because of a consequent reduction in the protective effect of the saliva. It is crucial to manage oral complications effectively because patients may experience considerable discomfort or develop secondary infections from the disruption of the oral mucosa. The likelihood of the development of stomatitis from a drug is dependent on the agent, the dose, and the schedule of administration. Continuous rather than intermittent administration is more likely to cause stomatitis with the antimetabolites.

Specific chemotherapy agents that may cause stomatitis include the following:
- Antimetabolites: methotrexate, fluorouracil (particularly continuous infusion), capecitabine, cytarabine, irinotecan
- Antitumor antibiotics: doxorubicin, idarubicin, dactinomycin, mitomycin, bleomycin
- Plant alkaloids: vincristine, vinblastine, vinorelbine
- Taxanes: docetaxel, paclitaxel Alkylating agents: high doses of busulfan, cyclophosphamide
- Biologic agents: interleukins, lymphokine-activated killer cell therapy

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Prevention and early detection. If oral complications are anticipated, it is important to implement a good oral hygiene program before the initiation of therapy. Dental consultation is recommended in specific groups of patients, including those undergoing bone marrow transplant and those with leukemia or head and neck malignancies. Maintaining good nutrition and dental hygiene is also a primary preventive measure. Normal saline is the preferred mouth rinse. Alternative rinsing agents such as sodium bicarbonate or nonalcoholic mouthwashes, if preferred by patients, may be used. Chlorhexidine and hydrogen peroxide mouth rinses should not be used. For patients receiving bolus fluorouracil, it is recommended that patients perform oral cryotherapy. This involves holding ice chips in the mouth starting 5 minutes before the bolus of fluorouracil and for 30 minutes after the administration of the drug. This intervention is effective for bolus administration only, and should not be done when oxaliplatin is also given because of the potential for increase in acute neurotoxicity. Systematic oral assessments should be integrated into the physical examination at regular intervals. Special attention should be given to the tongue, the gingiva, the buccal mucosa, the soft palate, and the lips. It is also important to assess the patient for soreness, functional ability to swallow, and any effects on eating.
Management of oral complications. Although the primary goal is prevention, once oral complications develop, the focus of care should shift to the continuation of good oral hygiene and treatment of symptoms. Agents used for oral care are categorized according to function: cleansing agents, lubricating agents, analgesic agents, and preventive agents. Table 27.7 lists several commonly used agents. Commercial mouthwashes and lemon glycerin swabs are not recommended for use because of their irritating and drying effects. If painful ulcerations do develop, topical relief may be best obtained by using single agent topical analgesics such as UlcerEase (Med-Derm Pharmaceuticals, Johnson City, TN) or lidocaine. Compounded analgesic mouth rinses such as magic mouthwash consisting of various components such as lidocaine, diphenhydramine, antacids, and/or sodium bicarbonate do not have established data to recommend in practice. Systemic pain control measures such as oral or parenteral narcotics should be implemented if topical analgesics are ineffective.
Xerostomia that follows radiation therapy to the mouth area may require treatment with artificial saliva. It may also be benefited by the administration of pilocarpine 5 to 10 mg PO t.i.d. before meals. Before the initiation of radiation therapy to the head and neck area, dental consultation is necessary to evaluate oral hygiene, the state of repair of the teeth, and the health of the gums. Amifostine shows promise as a protective agent for xerostomia and is used concurrently with radiation to the head and neck.

Secondary oral infections should be treated promptly and as accurately as possible. Fungal infections may be treated with nystatin suspension, clotrimazole troches, or

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oral fluconazole. Viral infections may be reactivated after chemotherapy and are commonly treated with oral or IV acyclovir. The benefit of prophylactic use of antiviral agents or antifungal agents is not well established. However, in patients with a known history of cold sores or positive herpes simplex virus titers, it may be advantageous to administer prophylactic acyclovir.

