Total cancer mortality in the United States has declined, and thus, cancer survival rates have improved correspondingly.1,2 However, increased survivorship is offset by multiple, persistent treatment-related symptoms.3 Taxane-induced musculoskeletal pain (TIMP) is defined as arthralgia (ie, joint pain) and/or myalgia (ie, diffuse muscle pain, usually accompanied by malaise) related to the administration of taxane-based chemotherapy.4 Paclitaxel is 1 of the most widely prescribed taxane agents in clinical practice and is predominately administered in populations of breast, ovarian, and non–small cell lung cancer.5 Across all populations of paclitaxel-treated patients, TIMP is likely common,6,7 and intensity appears to be dose dependent, with doses of paclitaxel greater than 200 mg/m2 leading to more frequent and intense TIMP.4 However, other common symptom assessment parameters such as distress, timing, quality, and concurrence (ie, co-occurring symptoms) of TIMP appear to be unstudied and unspecified, and although TIMP is likely common,6,7 true estimates of TIMP prevalence appear to be unknown.
In other nononcology patient populations, such as those seen in primary care settings, musculoskeletal pain is a significant problem. It is typically localized simultaneously in both the axial (head, neck, and spine, ribs, and pelvis) and peripheral (extremities) skeleton, affecting both areas of the body.8 Musculoskeletal pain can also arise from the muscles, ligaments, tendons, or joints and can be localized or generalized.9 These facts regarding persistent musculoskeletal pain in primary care suggest there is more to be understood about TIMP that is not adequately captured by intensity ratings alone. Because TIMP may importantly affect the health-related quality of life of cancer survivors, careful and comprehensive research examination of TIMP is warranted.4,10,11
To improve both health-related quality of life and patient-reported outcomes in cancer care, control of cancer treatment–related symptoms, such as TIMP, is essential.12 Symptoms are subjective experiences reflective of changes occurring in biophysical functioning, sensations, or cognition, and they are the most frequent reason individuals seek healthcare.13,14 The University of California–San Francisco Theory of Symptom Management and Lenz’s Theory of Unpleasant Symptoms are well-established theoretical frameworks with substantial empirical evidence for guiding a comprehensive assessment addressing the complexity of symptoms.13–17 These 2 theories are particularly suitable for guiding symptom management research in populations including those diagnosed with cancer.14,15,17 Both theories emphasize essential symptom management concepts including, but not limited to, contextual considerations (ie, person, environment, health, and illness variables), descriptions of the symptom experience (ie, intensity, distress, timing, quality, and concurrence variables), and the impact of symptoms on selected outcomes (ie, health-related quality of life, functional status, emotional status, need for additional treatment, and discontinuation of treatment or dose adjustment).13,14,16,18 Thus, both the University of California–San Francisco Theory of Symptom Management and Lenz’s Theory of Unpleasant Symptoms provide comprehensive and theoretical symptom assessment frameworks appropriate for guiding research, and they were combined to develop a conceptual framework that guided this review (Figure 1). In this framework, 4 types of contextual variables such as person variables (eg, age) or illness variables (eg, comorbid conditions) may influence the experience of TIMP, which may, in turn, influence outcomes.
Therefore, because it is imperative that symptom research reflects the complex nature of symptoms, the purpose of our article is to systematically review the literature examining the state of the science around TIMP. Specific aims were to evaluate (1) the conceptual clarity of TIMP; (2) descriptions of the TIMP symptom experience, including intensity, distress, timing, quality, and symptom concurrence; (3) contextual variables influencing TIMP including person, environment, health, and illness variables; and (4) the impact of TIMP on selected outcomes including health-related quality of life, functional status, emotional status, need for additional treatment, and discontinuation of treatment or dose adjustment. Findings from the review would therefore help to better delineate the framework (Figure 1).
