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n Article

Optimizing Patient Adherence to Targeted Therapies in Renal Cell Carcinoma: Practical Management Strategies in the Second-Line Setting Patricia A. Creel, BSN, RN, OCN®, CCRP

The current standard of care for treating metastatic renal cell carcinoma is sequential therapy with vascular endothelial growth factor–targeted agents (i.e., axitinib, bevacizumab, pazopanib, sorafenib, and sunitinib) and mammalian target of rapamycin inhibitors (i.e., everolimus and temsirolimus). To maximize adherence to and persistence with targeted therapy, which should help improve clinical benefit, a clear understanding of the tolerability profiles of these agents and implementation of early, appropriately aggressive adverse event (AE) prevention and management strategies are key. Active and aggressive AE management should improve the quality of life of patients during the course of their treatment. Nurses are in a unique position to educate patients on the potential AEs they may experience and their prevention and management. This © Eraxion/iStockphoto article reviews the safety and tolerability of currently available targeted therapies recommended for use in the second-line treatment setting, as well as their management in the context of maximizing clinical outcomes and patient quality of life. Patricia A. Creel, BSN, RN, OCN®, CCRP, is a clinical research associate at Duke University Medical Center in Durham, NC. The author takes full responsibility for the content of the article. Editorial assistance was provided by Melanie Leiby, PhD, of ApotheCom, funded by Novartis Pharmaceuticals Corporation. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships have been disclosed by the independent peer reviewers or editorial staff. Creel can be reached at [email protected], with copy to editor at CJONEditor@ ons.org. (Submitted March 2013. Revision submitted March 2014. Accepted for publication March 16, 2014.) Key words: adverse event management; mammalian target of rapamycin; renal cell carcinoma; vascular endothelial growth factor receptor; tyrosine kinase inhibitor Digital Object Identifier: 10.1188/14.CJON.694-700

A

bout 63,920 new cases of kidney cancer are expected to be diagnosed in 2014 in the United States (American Cancer Society, 2014), with a median age at diagnosis of 64 years and a higher incidence in men (21 per 100,000 men versus 10.6 per 100,000 women) (Surveillance, Epidemiology, and End Results Program, 2014). About 90% of kidney cancers are renal cell carcinoma (RCC) (American Cancer Society, 2014), for which the five-year relative survival rate increased from 50% in 1975–1977 to 71% in 2001–2007 (Siegel, Naishadham, & Jemal, 2012). This likely resulted from the combined effects of earlier diagnosis and improved therapeutic options (Siegel et al., 2012). The evolution of molecularly targeted therapy has contributed to significant improvement in outcomes for the almost two-thirds of patients with RCC who are either diagnosed with metastatic RCC (mRCC) or experience relapse following surgery for localized disease (American Cancer Society, 2014; National Comprehensive Cancer Network [NCCN], 2014; Siegel et al., 2012). Targeted therapies approved for treating advanced RCC include the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab (used 694

in combination with interferon alpha) (Escudier, Pluzanska, et al., 2007); the VEGF receptor tyrosine kinase inhibitors (VEGFrTKIs) sunitinib, sorafenib, pazopanib, and axitinib (Escudier, Eisen, et al., 2007; Motzer et al., 2007; Rini, Escudier, et al., 2011; Sternberg et al., 2010); and the mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus (Hudes et al., 2007; Motzer et al., 2008). Despite the significant benefit provided by first-line therapies, they are noncurative, and patients ultimately develop resistance and show disease progression. Therefore, sequential treatment with targeted therapies is the current standard of care for treating mRCC (NCCN, 2014). Although sequential treatment is recognized as the best option for maximizing disease control and survival in mRCC, the optimal therapeutic sequence is unknown (Porta et al., 2012). Given that the primary goals of second-line therapy are to control disease progression and maintain patient quality of life (NCCN, 2014), the choice of second-line therapy should be driven by efficacy, safety, and tolerability. This article reviews the safety and tolerability of available targeted therapies recommended for use as second-line treatment, as well as their

December 2014 • Volume 18, Number 6 • Clinical Journal of Oncology Nursing

management in the context of maximizing clinical outcomes and quality of life.

