- Email: [email protected]
Ongoing Screening and Treatment to Potentially Reduce Tyrosine Kinase Inhibitor-Related Fatigue in Renal Cell Carcinoma
Accepted Manuscript Ongoing Screening and Treatment to Potentially Reduce TKI-Related Fatigue in Renal Cell Carcinoma Deepa Anand, MD, Carmen P. Escalante, MD PII:
S0885-3924(15)00080-9
DOI:
10.1016/j.jpainsymman.2015.02.007
Reference:
JPS 8841
To appear in:
Journal of Pain and Symptom Management
Received Date: 10 September 2014 Revised Date:
20 January 2015
Accepted Date: 2 February 2015
Please cite this article as: Anand D, Escalante CP, Ongoing Screening and Treatment to Potentially Reduce TKI-Related Fatigue in Renal Cell Carcinoma, Journal of Pain and Symptom Management (2015), doi: 10.1016/j.jpainsymman.2015.02.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Review Article
14-00494R1
Ongoing Screening and Treatment to Potentially Reduce TKI-Related Fatigue in Renal
Deepa Anand, MD, and Carmen P. Escalante, MD
RI PT
Cell Carcinoma
Department of General Internal Medicine, The University of Texas M. D. Anderson Cancer
SC
Center, Houston, Texas, USA
M AN U
Address correspondence to: Carmen P. Escalante, MD
Department of General Internal Medicine, Unit 1465
1515 Holcombe Boulevard
EP
Houston, TX 77030, USA
TE D
The University of Texas M. D. Anderson Cancer Center
AC C
E-mail: [email protected]
1
ACCEPTED MANUSCRIPT
Abstract Context. Renal cell carcinoma (RCC) represents 1% to 4% of adult malignancies, and
RI PT
approximately 33% of patients with RCC present with metastatic disease and have a poor prognosis. Better understanding of RCC tumor biology has led to the development of several molecularly targeted agents such as tyrosine kinase inhibitors (TKIs) to manage advanced
SC
disease. Although evolving data suggest these drugs may be beneficial in RCC, they are
associated with significant toxicities. Cancer-related fatigue (CRF) is one of the most common
M AN U
toxicities associated with the TKIs used in RCC.
Objectives. To review the incidence, pathophysiology, and management of CRF in patients with RCC who are undergoing targeted therapy with TKIs.
Methods. A comprehensive database search was performed using PubMed, Ovid,
TE D
Embase, and MEDLINE. References of all cited articles also were reviewed. Data from articles published between 1975 and June 2014 were considered. A narrative review regarding the incidence, pathophysiology, and management of CRF in patients with RCC undergoing targeted
EP
therapy with TKIs was performed.
AC C
Results. CRF is one of the most common TKI toxicities in patients with metastatic RCC and often is the dose-limiting toxicity. Management of TKI-related CRF can be difficult and may necessitate various nonpharmacological and pharmacologic interventions. Conclusion. TKI-related CRF in patients with RCC is a highly distressing complication
of cancer therapy. CRF can substantially influence drug compliance, the ability to maximally treat, and quality of life. It is important to recognize this common, yet frequently underdiagnosed
2
ACCEPTED MANUSCRIPT
complication and initiate appropriate management strategies, in order to increase the likelihood for optimal outcomes.
Running head: TKI-Related Fatigue in Renal Cell Carcinoma
AC C
EP
TE D
M AN U
SC
Accepted for publication: February 2, 2015.
RI PT
Key Words: Renal cell carcinoma, tyrosine kinase inhibitors, cancer related fatigue
3
ACCEPTED MANUSCRIPT
Introduction Renal cell carcinoma (RCC) represents 1% to 4% of adult malignancies (1). RCC
RI PT
incidence is increasing, and it is estimated that 63,920 new cases of RCC will be diagnosed in the United States in 2014 (2). AU: PLS UPDATE Although partial or total nephrectomy is the standard of care in localized early-stage RCC, curative surgery is not possible in advanced metastatic
SC
disease. Approximately 33% of patients with RCC presents with metastatic disease and are associated with a poor prognosis (3).
M AN U
A better understanding of tumor biology and RCC molecular cytogenetics has led to the development of several novel molecularly targeted agents such as tyrosine kinase inhibitors (TKI) for the management of advanced RCC. Although evolving data suggest these drugs may be beneficial in RCC, they also are associated with significant toxicities (4).
TE D
Cancer-related fatigue (CRF) is one of the most frequent toxicities (36-85%) associated with the TKIs used in RCC, and often is the dose-limiting toxicity (4-17). CRF has been defined by the National Comprehensive Cancer Network (NCCN) as “a distressing persistent subjective
EP
sense of physical, emotional and/or cognitive tiredness or exhaustion related to cancer or cancer treatment, which interferes with usual functioning” (18). CRF is a highly distressing
AC C
complication of cancer therapy and may significantly influence drug compliance, the ability to maximally treat, and quality of life (19-22). Studies have shown that CRF is very common, and causes substantial functional and
psychological impairment, resulting in negative effects on quality of life (23-27). In a study involving 379 patients, 91% reported that CRF prevented a “normal” life, and 88% indicated it caused an alteration in their daily routine (25). CRF has been associated with impairment of daily 4
ACCEPTED MANUSCRIPT
functioning and self-care capabilities, increased difficulty in participating in social activities, impairment in standard cognitive tasks such as concentration and memory, and an increased sense of sadness, frustration and depression. CRF is also associated with significant adverse
RI PT
effects on economic productivity for caregivers by requiring them to take time off work. Finally, it may increase the cost of living by having to employ people for help with daily activities (25).
with RCC who are undergoing targeted therapy with TKIs.
M AN U
Methods
SC
This article reviews the incidence, pathophysiology, and management of CRF in patients
A comprehensive database search was performed using PubMed, Ovid, Embase, and MEDLINE. References of all cited articles also were reviewed. Data from articles published between 1975 and June 2014 were considered. A narrative review regarding the incidence,
with TKIs was performed.
TE D
pathophysiology, and management of CRF in patients with RCC undergoing targeted therapy
EP
Pathophysiology of TKI-Related Fatigue
Elucidation of the molecular pathways associated with RCC has led to use of several
AC C
different types of TKIs, anti-vascular endothelial growth factor (VEGF) monoclonal antibodies, and mammalian target of rapamycin pathway inhibitors. Among the TKIs, sorafenib, sunitinib, pazopanib, and axitinib are U.S. Food and Drug Administration-approved for treatment of advanced RCC (11) (Table 1). Other TKIs such as cediranib, lenvatinib, dovitinib, regorafenib, and cabozantinib are under investigation in clinical trials for management of advanced RCC (28). Although these targeted therapies may improve patient outcomes in RCC, their utility is often limited because of side effects that include CRF. 5
ACCEPTED MANUSCRIPT
The pathophysiology of TKI-related fatigue in RCC remains unclear and is poorly understood. It has been postulated that since TKIs differ in their mechanisms of action (Table 2), the differences in their side effect profiles may be directly related to their mode of action. For
RI PT
example, TKIs result in VEGF inhibition, which in turn can cause hypothyroidism,
hypoglycemia, hypophosphatemia, impaired muscle glucose uptake and excessive muscle loss, all of which can cause muscular weakness, resulting in fatigue (15, 29-33). TKI-induced VEGF
SC
inhibition also can cause anorexia, anemia and dehydration, which also results in fatigue (5, 34). TKI-induced endocrine disorders involving the adrenal glands, gonads, and bone and mineral
M AN U
metabolism also may contribute to fatigue (15, 35, 36). Further molecular studies exploring the role of TKI-induced inhibition of other receptors may help in better understanding the pathophysiology and management of TKI-induced fatigue. Besides mechanism of action, it also should be remembered that TKIs are currently being used for longer periods of time compared to
TE D
the conventional therapies (owing to the improved survival outcome), and hence the longer treatment duration also may be directly contributing to increasing incidence of TKI-related fatigue.
EP
The onset and course of fatigue after initiation of targeted therapy can vary, but studies
AC C
show that TKI-related fatigue resulting from sorafenib, sunitinib, and axitinib use may be most evident three to four weeks after initiating treatment (37, 38). Although all TKIs can cause fatigue in patients with RCC, some of these drugs pose higher risks for this toxicity. The various TKIs used in RCC, their usual dose, and their associated risks for fatigue are shown in Tables 1, 2 and 3 (6-10,12, 39-51). A 2014 meta-analysis demonstrated that sunitinib is associated with the highest incidence of all-grade fatigue (54%) in patients with RCC, followed by sorafenib (32%) and pazopanib (19%) (39). Sunitinib also poses the highest risk for inducing high-grade (grade
6
ACCEPTED MANUSCRIPT
3/4) fatigue more so than other TKIs [11% for sunitinib, 3% for sorafenib, and 2% for pazopanib] (39).
RI PT
Overall, fatigue is a common symptom among patients with cancer (18-20, 22, 52-54). Studies show that fatigue affects as many as 60% to 90% of patients with cancer (55-59).
Fatigue, however, may be secondary to the cancer itself and not necessarily a manifestation of
SC
drug-induced toxicity. As a subjective symptom, it may be difficult to evaluate if it is a
manifestation of the primary tumor or an adverse effect of targeted therapy. However, fatigue
M AN U
resulting directly from cancer tends to improve with therapy, whereas treatment-induced fatigue increases in severity as a function of the dose of anticancer therapy administered (60, 61). Clinical Significance of TKI-Related Fatigue
TKIs increasingly play an important role in managing advanced RCC and in improving
TE D
overall survival. However, TKI-related fatigue may be severe enough to warrant dose reduction or discontinuation, which may compromise oncological outcome. Porta and colleagues reported that sunitinib-induced fatigue was responsible for treatment discontinuation in 3.5% of patients
EP
and treatment interruption in 9.4%, and necessitated dose reduction in 16.5% (62). Similarly, sorafenib-induced fatigue was responsible for treatment discontinuation in 1.5% of patients and
AC C
dose reduction in 20%.
Further, studies in both the United States and Europe have shown that managing TKI-
related fatigue can amount to significant health care costs. It is estimated that the mean total costs of medical care services during 30 days associated with management of fatigue and/ or asthenia in patients with metastatic RCC receiving targeted therapy in the United States can amount to $7748 (63). Another study in Europe showed that the average cost per patient of 7
ACCEPTED MANUSCRIPT
managing all-grade fatigue related to sunitinib was 372 euros (64). Hence, early diagnosis and appropriate management of TKI-related fatigue is important to improve patient outcome (by
RI PT
avoiding dose reductions, interruptions and discontinuation) and reduce health care costs. Management of TKI-Related Fatigue
To the best of our knowledge, no randomized controlled studies comparing the efficacy
SC
of various management strategies for TKI-related fatigue in RCC are currently available.
However, the general principles of managing chemotherapy-related fatigue also apply to patients
M AN U
with RCC who experience TKI-related fatigue. Fatigue is a common and important dose-limiting toxicity among patients receiving TKIs. Patients may benefit from improved screening and earlier symptom management. It is important to actively screen for TKI-related fatigue during both the course of therapy and during post-treatment follow-up visits. Clinicians should ask
TE D
patients who are receiving TKIs to rate their level of fatigue on a scale of 0 to 10 to help identify those for whom TKI-related fatigue is a significant issue (a score of 1-3 indicates mild fatigue, 46 indicates moderate fatigue, and 7-10 indicates severe fatigue), and the brevity of the tool does
EP
not substantially influence time constraints in a busy clinic (19, 65-68). Several screening survey tools are available for this assessment, such as the visual analogue scale (rated from 0-10, with 0
AC C
being no fatigue and 10 being the worst imaginable fatigue), which is mentioned in the NCCN practice guidelines (69). Numerous unidimensional and multidimensional scales are available for CRF measurement (Table 4) (59, 70-79). A 2009 systematic review reported that unidimensional scales are the easiest to administer, and its authors recommended the use of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core30 fatigue subscale or the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) subscale
8
ACCEPTED MANUSCRIPT
(59). The choice of scale may be dictated by time constraints, clinic environment, and the assessment goal.