Methods and Search Strategy
Inclusion and Exclusion Criteria
Relevant studies addressing TIMP were identified using a comprehensive and systematic approach. Inclusion criteria were as follows: full-text articles, published in a peer-reviewed journal; population specific to adult cancer survivors 18 years or older; evaluated TIMP; and English language. Exclusion criteria were as follows: case reports, review articles, cost-effectiveness trials, study populations including patients with metastasis or patients with bone metastasis (ie, patients with a diagnosis of stage IV cancer), and studies including regimens with treatments or therapeutic interventions having known skeletal adverse effects (such as aromatase inhibitors or growth factor). The rationale for exclusion was to ensure that any reported arthralgia or myalgia could be exclusively attributed to the taxane agent rather than to metastases or other forms of therapy. Studies evaluating neuropathy (peripheral nerve pain) were also excluded. No limits were placed on year published, and the search was current as of August 4, 2014. Peer-reviewed literature was searched using the PubMed database. The search terms used were (pain or myalgia or arthralgia or musculoskeletal) and taxane and neoplasm. Reference lists of all relevant review articles were searched for additional, applicable citations (ie, “spooling”) before being excluded.
Articles were identified for inclusion by the primary author. A subset (2%) of articles was discussed with both coauthors before being eliminated for not meeting inclusion criteria. As shown in Figure 2, 688 articles were identified, and their titles and abstracts screened for exclusion. Of these, 676 were excluded, leaving a total of 12 articles. Common reasons for exclusion were a failure to address or report TIMP, sample populations composed of participants with bone metastasis, and sample populations composed of participants classified as having metastasis, whether or not stage or site of metastases was reported.
The data were abstracted and organized into 5 separate tables consistent with the review aims. All abstracted data were verified by a second reviewer. The first table used in the analysis included a general overview of the studies including focus (TIMP or toxicity as a primary vs secondary focus), type of taxane (docetaxel; paclitaxel; or nanoparticle, albumin-bound paclitaxel), dose and frequency of taxane, other chemotherapy regimen agents assessed and premedications administered (when discussed), cancer type(s), number of subjects, and specification of time points for TIMP data collection. The second table used during analysis included all identified terms describing TIMP, consistent with aim 1. The third table showed the dimension(s) of the symptom experience (intensity and measure used, distress, timing, quality, and symptom concurrence) addressed for each TIMP term used (aim 2). If symptom intensity was assessed for a given TIMP term(s), measures used to evaluate intensity were listed in the table. The fourth table (aim 3) listed person variables (demographic, psychological, sociological, and physiological), environment variables (situational, physical, social, and cultural), and health and illness variables (risk factors, injuries, or disabilities), the contextual variables that might influence TIMP. The fifth table used during the analysis (aim 4) showed the impact of TIMP on selected outcomes including health-related quality of life, functional status, emotional status, requirement of additional treatment, and discontinuation of treatment or dose adjustment. Only data from the first 3 of these 5 tables are reported in this article because so few of the included studies evaluated contextual variables influencing TIMP or the impact of TIMP on the prespecified, selected outcomes (Tables 1–3).
Critiquing the Evidence (Synthesis/Overall Purpose)
As shown in Table 1, a very limited number of studies were identified.19–30 Most studies were conducted in the United States,19,21,25,28,29 42% (n = 5), or Europe,20,22,24,27,30 42% (n = 5). Year published ranged from 1997 to 2013, with 83% (n = 10) of studies published in the year 2000 or later. Studies were evenly split relative to focus, with 50% (n = 6) having a primary focus on TIMP or cancer treatment–related toxicity21,26–30 and 50% (n = 6) having a secondary focus on TIMP or treatment-related toxicity.19,20,22–25
Paclitaxel was the most commonly evaluated taxane agent, used in 83% (n = 10) of studies.19–21,23,24,26–30 Docetaxel was used in 8% (n = 1),22 and nanoparticle, albumin-bound paclitaxel, was used in 8% (n = 1) of studies.25 Paclitaxel was administered at doses greater than 200 mg/m2 in 33% (n = 4) of the studies.19,27–29 The most frequently administered dose of paclitaxel was 175 mg/m2, given in 42% (n = 5) of studies.20,23,24,26,30 When specified, cycles of paclitaxel were usually administered every 21 days (every 3 weeks).19,20,22–30 Across all studies, there was an average of 2 additional chemotherapy regimen agents assessed (range, 0–5). Only 2 studies23,30 evaluated paclitaxel alone, and no other oral or intravenous chemotherapy regimen agents. Premedications were described in 58% (n = 7) of studies19,23,24,27–30 and included dexamethasone, diphenhydramine, chlorpheniramine, and cimetidine, as well as other nonspecified H2 receptor antagonists and corticosteroids.