Associated Adverse Events Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors The most common adverse events (AEs) observed in patients with mRCC treated with VEGFr-TKIs include hypertension or other cardiovascular side effects, gastrointestinal symptoms, fatigue, hematologic abnormalities, hypothyroidism, rash, palmar-plantar erythrodysesthesia (i.e., hand-foot syndrome), proteinuria, bleeding and wound-healing abnormalities, and hepatotoxicity (Castellano, Ravaud, Schmidinger, De Velasco, & Vazquez, 2013; Cohen & Oudard, 2012; Feinberg et al., 2012; Feldt et al., 2012; Patel & Srinivas, 2011; Ravaud, 2011) (see Table 1). The broad VEGFr-TKI AE profile is partly because of the other tyrosine kinases they inhibit. For example, sunitinib also inhibits the platelet-derived growth factor receptor, the stem cell factor receptor c-KIT, and colony-stimulating factor 1 receptor (AparicioGallego et al., 2011). Because inhibition of multiple receptor tyrosine kinases interferes with multiple signal transduction pathways and cellular processes, the AE profile of VEGFr-TKIs includes events beyond those associated with VEGFr inhibition. Within the VEGFr-TKI class, differences seem to exist in the relative frequency of certain AEs. This variation is likely related to the different tyrosine kinases targeted by individual agents and their relative inhibitory strengths. Conclusive evidence of the relative tolerability and frequency of individual AEs among agents is lacking because of the paucity of appropriately powered, controlled, direct comparisons of individual agents. One controlled study that provides information on the relative incidence of AEs among different agents is the phase III axitinib versus sorafenib in advanced RCC (AXIS) trial of patients when first-line therapy with sunitinib or cytokines failed the patient (Rini, Escudier, et al., 2011). An evaluation of AXIS suggests that AEs that occur more frequently with axitinib than sorafenib are hypertension (40% versus 29%), nausea (32% versus 22%), dysphonia (31% versus 14%), and hypothyroidism (19% versus 8%), whereas sorafenib may be associated with increased hand-foot syndrome (51% versus 27%), rash (32% versus 13%), alopecia (32% versus 4%), and anemia (52% versus 35%) (Rini, Escudier, et al., 2011). Aside from AE frequency, another way to assess tolerability is to evaluate rates of treatment discontinuation and interruptions and dose reductions from AEs. Using these surrogates, data from AXIS suggest that axitinib may be better tolerated than sorafenib because the rates of discontinuation and dose reduction from AEs were greater with sorafenib (8% versus 4% and 52% versus 31%, respectively).

One of the most common AEs associated with VEGFrTKIs is hypertension. Hypertension appears to be associated with better outcomes in recipients of VEGFr-TKI

TABLE 1. Incidence of Adverse Events and Laboratory Abnormalities Associated With VEGFr-TKIs in Pivotal Phase 3 Trials Sorafenib Sunitinib