Table 27.7. Agents for oral care

Agent	Indications and Comments
Cleansing agents
Normal saline solution (preferred) (1/2 tsp salt in 8 oz of water)	Economical, nondamaging
Sodium bicarbonate	Nonirritating, debriding
Lubricating agents
Saliva substitutes (mucin-based preferred)	Decreases dryness
Water- or oil-based lubricants	Useful emollient; oil-based lubricants should not be used in mouth because of danger of aspiration
Analgesic agents
a. *Healing and coating agents*
Vitamin E	Protection to mucosa, healing properties Effectiveness not yet established
Allopurinol	May decrease intensity of mucositis with fluorouracil
Gelclair bioadherent oral gel	May decrease intensity of mucositis with fluorouracil
L-Glutamine	May decrease mucositis intensity
b. *Topical anesthetics*
Lidocaine viscous	Transient pain relief, absorbed systemically
Diclonine hydrochloride	Transient pain relief
Benzocaine	Transient pain relief
Zilactin	Burns on application
Capsaicin	Active ingredient in chili peppers; given in candy vehicle will decrease pain Morphine
c. *Systemic analgesics*
Nonsteroidal anti-inflammatory drugs	Take before meals and as needed
Narcotic analgesics	Take before meals and as needed
Prevention agents hematologic growth factors
Filgrastim, Sargramostim	Less severe mucositis experienced by patients receiving growth factors
Keratinocyte growth factors (Palifermin)	Approved for patients with hematologic malignancies receiving stem cell transplant

Patients with dentures may be encouraged to remove them during the period after chemotherapy when they are at risk for infection, except at mealtime. In addition, the dentures should be cleansed before use. Although removal of the dentures may be detrimental to the patient's selfesteem, irritation of the dentures may lead to inflammation, ulceration, and secondary infection.

B. Alopecia

Chemotherapy-induced hair loss is not necessarily a serious physiologic complication, but psychologically, it can be one of the most devastating side effects. Partial or total hair loss can contribute to a perceived negative body image owing to the emphasis placed on the hair and overall appearance in society. The hair loss from chemotherapy, which often occurs 2 to 3 weeks after chemotherapy, is usually temporary. Hair growth begins in approximately 1 to 2 months after the treatment is completed, but it may be approximately 4 to 5 months before the patient will feel comfortable not wearing a wig. The new hair may have a different texture or color from its pretreatment characteristics. In addition to scalp hair loss, it is important to remind patients of the hair loss that may occur in other areas such as the eyebrows, eyelashes, axilla, pubis, and other fine hair.

Specific chemotherapy agents with a high potential of causing alopecia include doxorubicin, cyclophosphamide, ifosfamide, vincristine, and paclitaxel. Other drugs capable of causing alopecia include bleomycin, dactinomycin, daunorubicin, etoposide, vinblastine, methotrexate, and mitoxantrone. The extent of alopecia depends on the mechanism of the drug, the dose, the serum half-life, the infusion technique (bolus vs. continuous infusion), and the use of combinations of drugs.
Nursing interventions start with informing and preparing the patient for the possibility of alopecia. It is helpful to encourage purchasing wigs and other head wear before the alopecia occurs so that the hair color and style may be used in selecting a wig as well as allowing time for adjustment. It is important to encourage discussion of feelings regarding the hair loss for both men and women and to recognize their concerns and fears. The American Cancer Society's program Look Good, Feel Better is helpful in providing guidance about wigs, makeup, and skin care. Scalp hypothermia has been used in the past as an attempt to restrict the circulation to the scalp, with the goal of minimizing alopecia. Because of the concern for scalp metastases and sanctuary sites, scalp hypothermia is no longer recommended.