Breast cancer was the most commonly evaluated cancer type, assessed in 42% (n = 5) of studies.20–22,25,29 Other cancer types included ovarian, assessed in 25% (n = 3) of studies,23,26,30 non–small cell lung cancer (25%, n = 3),19,27,28 and small cell lung cancer (8%, n = 1).24 Half of studies (n = 6) had sample sizes of 35 or fewer,19,21,23–25,30 and half (n = 6) had sample sizes greater than 50.20,22,26–29 Time points for collecting assessments of TIMP, reported in 50% (n = 6) of studies,21,23,25,27–29 varied across this subset; 2 (17%)23,25 occurred after each chemotherapy cycle, 2 (17%)27,29 occurred throughout chemotherapy cycles, 1 (8%)21 occurred during the last cycle of chemotherapy, and 1 (8%)28 occurred after 2 cycles of preoperative chemotherapy and again after 3 cycles of postoperative chemotherapy. The studies specifying that assessments of TIMP were collected throughout chemotherapy cycles27,29 did not specify the exact intervals the assessments of TIMP were collected.
Terms Describing Taxane-Induced Musculoskeletal Pain (Aim 1)
As shown in Table 2 (aim 1), 6 different terms (adverse event, complication, adverse effect, symptom, syndrome, and toxicity) were used to describe TIMP. Although the individual studies used from 1 to 5 different terms, TIMP was described as a toxicity in 92% (n = 11).19,20,22–30
Descriptions of the Symptom Experience (Aim 2)
As shown in Table 3 (aim 2), 83% (n = 10) of studies19,20,22–28,30 used the terms arthralgia and/or myalgia to signify TIMP. Across studies, the average number of terms used to signify TIMP was 2.6 (range, 2–4). Other less commonly used terms for TIMP included bone pain and/or joint pain, used in 25% (n = 3) of studies.21,25,29
No studies evaluated all dimensions of the TIMP symptom experience. Intensity was measured in all studies, most commonly with the National Cancer Institute Common Toxicity Criteria, used in 50% (n = 6) of studies.19,25–29 The World Health Organization Dose Limiting Toxicity scale was used in 33% (n = 4) of studies.20,23,24,30 Intensity severity ranged from mild (grade 1) to life-threatening (grade 4). Among the terms arthralgia, myalgia, and bone pain, TIMP was estimated across the various studies to affect from 1.3% to 94% of study subjects. The intensity measure was not specified in 17% (n = 2) of studies.21,22 In 1 study,29 there was a conceptual-operational mismatch between the terms arthralgia and myalgia and the results from a linear analog scale for flulike symptoms, and therefore intensity grading was not reported for these TIMP terms. Distress was reported in only 8% (n = 1) of studies.21 Similarly, timing, for only 3 of 4 total TIMP terms used, was addressed in only 8% (n = 1) of studies,29 and quality was addressed in only 8% (n = 1) of studies.21 Concurrence (co-occurring symptoms) was not addressed by any of the studies included in our review.
Contextual Variables Relating to Taxane-Induced Musculoskeletal Pain (Aim 3)
Person, health, and illness domains influencing TIMP were addressed in only 17% (n = 2) of studies.26,29 No physical, social, or cultural variables comprising the environment domain were evaluated by any study included in our review.