TARGET

AXIS

Pazopanib

Axitinib

Adverse Event

%

%

%

%

%

Alopecia

12

27

32

–

4

Anorexia or decreased appetite

34

16

29

22

34

Asthenia

20

–

14

14

21

Diarrhea

61

43

53

52

55

Dyspepsia

31

–

–

–

–

Fatigue

54

37

32

19

39

Hand-foot syndrome

29

30

51

< 10

27

Hypertension

30

17

29

40

40

Hypothyroidism

14

–

8

< 10

19

Nausea

52

23

22

26

32

Rash

24

40

32

–

13

Stomatitis or mucositis

30

–

12

< 10

15

Vomiting

31

16

17

21

24

Laboratory Abnormality

%

%

%

ALT elevated

51

–

–

53

–

Anemia

79

8

52

–

35

AST elevated

56

–

–

53

–

Creatinine elevated

70

–

41

–

55

Hyperglycemia

–

–

–

41

–

Hypophosphatemia

31

13

50

34

13

Leukopenia

78

–

–

37

–

Lipase elevated

56

41

46

–

27

Lymphopenia

68

13a

36

31

33

Neutropenia

77

–

8

34

6

Thrombocytopenia

68

–

14

32

15

a

%

%

Only grade 3 and 4 events were reported. ALT—alanine aminotransferase; AST—aspartate aminotransferase; AXIS—axitinib versus sorafenib in advanced renal cell cancer; TARGET—Treatment Approaches in Renal Cancer Global Evaluation Trial; VEGFr-TKI— vascular endothelial growth factor receptor tyrosine kinase inhibitor Note. Missing values indicate data that were not reported. Note. Based on information from Escudier, Eisen, et al., 2007; Motzer et al., 2009; Rini, Escudier, et al., 2011; Sternberg et al., 2010. a

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(Rini, Cohen, et al., 2011; Szmit et al., 2012). In a retrospective analysis of 111 patients with mRCC treated with sunitinib, patients who developed hypertension during treatment had a significantly longer median progressionfree and overall survival than patients who did not develop hypertension (p < 0.00001 for each) (Szmit et al., 2012). In terms of incidence, hypertension appears more common with axitinib and pazopanib (40% each) compared with sorafenib (17%–29%) and sunitinib (30%) (Escudier, Eisen, et al., 2007; Motzer et al.,

TABLE 2. Incidence of Adverse Events and Laboratory Abnormalities Associated With Mammalian Target of Rapamycin Inhibitors Everolimus

Temsirolimus

Adverse Event

%

%

Anorexia

25

32

Asthenia

33

51

Cough

30

26

Diarrhea

30

27

Dyspnea

24

28

Fatigue

31

–

Infection

37

27

Nausea

26

37

Peripheral edema

25

27

Pyrexia

20

24

Rash

29

47

Stomatitis or mucositis

44

20

Vomiting

20

19

Laboratory Abnormality

%

%

ALT elevated

21

–

Anemia

92

45

AST elevated

25

8

Creatinine elevated

50

14

Hypercholesterolemia

77

24

Hyperglycemia

57

26

Hyperlipidemia

–

27

Hypertriglyceridemia

73

–

Hypophosphatemia

37

–

Lymphopenia

51

–

Thrombocytopenia

23

14

ALT—alanine aminotransferase; AST—aspartate aminotransferase Note. Based on information from Hudes et al., 2007; Motzer et al., 2010. 696

2009; Rini, Escudier, et al., 2011; Sternberg et al., 2010); severity is grade 3 or 4 in about one-third to one-half of these patients. Like almost all anticancer therapies, fatigue is common among recipients of VEGFr-TKI (Cohen & Oudard, 2012). Instances of severe, acute fatigue in recipients of VEGFr-TKI should be investigated further because rare cases of adrenal insufficiency being unmasked by the effects of VEGFr-TKI therapy have been reported (Yoshino et al., 2012). VEGFr-TKIs are also associated with hypothyroidism (Feldt et al., 2012), and patients who experience fatigue should be evaluated for the need for thyroid hormone replacement therapy. Management of fatigue is crucial to maintaining quality of life in patients with cancer. Strategies for managing fatigue include pacing of physical activity, postponing nonessential activities, maintaining a structured daily routine with activities scheduled for times of peak energy, starting or maintaining an exercise program, psychosocial interventions, and nutrition consultation (NCCN, 2013). Naps can be helpful, but duration should be limited to less than one hour to avoid interference with nighttime sleep. Hepatotoxicity is a particular concern with pazopanib, which is reflected in the inclusion of a black box warning on the approved prescribing information (Bourdeanu, Twardowski, & Pal, 2011; GlaxoSmithKline, 2012). Other metabolic and hematologic abnormalities observed with VEGFr-TKIs include hyponatremia, hypophosphatemia, hypomagnesemia, leukopenia, lymphocytopenia, neutropenia, and thrombocytopenia (Escudier, Pluzanska, et al., 2007; Motzer et al., 2007; Rini, Escudier, et al., 2011; Sternberg et al., 2010).