RI PT
Obtaining a thorough history that includes onset, duration, and intensity of fatigue; temporal changes over time; presence of other related symptoms; and factors associated with improvement or worsening of fatigue is vital to ensure appropriate treatment (53, 54, 80).
SC
Patients should be asked about symptoms such as pain, anxiety, depression, sleep disorders, weight loss/gain, caloric intake, and physical activity. Appropriate laboratory tests should be
M AN U
performed to evaluate for anemia and any associated endocrinopathy such as hypothyroidism, hypogonadism, diabetes mellitus, and adrenal insufficiency. Liver and renal function tests also may help to identify important comorbidities. In addition, electrolyte abnormalities should be considered. Further, it is important to obtain a detailed drug history and to evaluate for the possibility of fatigue caused by other drugs and/or drug-drug interactions among medications
TE D
taken for comorbid conditions and other symptoms. Patients also should be asked if they are taking herbals, supplements, or vitamins. They may not consider these substances as “medications,” but it is important to ask about their use because some of these, especially the
EP
herbals, may demonstrate a high level of drug-drug interactions. Treatable causes of fatigue such
AC C
as hypothyroidism, anemia, depression, and dehydration should be promptly diagnosed and treated (52, 81-83).
The importance of patient education and counseling in the management of CRF cannot be
overemphasized. Educating patients and their caregivers regarding patterns of fatigue associated with TKIs and possible fatigue severity levels and duration may help them better cope with this ailment. In the absence of clear communication, patients may not anticipate that fatigue could pose a problem during the course of therapy, which would leave them unprepared to tackle this 9
ACCEPTED MANUSCRIPT
complication when it arises (84). It is important to reinforce that fatigue is a common adverse effect of TKIs, and that new-onset fatigue is not necessarily a sign of recurrence or progression of disease. Patients should be encouraged to discuss this fear more openly. Maintaining
RI PT
communication between patients and clinical teams can ensure prompt CRF management. Patients should be encouraged to have an active lifestyle and pace themselves as
SC
treatment continues (85, 86). Energy conservation and distraction strategies may be useful,
especially in the management of mild CRF. Because patients have varying energy levels during
M AN U
the course of the day, it is useful to identify time periods during which patients have maximum energy levels so they can perform critical activities during these time periods and to reserve lesscritical activities for periods of low energy. Prioritizing activities, goal setting, and limiting energy expenditure to one activity at a time are potentially useful strategies. Active involvement
cope with fatigue.
TE D
in games, listening to music, and socializing are distraction techniques that can help patients
Managing severe fatigue can be more difficult and necessitate various nonpharmacologic
EP
and pharmacologic interventions. Psychosocial interventions and exercise are associated with the strongest evidence supporting management of CRF (87-91). Evaluating for underlying stress,
AC C
anxiety, and depression and adequately managing these conditions can be very helpful. Educating and counseling patients and psychosocial interventions such as support groups, coping strategies, stress-management training, and individualized behavioral interventions have been shown to reduce fatigue levels in many patients with CRF (and support routine clinical practice). Exercise is one of the most effective nonpharmacologic strategies for managing CRF (87, 89, 90). The type and duration of an exercise regimen may vary, but it is important that an
10
ACCEPTED MANUSCRIPT
exercise program be customized to patients based on their medical condition and other factors. Similar to management of chronic fatigue syndrome, an individualized exercise activity plan is recommended in CRF (92). Initial activities may be limited to brief durations of low impact
RI PT
exercises such as stretching. This can be increased gradually with further strengthening and conditioning exercises, helping to build strength and stamina. Graded exercise therapy involving active stretching followed by range-of-motion contractions and extensions may be effective, but
SC
it is important to ensure patients avoid extremes and take adequate rests between the exercise
M AN U
activities (92).
Appropriate management of sleep disturbances and disorders is important for patients with CRF. A complete history can help to identify contributory factors such as anxiety, depression, side effects from other medications, and daytime napping. Patient education that details good and healthy sleep habits can help to improve sleep quality and quantity. The role of
useful (93, 94).
TE D
acupuncture in CRF is not yet clear, but preliminary studies suggest this intervention may be
EP
Pharmacologic interventions have been used in CRF. The role of central nervous system stimulants such as methylphenidate and modafanil remains unclear. There have been mixed
AC C
results in several studies; however, some patients experience improvement anecdotally. It is important to bear in mind that a placebo effect has been noted in several trials, but side effects of these drugs in appropriate patient populations are fairly uncommon. Risks and benefits should always be weighed when considering these agents. Further study may be useful to further evaluate the role of central nervous system stimulants in CRF (21, 95-101).
11
ACCEPTED MANUSCRIPT
The role of antidepressants is also being evaluated in the management of CRF. Because depression and fatigue frequently coexist in this population, antidepressants such as paroxetine and sertraline can help to improve depression even though they have not demonstrated
RI PT
improvement in fatigue (102-104). Sedative antidepressants such as nortriptyline and
amitriptyline may help patients with insomnia. Some authors have reported that bupropion may help patients with CRF because of its stimulant-like features, but larger studies are needed to
SC
confirm these findings (105-107). Presently, bupropion should be entertained for CRF only if
M AN U
depression is an issue.
The role of steroids in CRF treatment is unclear. A 2013 study reported that dexamethasone may help reduce CRF in patients with advanced cancer, but further studies are needed in this area (108). Other medications such as acetylcholinesterase inhibitors (donepezil) also have been evaluated for CRF treatment, but proven benefits have not been identified (109).
TE D
Despite the availability of the strategies described here, it may be necessary to reduce the TKI dose or interrupt or discontinue treatment if CRF is intolerable.
EP
Future Challenges
Fatigue is one of the most common complications associated with TKIs in RCC. As a
AC C
multifactorial and multidimensional symptom, however, it is often difficult to diagnose and measure CRF in a standardized manner. This makes management of this condition highly challenging and can result in dose reduction or treatment discontinuation, which may produce poorer oncological outcomes (7-9, 27). The economic burden of TKI-related fatigue also is substantial (3, 63).
12
ACCEPTED MANUSCRIPT
A systematic approach may help manage fatigue (52, 53). Patients should be screened for this condition because it frequently is underreported and underdiagnosed. Determination of risk factors for CRF may allow early management of the most susceptible patients. In our experience,
RI PT
risk factors that may be associated with higher incidence of development of severe CRF include elderly female patients with solid tumors, progressive disease or relapsed disease, poor
performance status, hemoglobin levels < 10 g/dL, abnormal magnesium levels, abnormal systolic
SC
blood pressure, presence of gastrointestinal symptoms (especially diarrhea but also nausea,
vomiting and constipation), dyspnea, chest pain, depression, dizziness, severe pain, and opioid
M AN U
use (54). Baseline fatigue screening prior to TKI initiation may help to delineate the fatigue contribution from a drug. Studies have shown there often is a discrepancy between grades of fatigue reported by physicians and patients’ perceptions of tolerability (39). There also are differences in the grading of fatigue among the various assessment tools (39).
TE D
Education and counseling of patients and their caregivers is critical (4, 20, 53, 69, 88). Patients should be encouraged to discuss their condition candidly, and education regarding fatigue should be offered prior to TKI initiation. Reversible and treatable causes of CRF such as
EP
anemia, endocrine disorders (including hypothyroidism, adrenal insufficiency, vitamin D
AC C
deficiency, and glucose metabolism) should be promptly diagnosed and treated (4, 20, 22, 39, 53, 69, 88). Several nonpharmacological therapies (psychosocial interventions and exercise) and pharmacologic interventions (various stimulants) are currently available to manage CRF. Although these therapies are applicable for CRF and are commonly used in clinical practice, large randomized controlled trials would be useful to evaluate the efficacy of these therapies specifically for TKI-related fatigue in RCC, especially considering the high incidence of fatigue in this population and the significant economic burden and difficulty associated with treating it.
13
ACCEPTED MANUSCRIPT
Managing fatigue in patients with coexisting diabetes and hypertension and cardiovascular, pulmonary, and renal disorders can be challenging (12, 29). Future studies exploring ideal management in specific populations would be highly useful and clinically relevant to ensure
RI PT
adherence to evidence-based practice. Recent studies have reported that TKI-induced fatigue may act as surrogate markers of a drug's clinical activity and can be used to predict treatment outcomes in advanced RCC (110-114). In a retrospective analysis of clinical trials including 770
SC
patients with advanced RCC treated with sunitinib, asthenia and fatigue were significantly and independently associated with improved clinical outcome (PFS and OS) AU: PLS EXPAND PFS AND Kaplan–Meier and multivariate analyses (110, 111). Further studies would be
M AN U
OS by both
extremely useful to validate these findings and assess the role of fatigue as a biomarker of efficacy in patients with metastatic RCC treated with TKIs.
TE D
Disclosures and Acknowledgments
No funding was received for this work and the authors have no conflicts of interest to AU: PLS CONFIRM THIS IS ACCURATE
References
EP
disclose.
AC C
1. Eble JN Sauter G, Epstein JI, Sesterhenn IA, eds. Pathology and genetics. Tumors of the urinary system and male genital organs. Lyon: IARC Press, 2004. 2. American Cancer Society. Cancer facts and figures 2014. Atlanta, GA: American Cancer Society, 2014.
3. Gupta K, Miller JD, Li JZ, Russell MW, Charbonneau C. Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev 2008;34:193-205. 14
ACCEPTED MANUSCRIPT
4. Eisen T, Sternberg CN, Robert C, et al. Targeted therapies for renal cell carcinoma: review of adverse event management strategies. J Natl Cancer Inst 2012;104:93-113.
clinical relief. Cancer Biol Ther 2011;12:765-771.
RI PT
5. Aparicio LM, Pulido EG, Gallego GA. Sunitinib-induced asthenia: from molecular basis to
6. Edmonds K, Hull D, Spencer-Shaw A, et al. Strategies for assessing and managing the adverse events of sorafenib and other targeted therapies in the treatment of renal cell and hepatocellular
SC
carcinoma: recommendations from a European nursing task group. Eur J Oncol Nurs 2012;16:172-184.
Anticancer Ther 2010;10:305-317.
M AN U
7. Escudier B. Sunitinib for the management of advanced renal cell carcinoma. Expert Rev
8. Escudier B. Sorafenib for the management of advanced renal cell carcinoma. Expert Rev Anticancer Ther 2011;11:825-836.
TE D
9. Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 2009;27:3312-3318.
EP
10. Escudier B, Gore M. Axitinib for the management of metastatic renal cell carcinoma. Drugs R D 2011;11:113-26.
AC C
11. Kanesvaran R, Tan MH. Targeted therapy for renal cell carcinoma: the next lap. J Carcinog 2014;13:3.
12. Mendez-Vidal MJ, Martinez Ortega E, Montesa Pino A, Perez Valderrama B, Viciana R. Management of adverse events of targeted therapies in normal and special patients with metastatic renal cell carcinoma. Cancer Metastasis Rev 2012;31(Suppl 1):S19-27.
15
ACCEPTED MANUSCRIPT
13. Illouz F, Laboureau-Soares S, Dubois S, Rohmer V, Rodien P. Tyrosine kinase inhibitors and modifications of thyroid function tests: a review. Eur J Endocrinol 2009;160:331-336. 14. Kappers MH, van Esch JH, Smedts FM, et al. Sunitinib-induced hypothyroidism is due to
RI PT
induction of type 3 deiodinase activity and thyroidal capillary regression. J Clin Endocrinol Metab 2011;96:3087-3094.
15. Lodish MB, Stratakis CA. Endocrine side effects of broad-acting kinase inhibitors. Endocr
SC
Relat Cancer 2010;17:R233-244.