Of those reporting person domains potentially influencing TIMP, 1 study26 found arthralgia and myalgia caused by paclitaxel did not vary between older and younger groups of patients. This finding suggests that age may not be a risk factor for treatment-related symptom severity (P = .57) in women with ovarian cancer undergoing chemotherapy. Another study29 addressed the influence of physiological variables (also within the person domain) by evaluating plasma levels of inflammatory cytokines in relation to incidence and timing of musculoskeletal pain in breast cancer patients receiving chemotherapy. Increases in interleukin 10 correlated strongly and positively with joint pain (P = .003) in those who received weekly paclitaxel. In the 3-weekly paclitaxel group, interleukin 8 correlated positively with “flulike” symptoms (P = .008).29 This same study29 was also the only study to assess risk factors relating to TIMP by addressing correlations among paclitaxel, the release of inflammatory cytokines, and musculoskeletal symptoms, and their findings suggested that inflammatory cytokine release induced by paclitaxel may be a risk factor for musculoskeletal symptoms in breast cancer patients who are undergoing treatment with taxane-based chemotherapy.
Status Outcomes of Taxane-Induced Musculoskeletal Pain (Aim 4)
No studies addressed all of the outcomes of TIMP specified in our model. Most studies did not address health-related quality-of-life outcomes at all, and only 8% (n = 1) of studies partially addressed these outcomes.21 This study,21 which partially addressed health-related quality-of-life outcomes, was a qualitative evaluation of symptoms experienced by women undergoing chemotherapy, and descriptions of how treatment-related symptoms, including bone pain while on paclitaxel, affected quality of life emerged as a major theme and were discussed. This same study21 was also the only study to partially address functional status (8%) and emotional status (8%). Additional treatment for TIMP was addressed in 17% (n = 2) of the studies, including intravenous analgesics23 and nonsteroidal analgesics.24 Nonsteroidal analgesics were reported to be effective in managing complaints of TIMP24; efficacy of intravenous analgesics was not reported.23 Discontinuation of treatment or dose adjustment was a reported consequence in only 17% (n = 2) of studies.23,25 Discontinuation of treatment was reported in 1 study,23 for 1 participant receiving paclitaxel, secondary to severe arthralgia and myalgia, and another study25 found that dose reduction was required for 1 participant with complaints of severe myalgia from nanoparticle, albumin-bound paclitaxel.
Our review of the very limited research on TIMP had 4 major findings. First, research to date has involved inconsistent use of terms signifying TIMP, and this lack of conceptual clarity has been impeding our understanding of true estimates of prevalence of this cancer treatment–related symptom. Second, assessment of TIMP has largely been limited to symptom intensity. Third, most research to date has not examined contextual variables influencing TIMP, and fourth, most research to date has not evaluated the impact of TIMP on outcomes. Each of these findings is discussed in the following paragraphs.
First, research to date has been inconsistent in its use of terms to signify TIMP. Conceptual clarity is necessary to move forward with cancer symptom management research regarding the assessment of TIMP; for a concept such as TIMP to be solid and strong, it must clearly name that to which it refers (there must not be an excess of terms referring to TIMP), it must be clearly defined, and its use in theory should be clear so that anyone can understand exactly what is being described, explained, or predicted.31 In most current research, arthralgia and myalgia may be listed separately or alone, or these terms may even be grouped with a common neurotoxicity known as chemotherapy-induced peripheral neuropathy.4 Chemotherapy-induced peripheral neuropathy may appear to be similar to arthralgia and myalgia in that it is pain caused by many of the same chemotherapy agents; however, chemotherapy-induced peripheral neuropathy includes sensory nerve involvement with unusual or increased reaction to stimuli or a loss of sensation (paresthesias and pain).32 Furthermore, these symptoms commonly occur in the fingers and toes, thus presenting with a characteristic “glove and stocking” distribution.33 Inconsistent use of TIMP terms and a lack of research defining and differentiating TIMP from chemotherapy-induced peripheral neuropathy perpetuate a lack of conceptual clarity surrounding TIMP and have, in some cases, precluded notions regarding the relevancy of nonneuropathic pain components (TIMP) associated with chemotherapy. In turn, this negatively impacts healthcare providers’ ability to assess and manage TIMP effectively in clinical practice. These assertions are supported by a recent exploratory study34 evaluating symptom patterns indicative of neuropathic or musculoskeletal pain, or both, in cancer patients; 1 major finding was that, although chemotherapy-induced neuropathy-associated pain is usually regarded as neuropathic, movement-associated pain in approximately 60% of patients points to a musculoskeletal pain component as evidenced by a subgroup of patients with different clinical, somatosensory, and psychological parameters. Furthermore, 1 characteristic of musculoskeletal pain is its association with weight bearing or physical exercise, which is different from persisting pain occurring at rest or at night that alleviates while walking and is characteristic of neuropathic pain.34 Interestingly, anxiety was higher in patients with musculoskeletal pain components that could be explained by anxiety as a known risk factor for musculoskeletal pain where activation of the sympathetic nervous system releases stress hormones leading to impairment of muscle functioning essential for control of movements and posture.34,35 Therefore, one can infer that true estimates of prevalence cannot be determined without conceptual clarity of TIMP and the recognition of TIMP as separate and distinct from other types of treatment-related pain, as has been suggested by recent literature.
