Handbook of Cancer Chemotherapy (Lippincott Williams & Wilkins Handbook Series), 8th Ed.

26. Side Effects of Chemotherapy and Molecular Targeted Therapy

Janelle M. Tipton

The supportive care of patients receiving cancer chemotherapy and molecular targeted therapy has improved considerably over the last two decades. Contributions to the substantial improvements include better understanding of the pathophysiology of specific side effects, increased knowledge and attention to risk factors, and availability of newer agents for prevention and management of side effects. The side effects of systemic cancer treatment may be acute, self-limited, and mild, or can be chronic, permanent, and potentially life threatening in nature. 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. In addition, inadequately controlled side effects may lead to increased use of healthcare resources and costs, and may occasionally impact adherence to therapy. The implementation of evidence-based interventions has received recent emphasis and is critical in making appropriate clinical decisions for patient safety and 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 26.1.

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.

2. The incidence of extravasation for vesicant chemotherapy is recorded as 0.01% to 6.5% in the literature. 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.

3. Common signs and symptoms of extravasation are pain or burning at the intravenous (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 proven otherwise.

4. 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:

1. Stop administration of the chemotherapy agent.

2. Leave the needle/catheter in place and immobilize the extremity.

3. Attempt to aspirate any residual drug in the tubing, needle, or suspected extravasation site.

4. Notify the physician.

5. Administer the appropriate antidote, as shown in Table 26.1. This may include instillation of a drug antidote or application of heat or cold to the site. Consideration for antidote order sets and verification of antidote accessibility is recommended prior to administration.

6. 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.

7. Discuss the need for further intervention with the physician and photograph if indicated.

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8. Document extravasation occurrence according to institutional guidelines.

9. 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 time periods, if possible, are helpful in monitoring extent of injury and progress in healing.

5. Procedures for central extravasation are also critically important to follow, as extravasation of chemotherapy 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 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, these 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 decisions for future plans for venous access.

B. Infusion reactions: hypersensitivity, anaphylaxis, and cytokine-release syndrome

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 hours. 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 (e.g., paclitaxel and docetaxel), and platinum compounds (e.g., cisplatin, carboplatin, and 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. This is most commonly done for carboplatin, bleomycin, and asparaginase. A skin testing protocol for carboplatin skin testing is shown in Table 26.2.

1. TypeI hypersensitivity reactions (which may or maynotbe immune-mediated) 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 grade 1 or 2 type I reaction include flushing urticaria, fever, chills, rigors, dyspnea, and mild hypotension. Grade 3 and 4 reactions may involve bronchospasm, hypotension requiring treatment, and angioedema. Less common signs and symptoms of infusion reactions include back or abdominal pain, nausea, vomiting and diarrhea, incontinence, and anxiety. With appropriate premedication, the incidence of the hypersensitivity reactions has markedly decreased. 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 (Ambu, Inc., Glen Burnie, MD), and suction equipment. The following parenteral drugs should also be stocked in the treatment area: epinephrine 1:1000 or 1:10,000 solution, diphenhydramine 25 to 50 mg methylpredni-solone 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 26.3provides a sample preprinted standing order for the management of hypersensitivity and anaphylactic reactions.

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2. Cytokine-release syndrome, which is commonly referred to as infusion reaction, is a symptom complex that occurs most frequently when monoclonal antibodies are administered. This reaction is believed to be primarily related to the release of cytokines from targeted cells and other immune cells. Most monoclonal antibodies have the potential to cause this syndrome, and the appearance may be similar to the type I hypersensitivity reaction. In contrast, however, the cytokine-release reactions may be managed by short-term cessation of the infusion, administration of histamine blockers, and restarting the infusion at a slower rate. Table 26.4 compares the differences between chemotherapy and biotherapy infusion reactions.

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3. Retreatment and rechallenge of patients who have experienced paclitaxel-associated and platinum hypersensitivity reactions are supported in the literature. If a rechallenge is considered, the drug should be administered in the appropriate setting where immediate emergency situations may be handled. The decision to reinstitute the agent should be based on the clinical importance of using the drug in the particular disease setting. Patients have been successfully retreated within hours to days of the initial paclitaxel reactions at full doses; however, rechallenge with platinum compounds are generally less successful.

a. Reinstitution of paclitaxel. Patient management after experiencing a hypersensitivity reaction includes immediate discontinuation of the paclitaxel infusion at the onset of symptoms and rapid administration of additional diphenhydramine and methylprednisolone. Following stabilization of the patient and waiting approximately 30 minutes, the paclitaxel infusion is reinitiated, with initial infusion rates at 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 completed. An alternative is to pretreat the patient for 24 hours with dexamethasone 10 mg × 3 orally and to restart the infusion at the rate indicated above on the second day.