Mammalian Target of Rapamycin Inhibitors AEs commonly associated with mTOR inhibitors include stomatitis, rash, fatigue or asthenia, and diarrhea (Hudes et al., 2007; Motzer et al., 2010). Although no direct, controlled comparisons exist of oral everolimus and IV temsirolimus, examining AE data from their respective phase III studies suggests differences in the incidence of certain AEs (see Table 2). AEs more common with everolimus were stomatitis (44% versus 20%) and infections (37% versus 27%), whereas asthenia and rash were more common with temsirolimus (51% versus 33% and 47% versus 29%, respectively) (Hudes et al., 2007; Motzer et al., 2010). One of the AEs most commonly associated with mTOR inhibitors is stomatitis. Stomatitis involves inflammation of the mucous membranes of the mouth, inner surface of the lips, and tongue, and is associated with pain or a burning sensation, erythema, edema, and, in some cases, bleeding (Harris, Eilers, Harriman, Cashavelly, & Maxwell, 2008). These symptoms can be very unpleasant for patients, contribute to decreased quality of life, and, if uncontrolled, lead to significant clinical consequences such as pain, dehydration, malnutrition, and infections (Harris et al., 2008). Dermatologic AEs, including acneiform rash, maculopapular rash, dry skin, pruritus, herpes simplex lesions, and nail dystrophy, have also been observed in mTOR inhibitor recipients (Patel & Srinivas, 2011). Rashes generally occur during the first few weeks of treatment and, in clinical trials, were mostly mild to moderate in severity and reversible with supportive care (e.g., steroid medication) or dose reduction (Hudes et al., 2007; Patel & Srinivas, 2011). Although less common than stomatitis and rash, another AE associated with mTOR inhibitors is noninfectious pneumonitis,

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which is characterized by nonmalignant inflammatory infiltrates in the lungs (Albiges et al., 2012; White et al., 2010). It occurred in 13.5% of patients in the phase III everolimus trial (Motzer et al., 2010). Patients who develop mTOR inhibitor– associated noninfectious pneumonitis may initially present with respiratory symptoms (e.g., cough, dyspnea, hypoxemia) or systemic symptoms (e.g., fever, fatigue) (Albiges et al., 2012). Because mTOR inhibitors have immunosuppressive properties, patients may be more susceptible to opportunistic infections during therapy (Porta et al., 2011).

Importance of Tolerability Most of the AEs associated with targeted therapy are not permanent, but proactive avoidance and effective management are key to maximizing adherence, persistence, and quality of life in patients receiving second-line therapy. Managing these aspects of therapy should maximize clinical efficacy because patients who are adherent to and persistent with the recommended treatment regimen are more likely to receive a clinically effective dose intensity than patients who are nonadherent or nonpersistent (Cohen & Oudard, 2012; Porta et al., 2012; Ruddy, Mayer, & Partridge, 2009). Adherence and persistence are affected by tolerability and quality-of-life issues (Ruddy et al., 2009). Patients may be adherent to therapy on a daily basis but may discontinue the regimen before completion because they feel that any clinical benefit is outweighed by AEs that interfere with their daily life. Conversely, patients may be persistent but may skip doses throughout therapy because of AEs. Although the impact of AEs on health-related quality of life can be difficult to separate from the impact of the natural history of the disease itself, sequential use of targeted agents in RCC is generally associated with neutral or improved quality-of-life measures (Lambea et al., 2012; Trask et al., 2008). Limiting toxicity should be a goal for any line of therapy; however, it is particularly important in the second-line setting because excessive and cumulative toxicity may decrease performance status to such a degree that a patient is not eligible for further treatment. Therefore, for second and subsequent lines of therapy, cumulative toxicity is a major consideration. Cumulative toxicity refers to the concept that, if a patient receives a second drug from the same therapeutic class (particularly if given consecutively), AEs associated with that class may be more likely to occur or the AEs experienced will be more severe (Di Lorenzo et al., 2009; Escudier, Eisen, et al., 2007; Motzer et al., 2007; Oudard, Ravaud, & Escudier, 2010; Shepard et al., 2008). Some evidence of cumulative toxicity is provided by comparing AE rates of patients with cytokineand sunitinib-refractory mRCC enrolled in the phase III AXIS trial. Although these data have not been published, they were disclosed in the U.S. Food and Drug Administration (2011) Oncologic Drugs Advisory Committee briefing documents for axitinib. Those who received axitinib as second-line therapy following sunitinib versus following cytokines had higher rates of diarrhea (62% versus 49%), nausea (40% versus 21%), vomiting (32% versus 13%), and asthenia (28% versus 9%). Similar trends were observed among those who received sorafenib. Because the safety profiles of mTOR inhibitors and VEGFr-TKIs do not generally overlap, cumulative toxicity is