Second, most research has involved a limited evaluation of TIMP. Assessment of TIMP in our review was largely limited to symptom intensity. Indeed, this finding supports literature suggesting that most models of symptoms focus on 1 symptom and, specifically, on the intensity of the symptom and not on its other features, such as distress, timing, quality, or concurrence.17 Theoretical models such as the Theory of Symptom Management and the Theory of Unpleasant Symptoms, which helped to define our conceptual framework for this review, demonstrate the importance of fully evaluating all dimensions of the symptom experience in order to comprehensively understand a symptom and to inform the development of efficacious interventions. No studies comprehensively assessed TIMP using the common symptom assessment parameters of distress, timing, quality, and concurrence even though pain literature suggests healthcare providers evaluating pain for the first time should start with multidimensional instruments to obtain an overview of the symptom.36 Once core areas of the pain have been identified, then more specific, streamlined assessments (ie, intensity and interference with functional status only) can be used. Finally, it is important to note that addressing the dimension of symptom concurrence (both commonly co-occurring symptoms and the concept of cancer treatment–related symptom clusters) is a current research priority.15,37–40 Therefore, more thorough reporting of all symptom experience dimensions of TIMP is critical.
Finally, studies did not examine contextual variables influencing TIMP or address the impact of TIMP on selected outcomes. Person, environment, health, and illness variables serve as a reminder of the contextual considerations potentially capable of influencing symptoms.14 Therefore, these contextual variables must be evaluated in research on TIMP. To illustrate, a woman’s experience of TIMP may vary according to her age, reproductive status, and genetic risk factors (person domain); cultural beliefs about the meaning of her symptom or whether she is evaluated in a clinic or her home (environmental domain); and her current state of health or diagnosis (health and illness domains).14 Similarly, outcomes (both positive and negative) must also be assessed in evaluations of TIMP. Even when a disease is treated and/or controlled (survivorship), symptoms can remain a continued concern.13 Research suggests that symptoms may be associated with work impairments, resulting in a loss of work days or increased worker compensation.13,16 Overall, the lack of research addressing both contextual variables and outcomes relative to TIMP limits the ability of scientists and clinicians to understand the full impact of TIMP in cancer survivors undergoing taxane-based chemotherapy treatment.
Strengths and Limitations
To the best of our knowledge, this is the first comprehensive review to synthesize the literature on TIMP. However, there were limitations to our review. First, only the PubMed database was searched for relevant studies, and it is possible that some articles were missed. PubMed provides access to bibliographic information including more than 24 million citations and MEDLINE.41 The PubMed database was selected because biomedical topics and the sciences are the primary foci of articles contained in this database, and these content areas directly related to the topic for this systematic review. Thus, it was reasonable to believe our search strategy effectively captured most, if not all, of the evidence regarding TIMP, and any additional articles that may have been acquired from searching a database other than PubMed, such as CINAHL would not significantly alter the overall conclusions of our review. However, a larger review including multiple databases is likely needed to ascertain the full extent of this literature.