C. Diarrhea

Among the many causes of diarrhea in patients with cancer are chemotherapy, radiotherapy, the cancer itself, medications, supplemental feeding, and anxiety. Osmotic

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diarrhea refers to that caused by chemotherapy agents, where the actively dividing epithelial cells of the gastrointestinal tract are destroyed. Unabsorbable substances draw water into the intestinal lumen by osmosis, resulting in increased stool volume and weight. Secretory diarrhea may result from infectious causes (e.g., Clostridium difficile or other enterocolitis causing bacteria), with or without concurrent neutropenia. The opportunistic infection may intensify the inflammatory reaction in the gut, causing excessive intestinal mucosal secretion of electrolytes and fluids from the bacterial toxins. Prolonged diarrhea can lead to discomfort, severe electrolyte imbalances and dehydration, altered social life, and poor quality of life. In the past, little attention has been paid to the prompt evaluation and management of diarrhea, but with increasing use of agents such as irinotecan, the observation of severe and potentially life-threatening problems has heightened awareness of this side effect. The elderly, in particular, may be at increased risk for treatment-related diarrhea and may require close monitoring.

Chemotherapy and biologic agents may contribute to the development of diarrhea and most commonly include the antimetabolites such as fluorouracil, capecitabine, methotrexate, cytarabine, and irinotecan. In addition, agents such as dactinomycin, floxuridine, hydroxyurea, idarubicin, the nitrosoureas, and paclitaxel cause diarrhea relatively frequently. When diarrhea from fluorouracil, floxuridine, or irinotecan is present while on therapy, it is a sign of toxicity that must be monitored closely and that could escalate to severe levels at which the drug might need to be held or discontinued. With the increased use of biologic agents, diarrhea has been noted with interferon- and interleukin-2. High-dose chemotherapy regimens used in stem cell transplantation may also be associated with severe diarrhea and may be caused by acute graft-versus-host disease.
Assessment of a patient experiencing diarrhea should begin with a baseline history of usual elimination patterns, pattern of symptoms, and concurrent medications. The duration of the diarrhea and frequency of stool passage should be noted with reference to a stool diary if indicated. Physical examination may disclose abdominal tenderness, signs of dehydration, and disruption in perianal or peristomal skin integrity. Laboratory data may be obtained to assess serum chemistries, complete blood count, and stool samples for Clostridium difficile toxin and other enteropathic bacteria.

Management of treatment-related diarrhea is often symptomatic and requires little or no alteration in cancer therapy. Agents that decrease bowel motility should not be used for longer than 24 hours unless significant infections have been excluded. In the absence of obvious inflammation and infection, it is appropriate to treat most patients with nonspecific treatment for diarrhea, including opioids (loperamide, diphenoxylate, and codeine), anticholinergics (atropine, scopolamine), or both. More recently, it has been recognized that octreotide is often effective in

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controlling chemotherapy-related diarrhea and diarrhea associated with the carcinoid syndrome. Table 27.8 lists common agents used to treat diarrhea. Nonpharmacologic measures that may also assist in the prevention and management of diarrhea are a low-residue diet and increased fluids. If the diarrhea is severe, IV hydration is necessary to prevent serious hypovolemia, electrolyte disturbances, and shock. In patients who experience severe irinotecan-associated diarrhea, antibiotic therapy such as ciprofloxacin is recommended because of a high incidence of infectious contribution to the gastrointestinal problems, including functional ileus, which may be associated.

Table 27.8. Pharmacologic management strategies for diarrhea

Agent	Comments
Kaolin pectin (Kaopectate)	30 60 mL PO after each loose stool
Loperamide (Imodium)	2 capsules (4 mg) PO 4 h initially, then add 1 capsule (2 mg) after each loose stool; should not exceed 16 capsules daily
Diphenoxylate hydrochloride, atropine sulfate (Lomotil)	1 2 tablets PO 4 h; should not exceed 8 tablets daily; there may be anticholinergic effects due to atropine
Atropine	May give 0.25-1 mg IV before irinotecan, or IV/SQ for cholinergic symptoms
Paregoric	1 tsp PO 4 times/day; may alternate with Lomotil
Octreotide	May be useful for fluorouracil induced diarrhea; starting dose: 0.05 0.1 mg SC t.i.d; may be increased to 1.8 mg/day in refractory diarrhea Sandostatin LAR Depot is indicated for carcinoid and VIPomas. It is a slow-release drug that is dosed at 20 30 mg every 4 weeks.