16. Rini BI, Tamaskar I, Shaheen P, et al. Hypothyroidism in patients with metastatic renal cell
M AN U
carcinoma treated with sunitinib. J Natl Cancer Inst 2007;99:81-83.
17. Torino F, Corsello SM, Longo R, Barnabei A, Gasparini G. Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy. Nat Rev Clin Oncol 2009;6:219-228.
TE D
18. Mock V, Atkinson A, Barsevick A, et al. NCCN practice guidelines for cancer-related fatigue. Oncology (Williston Park) 2000;14:151-161. 19. Berger AM, Abernethy AP, Atkinson A, et al. Cancer-related fatigue. J Natl Compr Canc
EP
Netw 2010;8:904-931.
20. Bower JE, Bak K, Berger A, et al. Screening, assessment, and management of fatigue in
AC C
adult survivors of cancer: an american society of clinical oncology clinical practice guideline adaptation. J Clin Oncol 2014;32:1840-1850. 21. Escalante CP, Meyers C, Reuben JM, et al. A randomized, double-blind, 2-period, placebocontrolled crossover trial of a sustained-release methylphenidate in the treatment of fatigue in cancer patients. Cancer J 2014;20:8-14.
16
ACCEPTED MANUSCRIPT
22. Mortimer JE, Barsevick AM, Bennett CL, et al. Studying cancer-related fatigue: report of the NCCN scientific research committee. J Natl Compr Canc Netw 2010;8:1331-1339. 23. Curt GA. The impact of fatigue on patients with cancer: overview of fatigue 1 and 2.
RI PT
Oncologist 2000;5(Suppl 2):9-12.
24. Curt GA. Impact of fatigue on quality of life in oncology patients. Semin Hematol 2000;37:14-17.
SC
25. Curt GA, Breitbart W, Cella D, et al. Impact of cancer-related fatigue on the lives of patients: new findings from the Fatigue Coalition. Oncologist 2000;5:353-360.
M AN U
26. Hofman M, Ryan JL, Figueroa-Moseley CD, Jean-Pierre P, Morrow GR. Cancer-related fatigue: the scale of the problem. Oncologist 2007;12(Suppl 1):4-10. 27. Larkin JM, Pyle LM, Gore ME. Fatigue in renal cell carcinoma: the hidden burden of current targeted therapies. Oncologist 2010;15:1135-1146.
TE D
28. Aslam S, Eisen T. Vascular endothelial growth factor receptor tyrosine kinase inhibitors in metastatic renal cell cancer: latest results and clinical implications. Ther Adv Med Oncol 2013;5:324-333.
EP
29. Agostino NM, Chinchilli VM, Lynch CJ, et al. Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic and nondiabetic
AC C
patients in general clinical practice. J Oncol Pharm Pract 2011;17:197-202. 30. Baldazzi V, Tassi R, Lapini A, et al. Sunitinib-induced hyperparathyroidism: a possible mechanism to altered bone homeostasis. Cancer 2012;118:3165-3172. 31. Ballardini P, Margutti G, Aliberti C, Manfredini R. Onset of male gynaecomastia in a patient treated with sunitinib for metastatic renal cell carcinoma. Clin Drug Investig 2009;29:487-490.
17
ACCEPTED MANUSCRIPT
32. Brassard M, Neraud B, Trabado S, et al. Endocrine effects of the tyrosine kinase inhibitor vandetanib in patients treated for thyroid cancer. J Clin Endocrinol Metab 2011;96:2741-2749. 33. Patyna S, Arrigoni C, Terron A, et al. Nonclinical safety evaluation of sunitinib: a potent
RI PT
inhibitor of VEGF, PDGF, KIT, FLT3, and RET receptors. Toxicol Pathol 2008;36:905-916. 34. Theou-Anton N, Faivre S, Dreyer C, Raymond E. Benefit-risk assessment of sunitinib in gastrointestinal stromal tumours and renal cancer. Drug Safety 2009;32:717-734.
SC
35. Hartmann JT, Haap M, Kopp HG, Lipp HP. Tyrosine kinase inhibitors - a review on pharmacology, metabolism and side effects. Curr Drug Metab 2009;10:470-481.
M AN U
36. Lodish MB. Clinical review: kinase inhibitors: adverse effects related to the endocrine system. J Clin Endocrinol Metab 2013;98:1333-1342.
37. King CR. Multitargeted agents for therapeutically challenging tumor: an introduction for oncology nurses. ONS News 2006;21:57-58.
TE D
38. Mukohara T, Nakajima H, Mukai H, et al. Effect of axitinib (AG-013736) on fatigue, thyroid-stimulating hormone, and biomarkers: a phase I study in Japanese patients. Cancer Sci 2010;101:963-968.
EP
39. Santoni M, Conti A, Massari F, et al. Treatment-related fatigue with sorafenib, sunitinib and pazopanib in patients with advanced solid tumors: An up-to-date review and meta-analysis of
AC C
clinical trials. Int J Cancer 2015;136:1-10. 40. Cohen RB, Oudard S. Antiangiogenic therapy for advanced renal cell carcinoma: management of treatment-related toxicities. Invest New Drugs 2012;30:2066-2079. 41. Lee JL, Park I, Park K, et al. Efficacy and safety of vascular endothelial growth factor receptor tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma and poor risk features. J Cancer Res Clin Oncol 2012;138:687-693.
18
ACCEPTED MANUSCRIPT
42. Chu D, Lacouture ME, Weiner E, Wu S. Risk of hand-foot skin reaction with the multitargeted kinase inhibitor sunitinib in patients with renal cell and non-renal cell carcinoma: a meta-analysis. Clin Genitourin Cancer 2009;7:11-19.
RI PT
43. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:3584-3590.
cell carcinoma. N Engl J Med 2007;356:115-124.
SC
44. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-
M AN U
45. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125-134.
46. Escudier B, Porta C, Bono P, et al. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal
TE D
cell carcinoma: PISCES Study. J Clin Oncol 2014;32:1412-1418.
47. Escudier B, Szczylik C, Hutson TE, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin
EP
Oncol 2009;27:1280-1289.
48. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib
AC C
in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.[Erratum appears in Lancet 2012;380:1818]. Lancet 2011;378:1931-1939. 49. Rini BI, Stein M, Shannon P, et al. Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma. Cancer 2011;117:758-767. 50. Rini BI, Wilding G, Hudes G, et al. Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol 2009;27:4462-4468.
19
ACCEPTED MANUSCRIPT
51. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010;28:1061-1068. 52. Escalante CP, Kallen MA, Valdres RU, Morrow PK, Manzullo EF. Outcomes of a cancer-
RI PT
related fatigue clinic in a comprehensive cancer center. J Pain Symptom Manage 2010;39:691701.
53. Escalante CP, Manzullo EF. Cancer-related fatigue: the approach and treatment. J Gen Intern
SC
Med 2009;24(Suppl 2):S412-416.
54. Escalante CP, Manzullo EF, Lam TP, et al. Fatigue and its risk factors in cancer patients who
M AN U
seek emergency care. J Pain Symptom Manage 2008;36:358-366.
55. Stone P. The measurement, causes and effective management of cancer-related fatigue. Int J Palliat Nurs 2002;8:120-128.
56. Cella D, Peterman A, Passik S, Jacobsen P, Breitbart W. Progress toward guidelines for the
TE D
management of fatigue. Oncology (Williston Park) 1998;12:369-377. 57. Gaston-Johansson F, Fall-Dickson JM, Bakos AB, Kennedy MJ. Fatigue, pain, and depression in pre-autotransplant breast cancer patients. Cancer Pract 1999;7:240-247.
EP
58. Loscalzo MJ, Clark KL. Problem-related distress in cancer patients drives requests for help: a prospective study. Oncology (Williston Park) 2007;21:1133-1138.
AC C
59. Minton O, Stone P. A systematic review of the scales used for the measurement of cancerrelated fatigue (CRF). Ann Oncol 2009;20:17-25. 60. Spazzapan S, Bearz A, Tirelli U. Fatigue in cancer patients receiving chemotherapy: an analysis of published studies. Ann Oncol 2004;15:1576. 61. Seruga B, Gan HK, Knox JJ. Managing toxicities and optimal dosing of targeted drugs in advanced kidney cancer. Curr Oncol 2009;16(Suppl 1):S52-59.
20
ACCEPTED MANUSCRIPT
62. Porta C, Paglino C, Imarisio I, et al. Safety and treatment patterns of multikinase inhibitors in patients with metastatic renal cell carcinoma at a tertiary oncology center in Italy. BMC Cancer 2011;11:105.
RI PT
63. Hagiwara M, Hackshaw MD, Oster G. Economic burden of selected adverse events in
patients aged >65 years with metastatic renal cell carcinoma. J Med Econ 2013;16:1300-1306. 64. Mickisch G, Gore M, Escudier B, et al. Costs of managing adverse events in the treatment of
compared with sunitinib. Br J Cancer 2010;102:80-86.
SC
first-line metastatic renal cell carcinoma: bevacizumab in combination with interferon-alpha2a
M AN U
65. Butt Z, Wagner LI, Beaumont JL, et al. Use of a single-item screening tool to detect clinically significant fatigue, pain, distress, and anorexia in ambulatory cancer practice. J Pain Symptom Manage 2008;35:20-30.
66. Kirsh KL, Passik S, Holtsclaw E, Donaghy K, Theobald D. I get tired for no reason: a single
TE D
item screening for cancer-related fatigue. J Pain Symptom Manage 2001;22:931-937. 67. Strasser F, Muller-Kaser I, Dietrich D. Evaluating cognitive, emotional, and physical fatigue domains in daily practice by single-item questions in patients with advanced cancer: a cross-
EP
sectional pragmatic study. J Pain Symptom Manage 2009;38:505-514. 68. Temel JS, Pirl WF, Recklitis CJ, Cashavelly B, Lynch TJ. Feasibility and validity of a one-
AC C
item fatigue screen in a thoracic oncology clinic. J Thorac Oncol 2006;1:454-459. 69. Mock V, Atkinson A, Barsevick AM, et al. Cancer-related fatigue. Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2007;5:1054-1078. 70. Knobel H, Loge JH, Brenne E, et al. The validity of EORTC QLQ-C30 fatigue scale in advanced cancer patients and cancer survivors. Palliat Med 2003;17:664-672.
21
ACCEPTED MANUSCRIPT
71. Mendoza TR, Wang XS, Cleeland CS, et al. The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer 1999;85:1186-1196. 72. Norcross JC, Guadagnoli E, Prochaska JO. Factor structure of the Profile of Mood States
RI PT
(POMS): two partial replications. J Clin Psychol 1984;40:1270-1277.
73. Whitehead L. The measurement of fatigue in chronic illness: a systematic review of
unidimensional and multidimensional fatigue measures. J Pain Symptom Manage 2009;37:107-
SC
128.
74. Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E. Measuring fatigue and other
M AN U
anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Symptom Manage 1997;13:63-74.
75. Chalder T, Berelowitz G, Pawlikowska T, et al. Development of a fatigue scale. J Psychosom Res 1993;37:147-153.
TE D
76. Hann DM, Denniston MM, Baker F. Measurement of fatigue in cancer patients: further validation of the Fatigue Symptom Inventory. Qual Life Res 2000;9:847-854. 77. Piper BF, Dibble SL, Dodd MJ, et al. The revised Piper Fatigue Scale: psychometric
EP
evaluation in women with breast cancer. Oncol Nurs Forum 1998;25:677-684. 78. Schwartz AL. The Schwartz Cancer Fatigue Scale: testing reliability and validity. Oncol
AC C
Nurs Forum 1998;25:711-717.
79. Wu HS, Wyrwich KW, McSweeney M. Assessing fatigue in persons with cancer: further validation of the Wu Cancer Fatigue Scale. J Pain Symptom Manage 2006;32:255-265. 80. Manzullo E, Liu W, Escalante C. Treatment for cancer-related fatigue: an update. Expert Rev Anticancer Ther 2003;3:99-106.