Second, most studies were conducted in the United States19,21,25,28,29 or Europe,20,22,24,27,30 which limits the generalizability of our findings. International studies were retrieved from the search strategy previously described and were considered for inclusion in our review. Of note, these studies were eliminated on the basis of the prespecified exclusion criteria; the inclusion of growth factor in treatment regimens was the primary indication for exclusion of these studies. Third, the population for most studies was predominately female as breast cancer was the most commonly evaluated cancer type,20–22,25,29 and ovarian cancer was the second most commonly evaluated cancer type.23,26,30 Because paclitaxel is predominately administered in populations of breast, ovarian, and non–small cell lung cancer, it was not surprising sample populations were mostly female. Therefore, gender may prove an important demographic variable in evaluating TIMP.
Finally, 2 studies21,25 included in our review used the term bone pain in their assessment of treatment-related symptoms. Because these studies also included the terms myalgia and joint pain (terms highly consistent with the definition of musculoskeletal pain), they were included in our review. It is possible that the assessments from these studies may have additionally included measurement of a different symptom (ie, bone pain). However, this limitation does not significantly detract from the important findings of our review regarding the limited nature of research on TIMP. In particular, research to date has involved inconsistent use of terms signifying TIMP, which has impeded our understanding of true estimates of prevalence; assessment of TIMP has largely been limited to symptom intensity; most research to date has not examined contextual variables influencing TIMP; and most research to date has not evaluated the impact of TIMP on outcomes.
Taxane-induced musculoskeletal pain is a treatment-related symptom that oncology healthcare providers need to address in order to improve health-related quality of life in cancer survivors undergoing taxane-based chemotherapy. In research on TIMP, there has been little consistency in terms, and measurement has largely been limited to toxicity grading scales. Overall, little is known about TIMP. Future research should focus on comprehensive descriptions of TIMP, including evaluation of all dimensions of the symptom experience as well as the contextual variables influencing TIMP and the impact of TIMP on outcomes in cancer survivors. Consideration should be given to type of taxane agent (preferably with an emphasis on paclitaxel because it is the most commonly prescribed), as well as to the type of cancer to be evaluated. Sample populations with minimal confounding influences on the experience of musculoskeletal pain should be evaluated, at first, in order to capture the richest and clearest picture of TIMP possible. It is only with information gleaned from this type of foundational and multidimensional research that new strategies for better management of TIMP can be developed, our understanding of the mechanisms underlying TIMP can be improved, and the role that TIMP likely assumes in the cancer treatment–related symptom clusters (both known and unknown) that are experienced by cancer survivors undergoing taxane-based chemotherapy can be clearly elucidated.
Implications for Practice
Recognition of patient-reported outcomes, supported by the National Institutes of Health, is of growing research interest and requires attention to health-related quality-of-life outcomes in populations including cancer survivors.11,42 Cancer and cancer treatment–related symptoms can profoundly affect an individual’s health-related quality of life throughout their survivorship trajectory.10 In order to improve patient-reported outcomes in cancer care, control of treatment-related symptoms is essential. Further research about TIMP will address national priorities for generating new knowledge to advance symptom science. Importantly, these national priorities include the National Cancer Institute’s Office of Cancer Survivorship mission to enhance the quality of survival and minimize the physical and psychosocial adverse effects of cancer and its treatment that are experienced during survivorship in persons with cancer43 and the National Institute of Nursing Research Strategic Plan priority of Advancing Quality of Life through symptom management.44 Comprehensive assessment of and research about TIMP will address several national priorities for generating new knowledge to advance symptom science and will be directly relevant to the care of cancer survivors undergoing taxane-based chemotherapy. Oncology nurses must contribute to national initiatives to improve patient-reported outcomes by addressing the symptom management needs and health-related quality-of-life outcomes of cancer survivors.
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