less of a concern in patients who receive an mTOR inhibitor as second-line therapy following a first-line VEGFr-TKI (Escudier, Eisen, et al., 2007; Figlin et al., 2008; Larkin, Swanton, & Pickering, 2011; Motzer et al., 2007, 2010). However, some toxicities are common to VEGFr-TKIs and mTOR inhibitors, and these events need to be carefully managed to avoid cumulative effects that may leave a patient unable or unwilling to receive further treatment. In addition, development of cumulative toxicity may be patient specific, and a tailored approach to AE management is required to maximize benefit and minimize toxicity.

Practical Management of Specific Adverse Events Nurses play a critical role in counseling patients on AE prevention and management. Practical management strategies surrounding some of the more common AEs associated with VEGFrTKIs and mTOR inhibitors are summarized in Table 3 (Bourdeanu et al., 2011; Cohen & Oudard, 2012; Eisen et al., 2012). Gastrointestinal toxicities (e.g., diarrhea) are among the most common AEs associated with almost all anticancer therapies. Although healthcare providers may consider gastrointestinal side effects to be less serious than other AEs, patients may consider them to be of greater importance because they interfere with daily activities and lead to decreased quality of life. Because gastrointestinal AEs may lead to decreased adherence, prevention and proactive management are key. Diarrhea is one of the most troubling AEs for patients, but it also is well suited to proactive education. Using antimotility agents such as loperamide; ensuring adequate intake of electrolyte-balanced beverages, diluted juices, and noncaffeinated beverages; and eating small, frequent meals are all useful tips for patients. The avoidance of lactose, caffeine, alcohol, and foods high in insoluble fiber (e.g., raw fruits and vegetables, skins, seeds, legumes) as well as greasy or fried foods should also be emphasized. Good food options are high in soluble fiber but low in insoluble fiber (e.g., rice, noodles, bananas, white toast, skinned turkey or chicken, fish, mashed potatoes) (Bourdeanu et al., 2011). If a patient reports severe diarrhea, he or she should be carefully evaluated for signs of dehydration to avoid additional complications. Other gastrointestinal AEs for which nurses assess include nausea, vomiting, and anorexia. Nausea is often mistermed by patients because further assessment reveals that dyspepsia is the more accurate term. Ranitidine is often used as initial therapy for dyspepsia with the addition of a proton pump inhibitor for complete control. Patients with vomiting who require intervention may receive an oral or transdermal antiemetic medication or be counseled about progressive muscle relaxation and guided imagery (Bourdeanu et al., 2011). Patients who experience anorexia should be encouraged to weigh themselves at home and keep a record of their weight, appetite, and caloric intake. This log should be reviewed at each clinic visit. Individualized dietary counseling may be implemented, and the use of appetite stimulants should be discussed if necessary (Bourdeanu et al., 2011). Nurses can play an important role in managing dermatologic AEs (e.g., rash, hand-foot syndrome). Symptomatic relief may be achieved by use of topical therapies, such as intensified

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TABLE 3. Nursing Interventions for Adverse Events Associated With Targeted Therapies Used in the Treatment of Metastatic Renal Cell Cancer Adverse Event

Management

VEGFr-TKIs and mTOR Inhibitors Dermatologic changes

Educate patients on the possibility of rash and types of presentation. Report severe rashes to a 24/7 provider (e.g., patient care hotline, emergency department). Promote proactive use of emollient creams, and avoid alcohol-based or scented lotions.