22
ACCEPTED MANUSCRIPT
81. Escalante CP. Treatment of cancer-related fatigue: an update. Support Care Cancer 2003;11:79-83.
center: design and experiences. Cancer 2001;92:1708-1713.
RI PT
82. Escalante CP, Grover T, Johnson BA, et al. A fatigue clinic in a comprehensive cancer
83. Escalante CP, Manzullo E, Valdres R. A cancer-related fatigue clinic: opportunities and challenges. J Natl Compr Canc Netw 2003;1:333-343.
during cancer chemotherapy. Cancer 1989;63:604-612.
SC
84. Love RR, Leventhal H, Easterling DV, Nerenz DR. Side effects and emotional distress
M AN U
85. Grunwald V, Heinzer H, Fiedler W. Managing side effects of angiogenesis inhibitors in renal cell carcinoma. Onkologie 2007;30:519-524.
86. Wood LS, Manchen B. Sorafenib: a promising new targeted therapy for renal cell carcinoma. Clin J Oncol Nurs 2007;11:649-656.
Oncol 2005;23:899-909.
TE D
87. Galvao DA, Newton RU. Review of exercise intervention studies in cancer patients. J Clin
88. Kangas M, Bovbjerg DH, Montgomery GH. Cancer-related fatigue: a systematic and meta-
2008;134:700-741.
EP
analytic review of non-pharmacological therapies for cancer patients. Psychol Bull
AC C
89. Dimeo F, Schwartz S, Wesel N, Voigt A, Thiel E. Effects of an endurance and resistance exercise program on persistent cancer-related fatigue after treatment. Ann Oncol 2008;19:14951499.
90. Jacobsen PB, Donovan KA, Vadaparampil ST, Small BJ. Systematic review and metaanalysis of psychological and activity-based interventions for cancer-related fatigue. Health Psychol 2007;26:660-667.
23
ACCEPTED MANUSCRIPT
91. Mock V, Pickett M, Ropka ME, et al. Fatigue and quality of life outcomes of exercise during cancer treatment. Cancer Pract 2001;9:119-127. 92. White PD, Goldsmith KA, Johnson AL, et al. Comparison of adaptive pacing therapy,
RI PT
cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011;377:823-836.
93. Molassiotis A, Sylt P, Diggins H. The management of cancer-related fatigue after
SC
chemotherapy with acupuncture and acupressure: a randomised controlled trial. Complement Ther Med 2007;15:228-237.
M AN U
94. Vickers AJ, Straus DJ, Fearon B, Cassileth BR. Acupuncture for postchemotherapy fatigue: a phase II study. J Clin Oncol 2004;22:1731-1735.
95. Sarhill N, Walsh D, Nelson KA, et al. Methylphenidate for fatigue in advanced cancer: a prospective open-label pilot study. Am J Hosp Palliat Care 2001;18:187-192.
TE D
96. Bruera E, Valero V, Driver L, et al. Patient-controlled methylphenidate for cancer fatigue: a double-blind, randomized, placebo-controlled trial. J Clin Oncol 2006;24:2073-2078. 97. Gong S, Sheng P, Jin H, et al. Effect of methylphenidate in patients with cancer-related
EP
fatigue: a systematic review and meta-analysis. PLoS One 2014;9:e84391. 98. Blackhall L, Petroni G, Shu J, Baum L, Farace E. A pilot study evaluating the safety and
AC C
efficacy of modafinal for cancer-related fatigue. J Palliat Med 2009;12:433-439. 99. Minton O, Richardson A, Sharpe M, Hotopf M, Stone P. Drug therapy for the management of cancer-related fatigue. Cochrane Database Syst Rev 2010:CD006704. 100. Minton O, Richardson A, Sharpe M, Hotopf M, Stone P. A systematic review and metaanalysis of the pharmacological treatment of cancer-related fatigue. J Natl Cancer Inst 2008;100:1155-1166.
24
ACCEPTED MANUSCRIPT
101. Bruera E, Driver L, Barnes EA, et al. Patient-controlled methylphenidate for the management of fatigue in patients with advanced cancer: a preliminary report. J Clin Oncol 2003;21:4439-4443.
RI PT
102. Morrow GR, Hickok JT, Roscoe JA, et al. Differential effects of paroxetine on fatigue and depression: a randomized, double-blind trial from the University of Rochester Cancer Center Community Clinical Oncology Program. J Clin Oncol 2003;21:4635-1641.
SC
103. Roscoe JA, Morrow GR, Hickok JT, et al. Effect of paroxetine hydrochloride (Paxil) on fatigue and depression in breast cancer patients receiving chemotherapy. Breast Cancer Res
M AN U
Treat 2005;89:243-249.
104. Stockler MR, O'Connell R, Nowak AK, et al. Effect of sertraline on symptoms and survival in patients with advanced cancer, but without major depression: a placebo-controlled doubleblind randomised trial. Lancet Oncol 2007;8:603-612.
TE D
105. Moss EL, Simpson JS, Pelletier G, Forsyth P. An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners. Psychooncology 2006;15:259-267.
EP
106. Breitbart W, Alici Y. Pharmacologic treatment options for cancer-related fatigue: current state of clinical research. Clin J Oncol Nurs 2008;12:27-36.
AC C
107. Cullum JL, Wojciechowski AE, Pelletier G, Simpson JS. Bupropion sustained release treatment reduces fatigue in cancer patients. Can J Psychiatry 2004;49:139-144. 108. Yennurajalingam S, Frisbee-Hume S, Palmer JL, et al. Reduction of cancer-related fatigue with dexamethasone: a double-blind, randomized, placebo-controlled trial in patients with advanced cancer. J Clin Oncol 2013;31:3076-3082.
25
ACCEPTED MANUSCRIPT
109. Bruera E, El Osta B, Valero V, et al. Donepezil for cancer fatigue: a double-blind, randomized, placebo-controlled trial. J Clin Oncol 2007;25:3475-3481. 110. Davis MP, Figlin RA, Hutson TE, et al. . Asthenia and fatigue as potential biomarkers of
European Multidisciplinary Cancer Congress 2011:abstract 1139.
RI PT
sunitinib efficacy in metastatic renal cell carcinoma. [abstract]. Poster presentation at the
111. Donskov F, Michaelson MD, Puzanov I, et al. . Comparative assessment of sunitinib-
SC
associated adverse events (AEs) as potential biomarkers of efficacy in metastatic renal cell carcinoma (mRCC). [abstract]. Ann Oncol 2012;23(Suppl. 9):abstract 7850.
M AN U
112. Grellety T, Brugeres-Chakiba C, Chaminade A, et al. [Revision of therapeutic index for targeted treatment in kidney cancer: What if toxicity could predict efficacy?]. [In French]. Bull Cancer 2014;101:608-618.
113. Ravaud A, Schmidinger M. Clinical biomarkers of response in advanced renal cell
TE D
carcinoma. Ann Oncol 2013;24:2935-2942.
114. Schmidinger M, Larkin J, Ravaud A. Experience with sunitinib in the treatment of metastatic renal cell carcinoma. Ther Adv Urol 2012;4:253-265.
EP
115. Faivre S, Delbaldo C, Vera K, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol
AC C
2006;24:25-35.
116. Motzer RJ, Hutson TE, Olsen MR, et al. Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma. J Clin Oncol 2012;30:1371-1377. 117. Hurwitz HI, Dowlati A, Saini S, et al. Phase I trial of pazopanib in patients with advanced cancer. Clin Cancer Res 2009;15:4220-4227.
26
ACCEPTED MANUSCRIPT
118. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013;369:722-731.
carcinoma. N Engl J Med 2013;369:722-731.
RI PT
119. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell
120. Strumberg D, Clark JW, Awada A, et al. Safety, pharmacokinetics, and preliminary
refractory solid tumors. Oncologist 2007;12:426-437.
SC
antitumor activity of sorafenib: a review of four phase I trials in patients with advanced
121. Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma:
M AN U
final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 2009;27:3312-3318.
122. Bellmunt J, Fishman M, Eisen T, Quinn D. Expert opinion on the use of first-line sorafenib in selected metastatic renal cell carcinoma patients. Expert Rev Anticancer Ther 2010;10:825-
TE D
835.
123. Chen Y, Tortorici MA, Garrett M, et al. Clinical pharmacology of axitinib. Clin Pharmacokinet 2013;52:713-725.
EP
124. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet
AC C
2011;378:1931-1939.
125. Motzer RJ, Escudier B, Tomczak P, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial.[Erratum appears in Lancet Oncol 2013;14:e254]. Lancet Oncology 2013;14:552-562.
27
ACCEPTED MANUSCRIPT
Half-Life Dose
Sunitinib
41-86
50 mg oral dose taken
Approved for first-line therapy
hours
once daily for 4 weeks followed
in metastatic RCC; currently the
(115)
by 2 weeks off, on a 6-week
established standard first-line
course
therapy
(116) 31-35
800 mg given once daily
hours
(118)
(117)
Approved for first-line therapy
M AN U
Pazopanib
Use
RI PT
TKI
SC
Table 1. FDA-Approved TKIs for RCC
in metastatic RCC (studies show pazopanib is equally as effective as sunitinib but has a
Sorafenib
20-27
preferred by patients) (46, 119)
400 mg orally twice daily
Approved for first-line therapy
(45, 121)
and may be useful in elderly
EP
hours
TE D
better toxicity profile and is
AC C
(120)
Axitinib
2.5-6.1
5 mg twice daily (124)
patients with comorbidities. (122) Approved for second-line
hours
therapy in metastatic RCC
(123)
(125)
FDA = U.S. Food and Drug Administration; RCC= renal cell carcinoma; TKI= tyrosine kinase inhibitors. AU: THE JOURNAL PREFERS TO USE GENERIC DRUG NAMES ONLY; PRODUCT NAMES HAVE BEEN REMOVED. 28
ACCEPTED MANUSCRIPT
Table 2. TKI Mode of Action (Receptors Inhibited by TKIs) (4, 7, 8, 11, 28, 35, 106, 118, 122, 123) Platelet
Stem cell
Neurotrophic
approved TKI
tyrosine
derived
factor
factor receptor
inhibitor
kinase
growth factor
receptor (c-
(RET)
receptor
KIT),
+
+
+
Pazopanib
+
Axitinib
+
+
+ +
SC +
M AN U TE D
Sunitinib
+
EP
+
+
+
Other receptors
RI PT
FMS-like
Sorafenib
VEGFR
Fibroblast growth facor receptor; Rapidly Accelerated Fibrosarcoma; intracellular serine/ threonine kinase
+
+ +
AC C
FDA-
29
ACCEPTED MANUSCRIPT
Table 3. Extent of TKI-Related Fatigue (6-10, 12, 39-51) TKI
All-Grade Fatigue (%)
High-Grade Fatigue (Grade 3/4)
RI PT
(%) 53-81
4-11
Sorafenib
20-43
2-10
Axitinib
39
11
Pazopanib
19-44
SC
Sunitinib
2
AC C
EP
TE D
M AN U
TKI= tyrosine kinase inhibitor.
30
ACCEPTED MANUSCRIPT
Table 4. Unidimensional and Multidimensional Scales for CRF Measurement (59, 70-79) Multidimensional Scales
The Brief Fatigue Inventory (BFI)
Chalder Fatigue Scale or Fatigue Questionnaire (FQ)
European Organization for Research
RI PT
Unidimensional Scales
Fatigue Symptom Inventory (FSI)
SC
and Treatment of Cancer QLQ-C30 (QLQ C30)
Lee Fatigue Scale (or Visual Analogue
M AN U
Fatigue Severity Scale
Scale for Fatigue [VASF])
Functional Assessment of Cancer Therapy Fatigue (FACT F) subscale Profile of Mood States
Multidimensional Assessment of Fatigue
Multidimensional Fatigue Inventory
TE D
(MFI-20) Multidimensional Fatigue Symptom
AC C
EP
Inventory Short Form (MFSI-30) Revised Piper Fatigue Scale Schwartz Cancer Fatigue Scale Wu Cancer Fatigue Scale
CRF= cancer-related fatigue.