D. Constipation

In patients whose cancer has resulted in debility or immobility or in those who require narcotic analgesics, constipation can be a particular problem. Constipation may also develop in patients who have received neurotoxic chemotherapy agents including the vinca alkaloids, etoposide, and cisplatin, each of which may cause autonomic dysfunction. Decreased bowel motility due to intra-abdominal disease,

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hypercalcemia, dehydration, and antiemetic use can also contribute to constipation. Chronic constipation in patients with cancer is a problem that is more easily prevented than treated. A diet high in bulk fiber, fresh fruits and vegetables, and adequate fluid intake may help to minimize constipation. Patients started on narcotic analgesics should also begin a bowel regimen, first with mild stool softeners and bulk laxatives and then proceeding to stimulants or osmotic laxatives if the milder regimen is not effective. A bowel regimen example for a patient at risk for constipation is as follows:

Docusate sodium 100 mg b. i.d. alone or with casanthranol (Peri-Colace), 1 capsule b.i.d.
If no bowel movement, add:
- Senna at bedtime (dose varies with the preparation), or
- Milk of magnesia 30 mL at bedtime
If no bowel movement with the above, the following may be added:
- Bisacodyl one to three tablets or one 10-mg suppository, at bedtime, or
- Lactulose one to four tablespoons daily
Other more aggressive alternatives, if there is no impaction, include the following:
- Fleet enema
- Magnesium citrate 1 bottle
- Tap-water enema

E. Altered nutritional status

Patients with cancer often experience progressive loss of appetite and sometimes severe malnutrition during the course of the disease and treatment. Malnutritionmay result from a side effect of the therapy or a direct effect of the cancer (e.g., gut obstruction or hepatic or brain metastases). The resulting effects of malnutrition are a poorer response to therapy, increased incidence of infections, and an overall worsening of patient well-being. Many times, one of the presenting signs that lead to the diagnosis of cancer is weight loss; therefore, the patient is most likely experiencing some alteration already in nutritional status. Malnutrition is reported to occur in 50% to 80% of patients with advanced disease. Nutritional management of the patient with cancer involves early intervention using a supportive health care team.