Fatigue

Educate patients about planning adequate rest periods each day. Recommend a minimum level of exercise (e.g., a progressive walking program). Advise patients to stay hydrated.

Diarrhea

Before starting therapy, establish what normal bowel elimination patterns are for each patient. Provide parameters for the number of diarrhea stools or type of stool that requires reporting to a healthcare provider. Suggest the use of prophylactic probiotics. Educate patients about antidiarrheal preparations for home use with guidelines for when to start taking them. Provide information on diet modifications to help avoid or manage diarrhea.

Hyperglycemia and hyperlipidemia

To avoid exacerbation of any preexisting abnormalities, assess glucose and lipid levels to ensure that optimal glycemic and lipid control has been achieved prior to the start of therapy. Ensure that all patients have baseline hepatic function assessed. Consider other possible causes of hyperlipidemia (e.g., hypothyroidism, nephrotic syndrome, drugs such as thiazides). Monitor patients for liver function, and check muscles for symptoms of hyperlipidemia.

VEGFr-TKIs Hypertension

Ensure that blood pressure is well controlled (i.e., less than 140/90 mmHg) before starting therapy, or initiating or modifying an existing antihypertensive regimen. Blood pressure should be assessed in the clinic every two weeks during the first three months of therapy and monthly thereafter. Recommend or facilitate purchase of a blood pressure monitoring device for home use, and instruct patients on accurate blood pressure measurement. Ensure that patients self-monitor blood pressure daily and bring the device and blood pressure diary to the clinic to assess accuracy of readings. Provide parameters for reporting high blood pressure to a healthcare provider.

Hand-foot syndrome

Instruct patients about proactive, aggressive care of hands and feet. Suggest use of emollient creams that do not contain alcohol or fragrance. Suggest use of wider shoes or gel inserts for shoes. Recommend the use of thick cotton socks. Recommend that patients limit activities that cause excessive pressure on hands and feet. Recommend that patients elevate their feet when sitting.

Changes in skin or hair pigmentation

Warn patients about possible changes in skin and hair color to minimize concern. Advise patients who wish to color their hair that they should be free of any skin lesions on their scalp, should use temporary dyes because they are gentler than permanent dyes, and should follow all package instructions, particularly the recommendation to test a small area of skin for sensitivity.

mTOR Inhibitors Stomatitis or oral mucositis

Recommend that patients visit a dentist for a routine checkup and cleaning and address any dental issues (e.g., cavities, improperly fitting dentures) before starting treatment. Advise patients about good oral hygiene; recommend mouth rinses of one-half to one teaspoon of salt or baking soda per eight-ounce glass of water three to four times daily. Provide guidelines for reporting symptoms to a healthcare provider. Instruct the patient to contact physician if more than three lesions appear, if lesions last for more than three days, or if painful lesions interfere with ability to eat, drink, sleep, or speak. Recommend that patients avoid use of alcohol-based mouthwashes or mouthwashes and toothpastes containing hydrogen peroxide, as well as tooth whiteners. Instruct patients to avoid foods that may cause mucosal irritation (e.g., citrus, tomatoes, spicy or hard foods). Consider other possible causes of stomatitis (e.g., herpes virus, fungal infections).

Pneumonitis

Educate patients about potential risk of pneumonitis. Advise patients of symptoms (e.g., dyspnea, cough), and instruct them to inform a healthcare provider if symptoms occur.

Opportunistic infections

Inform patients of the increased risk of infection caused by immunosuppressive action of medication. Instruct patients to contact a healthcare provider for a temperature greater than 100°F (or other provider-specific threshold), new cough, increased shortness of breath, or pustules on skin.