31
S0885-3924(15)00080-9
DOI:
10.1016/j.jpainsymman.2015.02.007
Reference:
JPS 8841
To appear in:
Journal of Pain and Symptom Management
Received Date: 10 September 2014 Revised Date:
20 January 2015
Accepted Date: 2 February 2015
Please cite this article as: Anand D, Escalante CP, Ongoing Screening and Treatment to Potentially Reduce TKI-Related Fatigue in Renal Cell Carcinoma, Journal of Pain and Symptom Management (2015), doi: 10.1016/j.jpainsymman.2015.02.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Review Article
14-00494R1
Ongoing Screening and Treatment to Potentially Reduce TKI-Related Fatigue in Renal
Deepa Anand, MD, and Carmen P. Escalante, MD
RI PT
Cell Carcinoma
Department of General Internal Medicine, The University of Texas M. D. Anderson Cancer
SC
Center, Houston, Texas, USA
M AN U
Address correspondence to: Carmen P. Escalante, MD
Department of General Internal Medicine, Unit 1465
1515 Holcombe Boulevard
EP
Houston, TX 77030, USA
TE D
The University of Texas M. D. Anderson Cancer Center
AC C
E-mail: [email protected]
1
ACCEPTED MANUSCRIPT
Abstract Context. Renal cell carcinoma (RCC) represents 1% to 4% of adult malignancies, and
RI PT
approximately 33% of patients with RCC present with metastatic disease and have a poor prognosis. Better understanding of RCC tumor biology has led to the development of several molecularly targeted agents such as tyrosine kinase inhibitors (TKIs) to manage advanced
SC
disease. Although evolving data suggest these drugs may be beneficial in RCC, they are
associated with significant toxicities. Cancer-related fatigue (CRF) is one of the most common
M AN U
toxicities associated with the TKIs used in RCC.
Objectives. To review the incidence, pathophysiology, and management of CRF in patients with RCC who are undergoing targeted therapy with TKIs.
Methods. A comprehensive database search was performed using PubMed, Ovid,
TE D
Embase, and MEDLINE. References of all cited articles also were reviewed. Data from articles published between 1975 and June 2014 were considered. A narrative review regarding the incidence, pathophysiology, and management of CRF in patients with RCC undergoing targeted
EP
therapy with TKIs was performed.
AC C
Results. CRF is one of the most common TKI toxicities in patients with metastatic RCC and often is the dose-limiting toxicity. Management of TKI-related CRF can be difficult and may necessitate various nonpharmacological and pharmacologic interventions. Conclusion. TKI-related CRF in patients with RCC is a highly distressing complication
of cancer therapy. CRF can substantially influence drug compliance, the ability to maximally treat, and quality of life. It is important to recognize this common, yet frequently underdiagnosed
2
ACCEPTED MANUSCRIPT
complication and initiate appropriate management strategies, in order to increase the likelihood for optimal outcomes.
Running head: TKI-Related Fatigue in Renal Cell Carcinoma
AC C
EP
TE D
M AN U
SC
Accepted for publication: February 2, 2015.
RI PT
Key Words: Renal cell carcinoma, tyrosine kinase inhibitors, cancer related fatigue
3
ACCEPTED MANUSCRIPT
Introduction Renal cell carcinoma (RCC) represents 1% to 4% of adult malignancies (1). RCC
RI PT
incidence is increasing, and it is estimated that 63,920 new cases of RCC will be diagnosed in the United States in 2014 (2). AU: PLS UPDATE Although partial or total nephrectomy is the standard of care in localized early-stage RCC, curative surgery is not possible in advanced metastatic
SC
disease. Approximately 33% of patients with RCC presents with metastatic disease and are associated with a poor prognosis (3).
M AN U
A better understanding of tumor biology and RCC molecular cytogenetics has led to the development of several novel molecularly targeted agents such as tyrosine kinase inhibitors (TKI) for the management of advanced RCC. Although evolving data suggest these drugs may be beneficial in RCC, they also are associated with significant toxicities (4).
TE D
Cancer-related fatigue (CRF) is one of the most frequent toxicities (36-85%) associated with the TKIs used in RCC, and often is the dose-limiting toxicity (4-17). CRF has been defined by the National Comprehensive Cancer Network (NCCN) as “a distressing persistent subjective
EP
sense of physical, emotional and/or cognitive tiredness or exhaustion related to cancer or cancer treatment, which interferes with usual functioning” (18). CRF is a highly distressing
AC C
complication of cancer therapy and may significantly influence drug compliance, the ability to maximally treat, and quality of life (19-22). Studies have shown that CRF is very common, and causes substantial functional and
psychological impairment, resulting in negative effects on quality of life (23-27). In a study involving 379 patients, 91% reported that CRF prevented a “normal” life, and 88% indicated it caused an alteration in their daily routine (25). CRF has been associated with impairment of daily 4
ACCEPTED MANUSCRIPT
functioning and self-care capabilities, increased difficulty in participating in social activities, impairment in standard cognitive tasks such as concentration and memory, and an increased sense of sadness, frustration and depression. CRF is also associated with significant adverse
RI PT
effects on economic productivity for caregivers by requiring them to take time off work. Finally, it may increase the cost of living by having to employ people for help with daily activities (25).
with RCC who are undergoing targeted therapy with TKIs.
M AN U
Methods
SC
This article reviews the incidence, pathophysiology, and management of CRF in patients
A comprehensive database search was performed using PubMed, Ovid, Embase, and MEDLINE. References of all cited articles also were reviewed. Data from articles published between 1975 and June 2014 were considered. A narrative review regarding the incidence,
with TKIs was performed.
TE D
pathophysiology, and management of CRF in patients with RCC undergoing targeted therapy
EP
Pathophysiology of TKI-Related Fatigue
Elucidation of the molecular pathways associated with RCC has led to use of several
AC C
different types of TKIs, anti-vascular endothelial growth factor (VEGF) monoclonal antibodies, and mammalian target of rapamycin pathway inhibitors. Among the TKIs, sorafenib, sunitinib, pazopanib, and axitinib are U.S. Food and Drug Administration-approved for treatment of advanced RCC (11) (Table 1). Other TKIs such as cediranib, lenvatinib, dovitinib, regorafenib, and cabozantinib are under investigation in clinical trials for management of advanced RCC (28). Although these targeted therapies may improve patient outcomes in RCC, their utility is often limited because of side effects that include CRF. 5
ACCEPTED MANUSCRIPT
The pathophysiology of TKI-related fatigue in RCC remains unclear and is poorly understood. It has been postulated that since TKIs differ in their mechanisms of action (Table 2), the differences in their side effect profiles may be directly related to their mode of action. For
RI PT
example, TKIs result in VEGF inhibition, which in turn can cause hypothyroidism,
hypoglycemia, hypophosphatemia, impaired muscle glucose uptake and excessive muscle loss, all of which can cause muscular weakness, resulting in fatigue (15, 29-33). TKI-induced VEGF
SC
inhibition also can cause anorexia, anemia and dehydration, which also results in fatigue (5, 34). TKI-induced endocrine disorders involving the adrenal glands, gonads, and bone and mineral
M AN U
metabolism also may contribute to fatigue (15, 35, 36). Further molecular studies exploring the role of TKI-induced inhibition of other receptors may help in better understanding the pathophysiology and management of TKI-induced fatigue. Besides mechanism of action, it also should be remembered that TKIs are currently being used for longer periods of time compared to
TE D
the conventional therapies (owing to the improved survival outcome), and hence the longer treatment duration also may be directly contributing to increasing incidence of TKI-related fatigue.
EP
The onset and course of fatigue after initiation of targeted therapy can vary, but studies
AC C
show that TKI-related fatigue resulting from sorafenib, sunitinib, and axitinib use may be most evident three to four weeks after initiating treatment (37, 38). Although all TKIs can cause fatigue in patients with RCC, some of these drugs pose higher risks for this toxicity. The various TKIs used in RCC, their usual dose, and their associated risks for fatigue are shown in Tables 1, 2 and 3 (6-10,12, 39-51). A 2014 meta-analysis demonstrated that sunitinib is associated with the highest incidence of all-grade fatigue (54%) in patients with RCC, followed by sorafenib (32%) and pazopanib (19%) (39). Sunitinib also poses the highest risk for inducing high-grade (grade
6
ACCEPTED MANUSCRIPT
3/4) fatigue more so than other TKIs [11% for sunitinib, 3% for sorafenib, and 2% for pazopanib] (39).
RI PT
Overall, fatigue is a common symptom among patients with cancer (18-20, 22, 52-54). Studies show that fatigue affects as many as 60% to 90% of patients with cancer (55-59).
Fatigue, however, may be secondary to the cancer itself and not necessarily a manifestation of
SC
drug-induced toxicity. As a subjective symptom, it may be difficult to evaluate if it is a
manifestation of the primary tumor or an adverse effect of targeted therapy. However, fatigue
M AN U
resulting directly from cancer tends to improve with therapy, whereas treatment-induced fatigue increases in severity as a function of the dose of anticancer therapy administered (60, 61). Clinical Significance of TKI-Related Fatigue
TKIs increasingly play an important role in managing advanced RCC and in improving
TE D
overall survival. However, TKI-related fatigue may be severe enough to warrant dose reduction or discontinuation, which may compromise oncological outcome. Porta and colleagues reported that sunitinib-induced fatigue was responsible for treatment discontinuation in 3.5% of patients
EP
and treatment interruption in 9.4%, and necessitated dose reduction in 16.5% (62). Similarly, sorafenib-induced fatigue was responsible for treatment discontinuation in 1.5% of patients and
AC C
dose reduction in 20%.
Further, studies in both the United States and Europe have shown that managing TKI-
related fatigue can amount to significant health care costs. It is estimated that the mean total costs of medical care services during 30 days associated with management of fatigue and/ or asthenia in patients with metastatic RCC receiving targeted therapy in the United States can amount to $7748 (63). Another study in Europe showed that the average cost per patient of 7
ACCEPTED MANUSCRIPT
managing all-grade fatigue related to sunitinib was 372 euros (64). Hence, early diagnosis and appropriate management of TKI-related fatigue is important to improve patient outcome (by
RI PT
avoiding dose reductions, interruptions and discontinuation) and reduce health care costs. Management of TKI-Related Fatigue
To the best of our knowledge, no randomized controlled studies comparing the efficacy
SC
of various management strategies for TKI-related fatigue in RCC are currently available.
However, the general principles of managing chemotherapy-related fatigue also apply to patients
M AN U
with RCC who experience TKI-related fatigue. Fatigue is a common and important dose-limiting toxicity among patients receiving TKIs. Patients may benefit from improved screening and earlier symptom management. It is important to actively screen for TKI-related fatigue during both the course of therapy and during post-treatment follow-up visits. Clinicians should ask
TE D
patients who are receiving TKIs to rate their level of fatigue on a scale of 0 to 10 to help identify those for whom TKI-related fatigue is a significant issue (a score of 1-3 indicates mild fatigue, 46 indicates moderate fatigue, and 7-10 indicates severe fatigue), and the brevity of the tool does
EP
not substantially influence time constraints in a busy clinic (19, 65-68). Several screening survey tools are available for this assessment, such as the visual analogue scale (rated from 0-10, with 0
AC C
being no fatigue and 10 being the worst imaginable fatigue), which is mentioned in the NCCN practice guidelines (69). Numerous unidimensional and multidimensional scales are available for CRF measurement (Table 4) (59, 70-79). A 2009 systematic review reported that unidimensional scales are the easiest to administer, and its authors recommended the use of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core30 fatigue subscale or the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) subscale
8
ACCEPTED MANUSCRIPT
(59). The choice of scale may be dictated by time constraints, clinic environment, and the assessment goal.