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b. Desensitization approaches. Rechallenge after a severe hypersensitivity reaction of the second episode of hypersensitivity reaction to paclitaxel and platinum agents (cisplatin, carboplatin, oxaliplatin) 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 the morning of chemotherapy have been studied. A full 30 minutes before the chemotherapy, other IV premedications such as dexamethasone 20 mg diphenhydramine 50 mg and a H2-histamine antagonist are given. For paclitaxel, the desensitization procedure continues with 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 there is 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 20 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 the treatment is administered (anticipatory), that which follows within the first 24 hours after the treatment (acute), and that which occurs more than 24 hours after the 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 patient characteristics that may affect emesis include history of poor emetic control, history of alcoholism, age, gender, anxiety level, 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 26.5). 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 to not undertreat 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 26.6) come from various pharmacologic classes. They work by different mechanisms that may relate to the pathophysiologic processes causing nausea and vomiting. Within the last 20 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-l-receptor antagonists are now validated in their role in inhibiting nausea and vomiting with moderately and highly emetogenic chemotherapy. NK-l-receptor antagonists are thought to improve acute nausea and vomiting associated with chemotherapy when combined with standard regimens (i.e., dexamethasone and 5-HT3receptor antagonists) and to have additional effect during the period of delayed nausea and vomiting alone or in combination with dexamethasone.

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C. Combination antiemetic therapy

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

bull Combinations of antiemetics are more effective than single agents.

bull 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 26.7 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 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 Examples of Regimens for Antiemetic Prevention and chemotherapy treatments by eating foods that do not have offensive odors or spicy tastes. 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

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E. Herbal remedies: ginger

There have long been anecdotalfy 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. Early studies show safety and little toxicity; therefore, its use may be considered, but the actual benefit has not been established, and difficulty remains 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.

1. Specific chemotherapy agents that may cause stomatitis include the following:

bull Antimetabolites: methotrexate, fluorouracil (particularly continuous infusion), capecitabine, cytarabine, irinotecan

bull Antitumor antibiotics: doxorubicin, idarubicin, dactinomycin, mitomycin, bleomycin

bull Plant alkaloids: vincristine, vinblastine, vinorelbine

bull Taxanes: docetaxel, paclitaxel

bull Alkylating agents: high doses of busulfan, cyclophosphamide

bull Biologic agents: interleukins, lymphokine-activated killer cell therapy

2. 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 for those at risk, and particularly in specific groups of patients, including those with bone marrow transplant, leukemia, or head and neck malignancies. Maintaining good nutrition and dental hygiene are also primary preventive measures. Normal saline is the preferred mouth rinse. Alternative rinsing agents such as sodium bicarbonate or nonalcoholic mouth-washes, 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 prior to the bolus of fluo-rouracil 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, due to 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.

3. 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. Commercial mouth-washes 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 may be helpful, but do not have clear evidence of benefit. Systemic pain control measures such as oral or parenteral narcotics should be implemented if topical analgesics are ineffective.

4. 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 by mouth twice a day 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 is a protective agent for xerostomia and is sometimes used concurrently with radiation to the head and neck.

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

Patients with dentures should 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 self-esteem, irritation of the dentures can lead to inflammation, ulceration, and secondary infection.

B. Fatigue

Cancer treatment–related fatigue has become an increasingly reported side effect of cancer therapy, and it can be the most distressing. An estimated 80% to 100% of patients experience fatigue. Cancer treatment–related fatigue is a subjective feeling of tiredness that is disproportionate to the level of exertion. This symptom often interferes with activities of daily living and can be part of a symptom cluster, which can be debilitating if left untreated. Any chemotherapy or biotherapy agent may cause fatigue and all patients should be screened for potential etiologic factors and appropriate management.

1. Interventions recommended for fatigue include exercise, education, energy conservation and activity management, measures to optimize sleep quality, massage, and behavioral therapies such as relaxation and healing touch. Exercise has the strongest and most cumulative evidence in support as an intervention for fatigue. Exercise interventions should be individualized and based on the patient's specific disease and treatment. Medical management may have some benefit, particularly psychostimulants such as methylphenidate and modafinil, and antidepressants if depression is a causal factor. While erythropoiesis-stimulating agents should be used with caution, they may have some benefit in correcting fatigue associated with anemia.