Effects of chemotherapy and radiation therapy on nutrition. Chemotherapy has a major effect on nutritional status because of the direct insult on the gastrointestinal tract. Among the gastrointestinal effects are anorexia, nausea, vomiting, taste alterations, stomatitis, esophagitis, colitis, constipation, and diarrhea. Not only are the effects physiologic in nature, but also the added psychologic impact of the disease and therapy can result in anxiety and depression, which can contribute to the lack of interest in food.
Nutritional assessment. Early in the patient's treatment, a thorough nutritional assessment should be completed by the health care team. The assessment should include diet history, nutrient intake, anthropometric measurements (height, weight, and skin-fold thickness and midarm circumference, if possible), laboratory tests for
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anemia and serum albumin, and an evaluation of activity and functional status. A serum pre-albumin is a very sensitive indicator of changes in nutritional status. A level of <15 mg/dL is indicative of protein depletion. A good nutritional assessment may help identify patients who are already at risk of malnutrition or those who may be prone to developing problems during the course of the illness and treatment.
Nutritional intervention. Nutritional intervention should be considered during the initial and ongoing assessments. Situations that warrant nutritional intervention include involuntary weight loss (more than 10% within the last 6 months, especially when combined with weakness and fatigue), history of recent physiologic stress, serum albumin below 3.2 g/dL, or severe immunocompromise. Nurses, dietitians, and even family members can identify problems and may be the first to act to promote weight gain. Various approaches that help increase weight are changes in diet; symptomatic treatment of nausea and vomiting, stomatitis, and other gastrointestinal effects of chemotherapy, and supplemental nutrition.
- Nutritional supplements. Several nutritional supplements are commercially available for oral use. One benefit of nutritional supplements is that they are a concentrated form of nutrition for protein and calories. Some of the disadvantages are the unappealing taste and the high cost to the consumer. Some patients and their families are able to develop some creative highprotein and high-calorie supplements using household items with some suggestions from the health care team.
- Tube feedings. Enteral nutrition through a nasogastric or gastrostomy tube may be an alternative if oral intake is not possible. Enteral feedings are the recommended route if the gastrointestinal tract is functional. Advantages of enteral feeding include lower cost and fewer complications than with parenteral feedings and maintenance of normal gastrointestinal function. Some care and maintenance are involved with feeding tubes, and patients and their families need to be given information regarding available options for feeding.
- Total parenteral nutrition (TPN). Parenteral nutrition should be considered in patients who do not have a functioning gastrointestinal tract or in those for whom supplemental nutrition is anticipated for a short period of time. Patients who receive TPN usually require the insertion of a central venous catheter, which may result in other iatrogenic complications such as pneumothorax, vein thrombosis, and catheter-related infections. In many situations, TPN used in the patient with cancer increases morbidity, especially from infection, without improving survival. Thus, TPN has considerable economic, ethical, and medical consequences that must be evaluated in conjunction with the patient's overall prognosis.
Pharmacologic interventions. A recent area of interest is pharmacologic appetite stimulation. One of the agents currently used is megestrol acetate oral suspension
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800 mg/day (20 mL/day). Agents such as megestrol acetate have documented evidence in promoting increased weight gain in some patients and at least a decreased weight loss in others. Dronabinol (Marinol) is also an agent that may stimulate appetite.

F. Neurotoxicity

The incidence of neurotoxicity associated with chemotherapy is increasing, potentially because of the greater use of high-dose chemotherapy and newer drugs causing neurotoxicity used in combination. In many cases, early detection and treatment of neurotoxicity (i.e., reduction of drug dose or discontinuation) allow for the reversal of symptoms. The neurotoxic symptoms may manifest as altered level of consciousness or coma, cerebellar dysfunction, ototoxicity, or peripheral neuropathy, which may be temporary but can cause significant changes in functional ability that persist as a long-term effect. It is also important to assess renal function because poor renal function may reduce clearance of the chemotherapy agent, leading to increased neurotoxicity.

Chemotherapy and biologic agents with known potential for neurotoxicity include high-dose cytarabine, high-dose methotrexate, vincristine, vinblastine, vinorelbine, ifosfamide, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, procarbazine, bortezomib, thalidomide, interleukin 2, and the interferons.
Prevention and early detection of neurotoxicity is key to prevention of permanent neurologic damage. Assessment of symptoms of neurotoxicity should be documented on a routine basis. In certain treatment regimens, altering the drug sequence can markedly decrease the symptoms.
Management of peripheral neurotoxicity is being studied, with the goal of slowing, halting, and reversing the neuropathy. One agent that has shown some activity with mixed results is the cytoprotectant amifostine. Pyroxidine or vitamin B6 may also be used, 100 mg b.i.d., in an attempt to minimize peripheral neuropathy. Glutamine has been shown to reduce peripheral neuropathy associated with paclitaxel. If pain becomes a major concern, anticonvulsants (gabapentin or carbamazepine) or tricyclic antidepressants (amitriptyline) may also be used. The drug pregabalin (Lyrica), similar to gabapentin, has shown promise in postherpetic neuralgia and in diabetic neuropathy, and has increasing attention in chemotherapy-induced neuropathy. Dosages of 75 mg b.i.d. have been effective, with improvements observed within 1 week of starting pregabalin. Whether there is any advantage over gabapentin is not clear. Topical analgesics and opioids may also be effective. Conventional nondrug interventions with some report of effectiveness include exercise, physical therapy, massage, and transcutaneuous electric nerve stimulation (TENS).