RI PT
Obtaining a thorough history that includes onset, duration, and intensity of fatigue; temporal changes over time; presence of other related symptoms; and factors associated with improvement or worsening of fatigue is vital to ensure appropriate treatment (53, 54, 80).
SC
Patients should be asked about symptoms such as pain, anxiety, depression, sleep disorders, weight loss/gain, caloric intake, and physical activity. Appropriate laboratory tests should be
M AN U
performed to evaluate for anemia and any associated endocrinopathy such as hypothyroidism, hypogonadism, diabetes mellitus, and adrenal insufficiency. Liver and renal function tests also may help to identify important comorbidities. In addition, electrolyte abnormalities should be considered. Further, it is important to obtain a detailed drug history and to evaluate for the possibility of fatigue caused by other drugs and/or drug-drug interactions among medications
TE D
taken for comorbid conditions and other symptoms. Patients also should be asked if they are taking herbals, supplements, or vitamins. They may not consider these substances as “medications,” but it is important to ask about their use because some of these, especially the
EP
herbals, may demonstrate a high level of drug-drug interactions. Treatable causes of fatigue such
AC C
as hypothyroidism, anemia, depression, and dehydration should be promptly diagnosed and treated (52, 81-83).
The importance of patient education and counseling in the management of CRF cannot be
overemphasized. Educating patients and their caregivers regarding patterns of fatigue associated with TKIs and possible fatigue severity levels and duration may help them better cope with this ailment. In the absence of clear communication, patients may not anticipate that fatigue could pose a problem during the course of therapy, which would leave them unprepared to tackle this 9
ACCEPTED MANUSCRIPT
complication when it arises (84). It is important to reinforce that fatigue is a common adverse effect of TKIs, and that new-onset fatigue is not necessarily a sign of recurrence or progression of disease. Patients should be encouraged to discuss this fear more openly. Maintaining
RI PT
communication between patients and clinical teams can ensure prompt CRF management. Patients should be encouraged to have an active lifestyle and pace themselves as
SC
treatment continues (85, 86). Energy conservation and distraction strategies may be useful,
especially in the management of mild CRF. Because patients have varying energy levels during
M AN U
the course of the day, it is useful to identify time periods during which patients have maximum energy levels so they can perform critical activities during these time periods and to reserve lesscritical activities for periods of low energy. Prioritizing activities, goal setting, and limiting energy expenditure to one activity at a time are potentially useful strategies. Active involvement
cope with fatigue.
TE D
in games, listening to music, and socializing are distraction techniques that can help patients
Managing severe fatigue can be more difficult and necessitate various nonpharmacologic
EP
and pharmacologic interventions. Psychosocial interventions and exercise are associated with the strongest evidence supporting management of CRF (87-91). Evaluating for underlying stress,
AC C
anxiety, and depression and adequately managing these conditions can be very helpful. Educating and counseling patients and psychosocial interventions such as support groups, coping strategies, stress-management training, and individualized behavioral interventions have been shown to reduce fatigue levels in many patients with CRF (and support routine clinical practice). Exercise is one of the most effective nonpharmacologic strategies for managing CRF (87, 89, 90). The type and duration of an exercise regimen may vary, but it is important that an
10
ACCEPTED MANUSCRIPT
exercise program be customized to patients based on their medical condition and other factors. Similar to management of chronic fatigue syndrome, an individualized exercise activity plan is recommended in CRF (92). Initial activities may be limited to brief durations of low impact
RI PT
exercises such as stretching. This can be increased gradually with further strengthening and conditioning exercises, helping to build strength and stamina. Graded exercise therapy involving active stretching followed by range-of-motion contractions and extensions may be effective, but
SC
it is important to ensure patients avoid extremes and take adequate rests between the exercise
M AN U
activities (92).
Appropriate management of sleep disturbances and disorders is important for patients with CRF. A complete history can help to identify contributory factors such as anxiety, depression, side effects from other medications, and daytime napping. Patient education that details good and healthy sleep habits can help to improve sleep quality and quantity. The role of
useful (93, 94).
TE D
acupuncture in CRF is not yet clear, but preliminary studies suggest this intervention may be
EP
Pharmacologic interventions have been used in CRF. The role of central nervous system stimulants such as methylphenidate and modafanil remains unclear. There have been mixed
AC C
results in several studies; however, some patients experience improvement anecdotally. It is important to bear in mind that a placebo effect has been noted in several trials, but side effects of these drugs in appropriate patient populations are fairly uncommon. Risks and benefits should always be weighed when considering these agents. Further study may be useful to further evaluate the role of central nervous system stimulants in CRF (21, 95-101).
11
ACCEPTED MANUSCRIPT
The role of antidepressants is also being evaluated in the management of CRF. Because depression and fatigue frequently coexist in this population, antidepressants such as paroxetine and sertraline can help to improve depression even though they have not demonstrated
RI PT
improvement in fatigue (102-104). Sedative antidepressants such as nortriptyline and
amitriptyline may help patients with insomnia. Some authors have reported that bupropion may help patients with CRF because of its stimulant-like features, but larger studies are needed to
SC
confirm these findings (105-107). Presently, bupropion should be entertained for CRF only if
M AN U
depression is an issue.
The role of steroids in CRF treatment is unclear. A 2013 study reported that dexamethasone may help reduce CRF in patients with advanced cancer, but further studies are needed in this area (108). Other medications such as acetylcholinesterase inhibitors (donepezil) also have been evaluated for CRF treatment, but proven benefits have not been identified (109).
TE D
Despite the availability of the strategies described here, it may be necessary to reduce the TKI dose or interrupt or discontinue treatment if CRF is intolerable.
EP
Future Challenges
Fatigue is one of the most common complications associated with TKIs in RCC. As a
AC C
multifactorial and multidimensional symptom, however, it is often difficult to diagnose and measure CRF in a standardized manner. This makes management of this condition highly challenging and can result in dose reduction or treatment discontinuation, which may produce poorer oncological outcomes (7-9, 27). The economic burden of TKI-related fatigue also is substantial (3, 63).
12
ACCEPTED MANUSCRIPT
A systematic approach may help manage fatigue (52, 53). Patients should be screened for this condition because it frequently is underreported and underdiagnosed. Determination of risk factors for CRF may allow early management of the most susceptible patients. In our experience,
RI PT
risk factors that may be associated with higher incidence of development of severe CRF include elderly female patients with solid tumors, progressive disease or relapsed disease, poor
performance status, hemoglobin levels < 10 g/dL, abnormal magnesium levels, abnormal systolic
SC
blood pressure, presence of gastrointestinal symptoms (especially diarrhea but also nausea,
vomiting and constipation), dyspnea, chest pain, depression, dizziness, severe pain, and opioid
M AN U
use (54). Baseline fatigue screening prior to TKI initiation may help to delineate the fatigue contribution from a drug. Studies have shown there often is a discrepancy between grades of fatigue reported by physicians and patients’ perceptions of tolerability (39). There also are differences in the grading of fatigue among the various assessment tools (39).
TE D
Education and counseling of patients and their caregivers is critical (4, 20, 53, 69, 88). Patients should be encouraged to discuss their condition candidly, and education regarding fatigue should be offered prior to TKI initiation. Reversible and treatable causes of CRF such as
EP
anemia, endocrine disorders (including hypothyroidism, adrenal insufficiency, vitamin D
AC C
deficiency, and glucose metabolism) should be promptly diagnosed and treated (4, 20, 22, 39, 53, 69, 88). Several nonpharmacological therapies (psychosocial interventions and exercise) and pharmacologic interventions (various stimulants) are currently available to manage CRF. Although these therapies are applicable for CRF and are commonly used in clinical practice, large randomized controlled trials would be useful to evaluate the efficacy of these therapies specifically for TKI-related fatigue in RCC, especially considering the high incidence of fatigue in this population and the significant economic burden and difficulty associated with treating it.
13
ACCEPTED MANUSCRIPT
Managing fatigue in patients with coexisting diabetes and hypertension and cardiovascular, pulmonary, and renal disorders can be challenging (12, 29). Future studies exploring ideal management in specific populations would be highly useful and clinically relevant to ensure
RI PT
adherence to evidence-based practice. Recent studies have reported that TKI-induced fatigue may act as surrogate markers of a drug's clinical activity and can be used to predict treatment outcomes in advanced RCC (110-114). In a retrospective analysis of clinical trials including 770
SC
patients with advanced RCC treated with sunitinib, asthenia and fatigue were significantly and independently associated with improved clinical outcome (PFS and OS) AU: PLS EXPAND PFS AND Kaplan–Meier and multivariate analyses (110, 111). Further studies would be
M AN U
OS by both
extremely useful to validate these findings and assess the role of fatigue as a biomarker of efficacy in patients with metastatic RCC treated with TKIs.
TE D
Disclosures and Acknowledgments
No funding was received for this work and the authors have no conflicts of interest to AU: PLS CONFIRM THIS IS ACCURATE
References
EP
disclose.
AC C
1. Eble JN Sauter G, Epstein JI, Sesterhenn IA, eds. Pathology and genetics. Tumors of the urinary system and male genital organs. Lyon: IARC Press, 2004. 2. American Cancer Society. Cancer facts and figures 2014. Atlanta, GA: American Cancer Society, 2014.
3. Gupta K, Miller JD, Li JZ, Russell MW, Charbonneau C. Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev 2008;34:193-205. 14
ACCEPTED MANUSCRIPT
4. Eisen T, Sternberg CN, Robert C, et al. Targeted therapies for renal cell carcinoma: review of adverse event management strategies. J Natl Cancer Inst 2012;104:93-113.
clinical relief. Cancer Biol Ther 2011;12:765-771.
RI PT
5. Aparicio LM, Pulido EG, Gallego GA. Sunitinib-induced asthenia: from molecular basis to
6. Edmonds K, Hull D, Spencer-Shaw A, et al. Strategies for assessing and managing the adverse events of sorafenib and other targeted therapies in the treatment of renal cell and hepatocellular
SC
carcinoma: recommendations from a European nursing task group. Eur J Oncol Nurs 2012;16:172-184.
Anticancer Ther 2010;10:305-317.
M AN U
7. Escudier B. Sunitinib for the management of advanced renal cell carcinoma. Expert Rev
8. Escudier B. Sorafenib for the management of advanced renal cell carcinoma. Expert Rev Anticancer Ther 2011;11:825-836.
TE D
9. Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 2009;27:3312-3318.
EP
10. Escudier B, Gore M. Axitinib for the management of metastatic renal cell carcinoma. Drugs R D 2011;11:113-26.
AC C
11. Kanesvaran R, Tan MH. Targeted therapy for renal cell carcinoma: the next lap. J Carcinog 2014;13:3.
12. Mendez-Vidal MJ, Martinez Ortega E, Montesa Pino A, Perez Valderrama B, Viciana R. Management of adverse events of targeted therapies in normal and special patients with metastatic renal cell carcinoma. Cancer Metastasis Rev 2012;31(Suppl 1):S19-27.
15
ACCEPTED MANUSCRIPT
13. Illouz F, Laboureau-Soares S, Dubois S, Rohmer V, Rodien P. Tyrosine kinase inhibitors and modifications of thyroid function tests: a review. Eur J Endocrinol 2009;160:331-336. 14. Kappers MH, van Esch JH, Smedts FM, et al. Sunitinib-induced hypothyroidism is due to
RI PT
induction of type 3 deiodinase activity and thyroidal capillary regression. J Clin Endocrinol Metab 2011;96:3087-3094.
15. Lodish MB, Stratakis CA. Endocrine side effects of broad-acting kinase inhibitors. Endocr
SC
Relat Cancer 2010;17:R233-244.
16. Rini BI, Tamaskar I, Shaheen P, et al. Hypothyroidism in patients with metastatic renal cell
M AN U
carcinoma treated with sunitinib. J Natl Cancer Inst 2007;99:81-83.