C. Diarrhea

Among the many causes of diarrhea in patients with cancer are chemotherapy, radiotherapy, the cancer itself, medications, supplemental feedings, and anxiety. Chemotherapy may result in osmotic diarrhea or secretory diarrhea, and often is associated with destruction of actively dividing epithelial cells of the gastrointestinal tract. Secretory diarrhea also may result from infectious causes (e.g., Clostridium difficileor other enterocolitis-causing bacteria), with or without concurrent neutropenia. 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.

1. 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, hydroxyurea, idarubicin, the nitrosoureas, and paclitaxel may cause diarrhea. When diarrhea from fluorouracil or irinotecan is present while on therapy, it is a sign of toxicity that must be monitored closely because it can escalate rapidly to severe levels at which the drug must be held or discontinued. Diarrhea also has been noted with inter-feron-a and interleukin-2 and with oral small molecule targeted therapies, such as lapatinib, erlotinib, sorafenib, and sunitinib; diarrhea can be a problem but is manageable with proper education and reporting. 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.

2. 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. The 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 C. difficile toxin and other enteropathic bacteria.

3. 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 and scopolamine), or both. Octreotide is often effective in controlling chemotherapy-related diarrhea as well as diarrhea associated with the carcinoid syndrome. Table 26.8 lists common agents used to treat diarrhea. Nonphar-macologic 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 an infectious contribution to gastrointestinal problems, which may include a functional ileus.

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 mtra-abdominal disease, 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, as well as 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. Methyl-naltrexone is a new agent now approved for use with opioid-induced constipation and has clear evidence-based benefit A bowel regimen example for a patient at risk for constipation is as follows:

1. Docusate sodium 100 mg twice a day alone or with casanthranol one capsule twice a day

2. If no bowel movement, add:

a. Senna at bedtime (dose varies with the preparation), or

b. Milk of magnesia 30 mL at bedtime.

3. If no bowel movement with the above, may add:

a. Bisacodyl one to three tablets or one 10-mg suppository at bedtime, or

b. Lactulose one to four tablespoons daily or

c. Polyethylene glycol 17 g daily.

4. Other more aggressive alternatives, if there is no impaction, include:

a. Fleet enema

b. Magnesium citrate 1 bottle

c. Tap-water enema.

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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. Malnutrition may 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 leads to the diagnosis of cancer is weight loss; therefore, the patient is most likely already experiencing some alteration 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 healthcare team.

1. 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 the added psychologic impact of the disease and therapy can also result in anxiety and depression, which can contribute to the lack of interest in food. Any patient receiving concurrent therapy with chemotherapy and radiation therapy to the head/neck or aerodiges-tive tract will likely experience difficulty in swallowing, appetite, and inadequate nutritional intake. Such high-risk patients need early assessment by a clinical dietician and proactive interventions, including consideration of a feeding tube.

2. Nutritional assessment. Early in the patient's treatment, a thorough nutritional assessment should be completed by the healthcare 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 anemia, serum albumin, and prealbumin; and an evaluation of activity and functional status. A good nutritional assessment may help to identify patients who are already at risk of malnutrition or those who may be prone to develop problems during the course of the illness and treatment.

3. 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 immuno-compromise. Nurses, dietitians, and even family members can identify problems and may be the first to act to promote weight gain. Various approaches to help increase weight are changes in diet; symptomatic treatment of nausea and vomiting, stomatitis, and other gastrointestinal effects of chemotherapy; and supplemental nutrition. Individual dietary counseling is recommended in the literature to be an effective intervention.

a. 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 high-protein and -calorie supplements using household items with some suggestions from the healthcare team.

b. Tube feedings. Enteral nutrition through a nasogastric, gas-trostomy, or jejunostomy 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.

c. 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.

4. Pharmacologic interventions. A recent area of interest is pharmacologic appetite stimulation. Current evidence supports the use of corticosteroids and progestins, one of which is megestrol acetate oral suspension 800 mg/day (20 mL/day).

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.

1. 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, ixabepilone, procarbazine, bortezomib, thalidomide, interleukin-2, and the interferons.