G. Palmar plantar erythrodysesthesia or hand foot syndrome

Palmar plantar erythrodysesthesia (PPE) is not a new side effect due to cancer chemotherapy. It has been seen with continuous-infusion fluorouracil in the past but has captured attention recently because of a high incidence with some newer chemotherapeutic drugs such as capecitabine and liposomal doxorubicin. PPE is a toxic drug reaction that begins

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as a cutaneous eruption of the integument on the palms of the hands and plantar surfaces of the feet. It has been postulated that PPE occurs because of drug extravasation in the microcapillaries of the hands and feet due to local everyday trauma or by drug concentration and accumulation in sweat glands found in the palms and soles with resultant tissue damage. PPE is time exposure dependent and occurs with protracted, chronic exposure over long periods (i.e., >3 to 4 weeks).

Prevention or minimization of PPE has been observed through regional cooling during the infusion of pegylated liposomal doxorubicin by having patients keep ice packs around the wrists and ankles, and consume iced liquids. These interventions were continued for 24 hours after completion of the chemotherapy. In this study, regional cooling decreased the frequency and severity of PPE in 94% of the patients in the intervention group. Although this is a single study, the minimal cost, relatively simple procedure, and well-tolerated intervention may be helpful.

Chemotherapeutic agents with a known potential for the development for PPE include fluorouracil (primarily with continuous infusions), capecitabine, doxorubicin, and liposome-encapsulated doxorubicin.
Clinical findings of PPE include tingling, numbness, pain, dryness, erythema, swelling, rash, blister formation, and pruritus of the hands and feet. Clinical knowledge of the potential for PPE and early assessment is imperative for adjustments of dose or withholding of therapy. Table 27.9 shows a staging scale that can be utilized to evaluate functional and clinical criteria for dose modification.

Management of PPE and symptomatic treatment result from prompt identification of symptoms. At the first sign of PPE, the drug should be stopped, or the interval between doses should be increased, or the drug dose should be reduced. If identified at grade 2 toxicity, symptoms typically improve within a few days of stopping the drug. If

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untreated, grade 2 side effects may quickly progress to grade 3 or 4, requiring more intense medical concern and intervention. Depending on the drug used, recommendations are available for dose modifications. Education on preventative measures should be given to patients before beginning the drug where PPE is likely. Patients should be counseled to avoid tight-fitting shoes and rings or repetitive rubbing pressure to the hands or feet. Other precautionary measures include avoiding excessive pressure and heat on the skin for 3 to 5 days after treatment, avoidance of hot baths, showers, or hot tubs (hot water for 24 hours before and 72 hours after treatment), and friction-causing activities such as exercise for 3 to 5 days after treatment. Patients should also be advised to use emollients such as BagBalm (Dairy Association Co., Lyndonville, VT), Udderly Smooth (Redex Industries, Salem, OH), or other petroleumor lanolin-containing creams liberally and frequently. Patients should also be instructed to notify their health care providers at the first signs or symptoms of PPE. If the grade of toxicity worsens, supportive care related to analgesia and prevention of infection is important. Other anecdotal interventions include topical steroids and oral premedication with steroids, application of a nicotine patch, and oral administration of pyridoxine. Further studies need to be done to evaluate which interventions are helpful for PPE and do not exacerbate the skin toxicity.

Table 27.9. Hand foot syndrome (palmar plantar erythrodysesthesia) grading scale

Grade 1	Grade 2	Grade 3	Grade 4
Painless erythema, or welling, numbness, dysesthesia / paresthesia, and tingling that do not disrupt activities of daily living	Painful erythema with swelling that affects activities of daily living, blisters or ulcerations <2 cm	Moist desquamation, ulceration, blistering, and severe pain, interference with normal daily activities, cannot wear regular clothing	Diffuse or local process causing infectious complications, a bed-ridden state or hospitalization
Based on National Cancer Institute of Canada CTG Expanded Common Toxicity Criteria.