mTOR—mammalian target of rapamycin; VEGr-TKI—vascular endothelial growth factor receptor tyrosine kinase inhibitor Note. For more information, see resources available at www.kidneycancer.org/knowledge/learn/drug-information-sheets. Note. Based on information from Esper, 2012; Porta et al., 2011; Visich & Yeo, 2010; Yeo et al., 2012. 698

sk i n moistu r izers, u reacontaining lotions, and steroids, but prolonged topical steroid use should be avoided in recipients of mTOR inhibitor because of an increased risk of topical infection (Eisen et al., 2012). Nonserious rashes that are erythematous or papulosquamous and moderate in intensity should be differentiated from more serious hypersensitivity reactions, potentially requiring treatment discontinuation. Signs of serious rashes include mucosal involvement, bullous lesions, and systemic symptoms such as fever, hypereosinophilia, and hepatitis (Eisen et al., 2012). Patients receiving VEGFr-TKIs should be educated on the signs and symptoms of hand-foot syndrome. Prevention strategies, such as avoiding excessive pressure and friction on the palms and soles of the feet and avoiding prolonged exposure to hot water, should be emphasized at the start of treatment. Patients who develop hand-foot syndrome should be advised to keep the areas as cool as possible, avoid excessive friction, and use alcohol- and fragrance-free moisturizing creams. Because of the high incidence of hypertension in recipients of VEGFr-TKI, particularly in those who receive axitinib and pazopanib, regular blood pressure monitoring is key (Bourdeanu et al., 2011). Consultation with an internist or a cardiologist may be of benefit in devising an effective treatment plan for patients who develop treatmentrelated hypertension. Nurses should instruct patients to regularly monitor blood pressure and bring a blood pressure diary to each clinic visit. Because of the risk of hypothyroidism associated with VEGFr-TKIs, thyroidstimulating hormone levels

December 2014 • Volume 18, Number 6 • Clinical Journal of Oncology Nursing

Implications for Practice u

Employ sequential use of targeted therapy as the current standard of care for treating advanced renal cell carcinoma.

u

Maximize patient adherence, persistence, quality of life, and efficacy in the second-line treatment setting by performing appropriately aggressive, proactive management of adverse events.

u

Educate patients on the types of adverse events they may experience, as well as prevention and management.

should be measured at baseline and routinely throughout treatment (Feldt et al., 2012). If thyroid function is not routinely monitored and a patient reports symptoms consistent with hypothyroidism (e.g., fatigue; pale, dry skin; brittle finger nails and hair; puffy face; depression), a thyroid function assessment should be performed. Aside from changes in hair texture that may occur because of VEGFr-TKI–induced hypothyroidism, hair color changes may also occur with VEGFr-TKIs, particularly pazopanib. Although no preventive treatment exists for hair color changes, informing patients of this potential cosmetic change is important to give them time to prepare to cope with it. Managing stomatitis and oral mucositis is important for mTOR inhibitor recipients. Before initiating an mTOR inhibitor, all patients should be advised of the importance of maintaining good oral hygiene throughout treatment and avoiding agents containing hydrogen peroxide, iodine, or thyme derivatives (Porta et al., 2011). Nurses play a key role in preventing and managing stomatitis and mucositis by teaching proper oral care, regularly assessing signs and symptoms of stomatitis, helping patients cope with symptom distress, and administering required medications such as a nonalcoholic mouthwash or 0.9% salt water rinse for minor cases and topical oral analgesic treatments or corticosteroids for more serious cases (Harris et al., 2008). Topical antifungal therapy may be necessary for fungal infections and should be considered on a case-by-case basis. When starting therapy with an mTOR inhibitor, patients should be educated on signs and symptoms of noninfectious pneumonitis, including dyspnea, cough, and chest pain, and the importance of reporting them at clinic visits. If patients present with clinical symptoms of noninfectious pneumonitis during therapy, they should be referred for further testing as soon as possible because prompt imaging is needed to exclude differential diagnoses.

Conclusions Sequential therapy with VEGF-targeted agents and mTOR inhibitors can produce significant clinical benefit for patients with mRCC. However, to maximize adherence, persistence, and clinical benefit, a clear understanding of the tolerability profiles of these agents and implementation of early, appropriately aggressive AE prevention and management strategies are key. Active and aggressive AE management should improve patient quality of life during treatment, allowing patients to maintain therapy for a prolonged period of time. Because of their close relationships with patients, nurses play an invaluable role in this

process by counseling patients on AE recognition, prevention, and management.

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December 2014 • Volume 18, Number 6 • Clinical Journal of Oncology Nursing

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