2. Prevention and early detection of neurotoxicity is key to the 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.

3. Management of peripheral neurotoxicity is being studied, with the goal of slowing, halting, and reversing the neuropathy. Dose reduction of the suspect agent, particularly with the microtubule inhibitors and epothilones, may be warranted, depending on the grade and duration of neuropathy. There is very little evidence to support specific interventions for peripheral neuropathy. Anecdotally, B complex vitamins such as pyroxidine or vitamin B6 may be used, 100 mg twice a day in attempt to minimize the peripheral neuropathy. Glutamine, anticonvulsants (gabapentin, pregabalin, or carbamazepine), or tricyclic antidepressants (amitriptyline) have been studied in phase II trials and may be considered. Topical analgesics and opioids may also be effective. Conventional nondrug interventions with some report of effectiveness include exercise, physical therapy, massage, and transcutaneous electrical nerve stimulation. Patient safety is critical and patient education on self-care measures is recommended.

G. Palmar–plantar erythrodysesthesia (PPE) or hand-foot syndrome

PPE is dose-limiting and the most common cumulative toxicity associated with continuous-infusion fluorouracil in the past but has captured recent attention with newer chemotherapy drugs such as capecitabine and liposomal doxorubicin with high incidence. PPE is a toxic drug reaction that begins 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., more than 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. A second retrospective study also showed benefit of regional cooling during the chemotherapy infusion. While regional cooling decreased the frequency and severity of PPE in patients in the intervention group, data are not sufficient to support routine use in clinical practice. Conversely, this intervention appears promising, and the minimal cost, relatively simple procedure, and well-tolerated intervention may be helpful. Other preventive interventions that have few studies or case report support include pyroxidine, oral corticosteroids, supportive care with topical wound care, and patient education.

1. Chemotherapy agents with a known potential for the development for PPE include fluorouracil (primarily with continuous infusions), capecitabine, doxorubicin, and liposome-encapsulated doxorubicin.

2. 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.

3. Management of PPE and symptomatic treatment result from prompt identification of symptoms. The grading scale for PPE is shown in Table 26.9. At the first sign of PPE, the drug should be stopped, 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 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. In situations where PPE is likely, education on preventative measures should be given to patients before beginning the drug. 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 prior to 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 Bag Balm (Dairy Association Co., Lyndonville, VT), Udderly Smooth (Redex Industries, Salem, OH), or other petroleum- or lanolin-containing creams liberally and frequently. Patients should also be instructed to notify their healthcare 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. Further studies need to be done to evaluate which interventions are helpful for PPE and do not exacerbate the skin toxicity.

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H. Skin reactions

With the advent of epidermal growth factor receptor (EGFR) antagonist drugs and small molecule targeted therapies, dermatologic toxicities have become relevant to patients and oncology healthcare providers. The dermatologic toxicities can vary in their type, time of onset, severity, duration, and response to therapeutic interventions. Reactions can include dry skin, rashes, pruritus, blistering, and desquamation. While such reactions do not often lead to alteration in therapy, they do pose a new challenge for symptomatic treatment.

1. Common EGFR inhibitors and small molecule targeted therapiesknown to cause skin reactions include cetuximab, panitumumab, erlotinib, lapatinib, sunitinib, and sorafenib.

2. Clinical findings for EGFR skin reactions are primarily a pustulopapular rash that is often mild to moderate in severity. The rash can cause pruritus and some discomfort, and patients may have difficulty coping with the appearance and body image changes. While often not severe in nature, the rash may contribute to the development of secondary infections.

3. Management of skin reactions from consensus guidelines emphasizes the importance of utilizing an interdisciplinary approach to management, involving specialists in oncology and dermatology. Important to any skin reaction is the understanding of the etiology and aggravating factors. As more data becomes available, particular agents to avoid as well as therapeutic options are critical in supportive care. For example, traditional acne medications and retinoids may actually enhance inflammation and exacerbate the rash, and alcohol-based gels and lotions may irritate the skin and exacerbate xerosis. A proactive, stepwise intervention strategy based on rash severity may be helpful. For a localized and minimally symptomatic rash, no intervention or topical hydrocortisone 1% or 2.5% cream and/or clindamycin 1% gel may be used. Reassessment within a few weeks is recommended by a healthcare professional or patient self-report if the reaction worsens or does not improve. For a moderate reaction, where there is a more generalized rash with some mild symptoms such as pruritus, options may include hydrocortisone cream 2.5%, clindamycin 1% gel, or pimecrolimus 1% cream in addition to doxycycline 100 mg by mouth twice a day or minocycline 100 mg by mouth twice a day. If the rash continues to worsen, symptoms are severe and impact functional status, and the potential for superinfection is present, a corticoid dose pack may need to be added to the moderate reaction interventions.

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