17. Torino F, Corsello SM, Longo R, Barnabei A, Gasparini G. Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy. Nat Rev Clin Oncol 2009;6:219-228.
TE D
18. Mock V, Atkinson A, Barsevick A, et al. NCCN practice guidelines for cancer-related fatigue. Oncology (Williston Park) 2000;14:151-161. 19. Berger AM, Abernethy AP, Atkinson A, et al. Cancer-related fatigue. J Natl Compr Canc
EP
Netw 2010;8:904-931.
20. Bower JE, Bak K, Berger A, et al. Screening, assessment, and management of fatigue in
AC C
adult survivors of cancer: an american society of clinical oncology clinical practice guideline adaptation. J Clin Oncol 2014;32:1840-1850. 21. Escalante CP, Meyers C, Reuben JM, et al. A randomized, double-blind, 2-period, placebocontrolled crossover trial of a sustained-release methylphenidate in the treatment of fatigue in cancer patients. Cancer J 2014;20:8-14.
16
ACCEPTED MANUSCRIPT
22. Mortimer JE, Barsevick AM, Bennett CL, et al. Studying cancer-related fatigue: report of the NCCN scientific research committee. J Natl Compr Canc Netw 2010;8:1331-1339. 23. Curt GA. The impact of fatigue on patients with cancer: overview of fatigue 1 and 2.
RI PT
Oncologist 2000;5(Suppl 2):9-12.
24. Curt GA. Impact of fatigue on quality of life in oncology patients. Semin Hematol 2000;37:14-17.
SC
25. Curt GA, Breitbart W, Cella D, et al. Impact of cancer-related fatigue on the lives of patients: new findings from the Fatigue Coalition. Oncologist 2000;5:353-360.
M AN U
26. Hofman M, Ryan JL, Figueroa-Moseley CD, Jean-Pierre P, Morrow GR. Cancer-related fatigue: the scale of the problem. Oncologist 2007;12(Suppl 1):4-10. 27. Larkin JM, Pyle LM, Gore ME. Fatigue in renal cell carcinoma: the hidden burden of current targeted therapies. Oncologist 2010;15:1135-1146.
TE D
28. Aslam S, Eisen T. Vascular endothelial growth factor receptor tyrosine kinase inhibitors in metastatic renal cell cancer: latest results and clinical implications. Ther Adv Med Oncol 2013;5:324-333.
EP
29. Agostino NM, Chinchilli VM, Lynch CJ, et al. Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic and nondiabetic
AC C
patients in general clinical practice. J Oncol Pharm Pract 2011;17:197-202. 30. Baldazzi V, Tassi R, Lapini A, et al. Sunitinib-induced hyperparathyroidism: a possible mechanism to altered bone homeostasis. Cancer 2012;118:3165-3172. 31. Ballardini P, Margutti G, Aliberti C, Manfredini R. Onset of male gynaecomastia in a patient treated with sunitinib for metastatic renal cell carcinoma. Clin Drug Investig 2009;29:487-490.
17
ACCEPTED MANUSCRIPT
32. Brassard M, Neraud B, Trabado S, et al. Endocrine effects of the tyrosine kinase inhibitor vandetanib in patients treated for thyroid cancer. J Clin Endocrinol Metab 2011;96:2741-2749. 33. Patyna S, Arrigoni C, Terron A, et al. Nonclinical safety evaluation of sunitinib: a potent
RI PT
inhibitor of VEGF, PDGF, KIT, FLT3, and RET receptors. Toxicol Pathol 2008;36:905-916. 34. Theou-Anton N, Faivre S, Dreyer C, Raymond E. Benefit-risk assessment of sunitinib in gastrointestinal stromal tumours and renal cancer. Drug Safety 2009;32:717-734.
SC
35. Hartmann JT, Haap M, Kopp HG, Lipp HP. Tyrosine kinase inhibitors - a review on pharmacology, metabolism and side effects. Curr Drug Metab 2009;10:470-481.
M AN U
36. Lodish MB. Clinical review: kinase inhibitors: adverse effects related to the endocrine system. J Clin Endocrinol Metab 2013;98:1333-1342.
37. King CR. Multitargeted agents for therapeutically challenging tumor: an introduction for oncology nurses. ONS News 2006;21:57-58.
TE D
38. Mukohara T, Nakajima H, Mukai H, et al. Effect of axitinib (AG-013736) on fatigue, thyroid-stimulating hormone, and biomarkers: a phase I study in Japanese patients. Cancer Sci 2010;101:963-968.
EP
39. Santoni M, Conti A, Massari F, et al. Treatment-related fatigue with sorafenib, sunitinib and pazopanib in patients with advanced solid tumors: An up-to-date review and meta-analysis of
AC C
clinical trials. Int J Cancer 2015;136:1-10. 40. Cohen RB, Oudard S. Antiangiogenic therapy for advanced renal cell carcinoma: management of treatment-related toxicities. Invest New Drugs 2012;30:2066-2079. 41. Lee JL, Park I, Park K, et al. Efficacy and safety of vascular endothelial growth factor receptor tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma and poor risk features. J Cancer Res Clin Oncol 2012;138:687-693.
18
ACCEPTED MANUSCRIPT
42. Chu D, Lacouture ME, Weiner E, Wu S. Risk of hand-foot skin reaction with the multitargeted kinase inhibitor sunitinib in patients with renal cell and non-renal cell carcinoma: a meta-analysis. Clin Genitourin Cancer 2009;7:11-19.
RI PT
43. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:3584-3590.
cell carcinoma. N Engl J Med 2007;356:115-124.
SC
44. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-
M AN U
45. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125-134.
46. Escudier B, Porta C, Bono P, et al. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal
TE D
cell carcinoma: PISCES Study. J Clin Oncol 2014;32:1412-1418.
47. Escudier B, Szczylik C, Hutson TE, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin
EP
Oncol 2009;27:1280-1289.
48. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib
AC C
in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.[Erratum appears in Lancet 2012;380:1818]. Lancet 2011;378:1931-1939. 49. Rini BI, Stein M, Shannon P, et al. Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma. Cancer 2011;117:758-767. 50. Rini BI, Wilding G, Hudes G, et al. Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol 2009;27:4462-4468.
19
ACCEPTED MANUSCRIPT
51. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010;28:1061-1068. 52. Escalante CP, Kallen MA, Valdres RU, Morrow PK, Manzullo EF. Outcomes of a cancer-
RI PT
related fatigue clinic in a comprehensive cancer center. J Pain Symptom Manage 2010;39:691701.
53. Escalante CP, Manzullo EF. Cancer-related fatigue: the approach and treatment. J Gen Intern
SC
Med 2009;24(Suppl 2):S412-416.
54. Escalante CP, Manzullo EF, Lam TP, et al. Fatigue and its risk factors in cancer patients who
M AN U
seek emergency care. J Pain Symptom Manage 2008;36:358-366.
55. Stone P. The measurement, causes and effective management of cancer-related fatigue. Int J Palliat Nurs 2002;8:120-128.
56. Cella D, Peterman A, Passik S, Jacobsen P, Breitbart W. Progress toward guidelines for the
TE D
management of fatigue. Oncology (Williston Park) 1998;12:369-377. 57. Gaston-Johansson F, Fall-Dickson JM, Bakos AB, Kennedy MJ. Fatigue, pain, and depression in pre-autotransplant breast cancer patients. Cancer Pract 1999;7:240-247.
EP
58. Loscalzo MJ, Clark KL. Problem-related distress in cancer patients drives requests for help: a prospective study. Oncology (Williston Park) 2007;21:1133-1138.
AC C
59. Minton O, Stone P. A systematic review of the scales used for the measurement of cancerrelated fatigue (CRF). Ann Oncol 2009;20:17-25. 60. Spazzapan S, Bearz A, Tirelli U. Fatigue in cancer patients receiving chemotherapy: an analysis of published studies. Ann Oncol 2004;15:1576. 61. Seruga B, Gan HK, Knox JJ. Managing toxicities and optimal dosing of targeted drugs in advanced kidney cancer. Curr Oncol 2009;16(Suppl 1):S52-59.
20
ACCEPTED MANUSCRIPT
62. Porta C, Paglino C, Imarisio I, et al. Safety and treatment patterns of multikinase inhibitors in patients with metastatic renal cell carcinoma at a tertiary oncology center in Italy. BMC Cancer 2011;11:105.
RI PT
63. Hagiwara M, Hackshaw MD, Oster G. Economic burden of selected adverse events in
patients aged >65 years with metastatic renal cell carcinoma. J Med Econ 2013;16:1300-1306. 64. Mickisch G, Gore M, Escudier B, et al. Costs of managing adverse events in the treatment of
compared with sunitinib. Br J Cancer 2010;102:80-86.
SC
first-line metastatic renal cell carcinoma: bevacizumab in combination with interferon-alpha2a
M AN U
65. Butt Z, Wagner LI, Beaumont JL, et al. Use of a single-item screening tool to detect clinically significant fatigue, pain, distress, and anorexia in ambulatory cancer practice. J Pain Symptom Manage 2008;35:20-30.
66. Kirsh KL, Passik S, Holtsclaw E, Donaghy K, Theobald D. I get tired for no reason: a single
TE D
item screening for cancer-related fatigue. J Pain Symptom Manage 2001;22:931-937. 67. Strasser F, Muller-Kaser I, Dietrich D. Evaluating cognitive, emotional, and physical fatigue domains in daily practice by single-item questions in patients with advanced cancer: a cross-
EP
sectional pragmatic study. J Pain Symptom Manage 2009;38:505-514. 68. Temel JS, Pirl WF, Recklitis CJ, Cashavelly B, Lynch TJ. Feasibility and validity of a one-
AC C
item fatigue screen in a thoracic oncology clinic. J Thorac Oncol 2006;1:454-459. 69. Mock V, Atkinson A, Barsevick AM, et al. Cancer-related fatigue. Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2007;5:1054-1078. 70. Knobel H, Loge JH, Brenne E, et al. The validity of EORTC QLQ-C30 fatigue scale in advanced cancer patients and cancer survivors. Palliat Med 2003;17:664-672.
21
ACCEPTED MANUSCRIPT
71. Mendoza TR, Wang XS, Cleeland CS, et al. The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer 1999;85:1186-1196. 72. Norcross JC, Guadagnoli E, Prochaska JO. Factor structure of the Profile of Mood States
RI PT
(POMS): two partial replications. J Clin Psychol 1984;40:1270-1277.
73. Whitehead L. The measurement of fatigue in chronic illness: a systematic review of
unidimensional and multidimensional fatigue measures. J Pain Symptom Manage 2009;37:107-
SC
128.
74. Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E. Measuring fatigue and other
M AN U
anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Symptom Manage 1997;13:63-74.
75. Chalder T, Berelowitz G, Pawlikowska T, et al. Development of a fatigue scale. J Psychosom Res 1993;37:147-153.
TE D
76. Hann DM, Denniston MM, Baker F. Measurement of fatigue in cancer patients: further validation of the Fatigue Symptom Inventory. Qual Life Res 2000;9:847-854. 77. Piper BF, Dibble SL, Dodd MJ, et al. The revised Piper Fatigue Scale: psychometric
EP
evaluation in women with breast cancer. Oncol Nurs Forum 1998;25:677-684. 78. Schwartz AL. The Schwartz Cancer Fatigue Scale: testing reliability and validity. Oncol
AC C
Nurs Forum 1998;25:711-717.
79. Wu HS, Wyrwich KW, McSweeney M. Assessing fatigue in persons with cancer: further validation of the Wu Cancer Fatigue Scale. J Pain Symptom Manage 2006;32:255-265. 80. Manzullo E, Liu W, Escalante C. Treatment for cancer-related fatigue: an update. Expert Rev Anticancer Ther 2003;3:99-106.
22
ACCEPTED MANUSCRIPT
81. Escalante CP. Treatment of cancer-related fatigue: an update. Support Care Cancer 2003;11:79-83.
center: design and experiences. Cancer 2001;92:1708-1713.
RI PT
82. Escalante CP, Grover T, Johnson BA, et al. A fatigue clinic in a comprehensive cancer
83. Escalante CP, Manzullo E, Valdres R. A cancer-related fatigue clinic: opportunities and challenges. J Natl Compr Canc Netw 2003;1:333-343.
during cancer chemotherapy. Cancer 1989;63:604-612.
SC
84. Love RR, Leventhal H, Easterling DV, Nerenz DR. Side effects and emotional distress
M AN U
85. Grunwald V, Heinzer H, Fiedler W. Managing side effects of angiogenesis inhibitors in renal cell carcinoma. Onkologie 2007;30:519-524.
86. Wood LS, Manchen B. Sorafenib: a promising new targeted therapy for renal cell carcinoma. Clin J Oncol Nurs 2007;11:649-656.
Oncol 2005;23:899-909.
TE D
87. Galvao DA, Newton RU. Review of exercise intervention studies in cancer patients. J Clin
88. Kangas M, Bovbjerg DH, Montgomery GH. Cancer-related fatigue: a systematic and meta-
2008;134:700-741.
EP
analytic review of non-pharmacological therapies for cancer patients. Psychol Bull
AC C
89. Dimeo F, Schwartz S, Wesel N, Voigt A, Thiel E. Effects of an endurance and resistance exercise program on persistent cancer-related fatigue after treatment. Ann Oncol 2008;19:14951499.
90. Jacobsen PB, Donovan KA, Vadaparampil ST, Small BJ. Systematic review and metaanalysis of psychological and activity-based interventions for cancer-related fatigue. Health Psychol 2007;26:660-667.
23
ACCEPTED MANUSCRIPT
91. Mock V, Pickett M, Ropka ME, et al. Fatigue and quality of life outcomes of exercise during cancer treatment. Cancer Pract 2001;9:119-127. 92. White PD, Goldsmith KA, Johnson AL, et al. Comparison of adaptive pacing therapy,
RI PT
cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011;377:823-836.
93. Molassiotis A, Sylt P, Diggins H. The management of cancer-related fatigue after
SC
chemotherapy with acupuncture and acupressure: a randomised controlled trial. Complement Ther Med 2007;15:228-237.
M AN U
94. Vickers AJ, Straus DJ, Fearon B, Cassileth BR. Acupuncture for postchemotherapy fatigue: a phase II study. J Clin Oncol 2004;22:1731-1735.
95. Sarhill N, Walsh D, Nelson KA, et al. Methylphenidate for fatigue in advanced cancer: a prospective open-label pilot study. Am J Hosp Palliat Care 2001;18:187-192.
TE D
96. Bruera E, Valero V, Driver L, et al. Patient-controlled methylphenidate for cancer fatigue: a double-blind, randomized, placebo-controlled trial. J Clin Oncol 2006;24:2073-2078. 97. Gong S, Sheng P, Jin H, et al. Effect of methylphenidate in patients with cancer-related
EP
fatigue: a systematic review and meta-analysis. PLoS One 2014;9:e84391. 98. Blackhall L, Petroni G, Shu J, Baum L, Farace E. A pilot study evaluating the safety and
AC C
efficacy of modafinal for cancer-related fatigue. J Palliat Med 2009;12:433-439. 99. Minton O, Richardson A, Sharpe M, Hotopf M, Stone P. Drug therapy for the management of cancer-related fatigue. Cochrane Database Syst Rev 2010:CD006704. 100. Minton O, Richardson A, Sharpe M, Hotopf M, Stone P. A systematic review and metaanalysis of the pharmacological treatment of cancer-related fatigue. J Natl Cancer Inst 2008;100:1155-1166.
24
ACCEPTED MANUSCRIPT
101. Bruera E, Driver L, Barnes EA, et al. Patient-controlled methylphenidate for the management of fatigue in patients with advanced cancer: a preliminary report. J Clin Oncol 2003;21:4439-4443.
RI PT
102. Morrow GR, Hickok JT, Roscoe JA, et al. Differential effects of paroxetine on fatigue and depression: a randomized, double-blind trial from the University of Rochester Cancer Center Community Clinical Oncology Program. J Clin Oncol 2003;21:4635-1641.
SC
103. Roscoe JA, Morrow GR, Hickok JT, et al. Effect of paroxetine hydrochloride (Paxil) on fatigue and depression in breast cancer patients receiving chemotherapy. Breast Cancer Res
M AN U
Treat 2005;89:243-249.
104. Stockler MR, O'Connell R, Nowak AK, et al. Effect of sertraline on symptoms and survival in patients with advanced cancer, but without major depression: a placebo-controlled doubleblind randomised trial. Lancet Oncol 2007;8:603-612.
TE D
105. Moss EL, Simpson JS, Pelletier G, Forsyth P. An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners. Psychooncology 2006;15:259-267.
EP
106. Breitbart W, Alici Y. Pharmacologic treatment options for cancer-related fatigue: current state of clinical research. Clin J Oncol Nurs 2008;12:27-36.
AC C
107. Cullum JL, Wojciechowski AE, Pelletier G, Simpson JS. Bupropion sustained release treatment reduces fatigue in cancer patients. Can J Psychiatry 2004;49:139-144. 108. Yennurajalingam S, Frisbee-Hume S, Palmer JL, et al. Reduction of cancer-related fatigue with dexamethasone: a double-blind, randomized, placebo-controlled trial in patients with advanced cancer. J Clin Oncol 2013;31:3076-3082.
25
ACCEPTED MANUSCRIPT
109. Bruera E, El Osta B, Valero V, et al. Donepezil for cancer fatigue: a double-blind, randomized, placebo-controlled trial. J Clin Oncol 2007;25:3475-3481. 110. Davis MP, Figlin RA, Hutson TE, et al. . Asthenia and fatigue as potential biomarkers of
European Multidisciplinary Cancer Congress 2011:abstract 1139.
RI PT
sunitinib efficacy in metastatic renal cell carcinoma. [abstract]. Poster presentation at the
111. Donskov F, Michaelson MD, Puzanov I, et al. . Comparative assessment of sunitinib-
SC
associated adverse events (AEs) as potential biomarkers of efficacy in metastatic renal cell carcinoma (mRCC). [abstract]. Ann Oncol 2012;23(Suppl. 9):abstract 7850.
M AN U
112. Grellety T, Brugeres-Chakiba C, Chaminade A, et al. [Revision of therapeutic index for targeted treatment in kidney cancer: What if toxicity could predict efficacy?]. [In French]. Bull Cancer 2014;101:608-618.
113. Ravaud A, Schmidinger M. Clinical biomarkers of response in advanced renal cell
TE D
carcinoma. Ann Oncol 2013;24:2935-2942.
114. Schmidinger M, Larkin J, Ravaud A. Experience with sunitinib in the treatment of metastatic renal cell carcinoma. Ther Adv Urol 2012;4:253-265.
EP
115. Faivre S, Delbaldo C, Vera K, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol
AC C
2006;24:25-35.
116. Motzer RJ, Hutson TE, Olsen MR, et al. Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma. J Clin Oncol 2012;30:1371-1377. 117. Hurwitz HI, Dowlati A, Saini S, et al. Phase I trial of pazopanib in patients with advanced cancer. Clin Cancer Res 2009;15:4220-4227.
26
ACCEPTED MANUSCRIPT
118. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013;369:722-731.
carcinoma. N Engl J Med 2013;369:722-731.
RI PT
119. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell
120. Strumberg D, Clark JW, Awada A, et al. Safety, pharmacokinetics, and preliminary
refractory solid tumors. Oncologist 2007;12:426-437.
SC
antitumor activity of sorafenib: a review of four phase I trials in patients with advanced
121. Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma:
M AN U
final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 2009;27:3312-3318.
122. Bellmunt J, Fishman M, Eisen T, Quinn D. Expert opinion on the use of first-line sorafenib in selected metastatic renal cell carcinoma patients. Expert Rev Anticancer Ther 2010;10:825-
TE D
835.
123. Chen Y, Tortorici MA, Garrett M, et al. Clinical pharmacology of axitinib. Clin Pharmacokinet 2013;52:713-725.
EP
124. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet
AC C
2011;378:1931-1939.
125. Motzer RJ, Escudier B, Tomczak P, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial.[Erratum appears in Lancet Oncol 2013;14:e254]. Lancet Oncology 2013;14:552-562.
27
ACCEPTED MANUSCRIPT
Half-Life Dose
Sunitinib
41-86
50 mg oral dose taken
Approved for first-line therapy
hours
once daily for 4 weeks followed
in metastatic RCC; currently the
(115)
by 2 weeks off, on a 6-week
established standard first-line
course
therapy
(116) 31-35
800 mg given once daily
hours
(118)
(117)
Approved for first-line therapy
M AN U
Pazopanib
Use
RI PT
TKI
SC
Table 1. FDA-Approved TKIs for RCC
in metastatic RCC (studies show pazopanib is equally as effective as sunitinib but has a
Sorafenib
20-27
preferred by patients) (46, 119)
400 mg orally twice daily
Approved for first-line therapy
(45, 121)
and may be useful in elderly
EP
hours
TE D
better toxicity profile and is
AC C
(120)
Axitinib
2.5-6.1
5 mg twice daily (124)
patients with comorbidities. (122) Approved for second-line
hours
therapy in metastatic RCC
(123)
(125)
FDA = U.S. Food and Drug Administration; RCC= renal cell carcinoma; TKI= tyrosine kinase inhibitors. AU: THE JOURNAL PREFERS TO USE GENERIC DRUG NAMES ONLY; PRODUCT NAMES HAVE BEEN REMOVED. 28
ACCEPTED MANUSCRIPT
Table 2. TKI Mode of Action (Receptors Inhibited by TKIs) (4, 7, 8, 11, 28, 35, 106, 118, 122, 123) Platelet
Stem cell
Neurotrophic
approved TKI
tyrosine
derived
factor
factor receptor
inhibitor
kinase
growth factor
receptor (c-
(RET)
receptor
KIT),
+
+
+
Pazopanib
+
Axitinib
+
+
+ +
SC +
M AN U TE D
Sunitinib
+
EP
+
+
+
Other receptors
RI PT
FMS-like
Sorafenib
VEGFR
Fibroblast growth facor receptor; Rapidly Accelerated Fibrosarcoma; intracellular serine/ threonine kinase
+
+ +
AC C
FDA-
29
ACCEPTED MANUSCRIPT
Table 3. Extent of TKI-Related Fatigue (6-10, 12, 39-51) TKI
All-Grade Fatigue (%)
High-Grade Fatigue (Grade 3/4)
RI PT
(%) 53-81
4-11
Sorafenib
20-43
2-10
Axitinib
39
11
Pazopanib
19-44
SC
Sunitinib
2
AC C
EP
TE D
M AN U
TKI= tyrosine kinase inhibitor.
30
ACCEPTED MANUSCRIPT
Table 4. Unidimensional and Multidimensional Scales for CRF Measurement (59, 70-79) Multidimensional Scales
The Brief Fatigue Inventory (BFI)
Chalder Fatigue Scale or Fatigue Questionnaire (FQ)
European Organization for Research
RI PT
Unidimensional Scales
Fatigue Symptom Inventory (FSI)
SC
and Treatment of Cancer QLQ-C30 (QLQ C30)
Lee Fatigue Scale (or Visual Analogue
M AN U
Fatigue Severity Scale
Scale for Fatigue [VASF])
Functional Assessment of Cancer Therapy Fatigue (FACT F) subscale Profile of Mood States
Multidimensional Assessment of Fatigue
Multidimensional Fatigue Inventory
TE D
(MFI-20) Multidimensional Fatigue Symptom
AC C
EP
Inventory Short Form (MFSI-30) Revised Piper Fatigue Scale Schwartz Cancer Fatigue Scale Wu Cancer Fatigue Scale
CRF= cancer-related fatigue.
31