CIPN is defined as the damage to the peripheral nervous system experienced by patients receiving neurotoxic chemotherapies. The symptoms of CIPN range from burning, stabbing, pricking, tingling, or numbness in the toes and fingers to generalized symptoms that may be immobilizing.[1], [2] and [3] While each chemotherapy agent has its own mechanism of action, CIPN generally affects the fingers and toes first; and with cumulative doses, symptoms progress proximally to the hands and feet, arms and ankles, and then calves (stocking-glove distribution).[3] and [4] Sensory symptoms and signs typically develop before motor symptoms, and a subset of patients also suffer from neuropathic pain. CIPN occurrence estimates have ranged from 10% to 92% and vary depending on the chemotherapy regimen, dosing, and comorbidity. Patients with preexisting peripheral neuropathy are more likely to develop a severe and persistent CIPN compared to those without any history of neuropathy.5
Although several agents show promise in preventing CIPN, the evidence of the efficacy of these options is mixed, and treatment of CIPN is still largely symptomatic. Corticosteroids, antidepressants, anticonvulsants, and analgesics are potential options available to clinicians, although none has shown significant efficacy in treating CIPN symptoms. As a result, in the event of significant neuropathy, dose reduction or discontinuing chemotherapy is the only option to stop and reverse progression of peripheral neuropathy; and such steps potentially could impact overall cancer treatment outcomes.[6], [7] and [8] Alternatively, patients may choose to continue chemotherapy with compromised HRQL; specific reductions in HRQL scores due to CIPN symptoms have been estimated to be from 15% to 20%.9
A key issue for clinicians is understanding the extent of functional impairment a given patient may have when experiencing CIPN. Although physicians often are able to diagnose severe symptoms more accurately relative to less severe CIPN symptoms, Postma and colleagues10 and other researchers have shown that there is substantial discrepancy in severity grading among physicians as well as between patients and physicians, with physicians often underestimating the severity of symptoms. Contributing to this problem is the lack of consistency in diagnostic tools used, with no gold standard for CIPN measurement. This review therefore examines the symptoms and impacts of CIPN from the patient perspective, identifies concepts and issues that should be considered when evaluating CIPN, and compares existing patient-reported outcomes (PRO) measures that have been used in CIPN assessment.
Methods
The review of the literature, performed in January 2009, focused on abstracts or articles that assessed the HRQL of CIPN over the past 5 years. The review included six article databases (OVID, which includes Medline and Embase; Proquest digital dissertations; CINHAL; IPA; Health and psychological instruments; Psycharticles) and five conference proceedings (ASCO, AACR, NCRI, San Antonio Breast Cancer Symposium, Annual Symposia of the American Society of Breast Disease). The comprehensive search combined the clinical terms “peripheral neuropathy,” “neurotoxicity,” “paresthesias,” “dysesthesias,” etc. with the term “chemotherapy” and with specific chemotherapy drugs (eg, cisplatin, paclitaxel, vincristine). These terms were further combined with quality of life (eg, preference, quality of life, patient perspective, daily activities). Only those studies focusing on neuropathy related to chemotherapy were included in this review; studies of diabetes, acquired immunodeficiency syndrome (AIDS), B12 deficiency, or arthritis-related neuropathy were excluded.
A total of 5,671 studies across the article databases and 355 conference abstracts underwent initial review. After removing duplicates, commentaries, review articles, and articles discussing neuropathy associated with diabetes, human immunodeficiency virus (HIV), and rheumatoid arthritis, 41 potentially relevant abstracts were identified, and full-text article paper copies were obtained for these studies. The final review then identified 31 articles and 10 relevant conference abstracts to be incorporated.
Results
The findings from this review are discussed in three sections: (1) qualitative studies, (2) patient preference studies, and (3) PRO measures used to assess CIPN outcomes.
Qualitative Studies
Four qualitative studies were identified in which CIPN was discussed.[11], [12], [13] and [14] Bakitas11 evaluated CIPN experience among patients of all cancer types, while the other three studies examined the effects of a range of chemotherapy side effects in disease-specific populations, including breast cancer12 and colorectal cancer.[13] and [14]
In summary, the qualitative studies showed that CIPN can lead to a range of physical and emotional impacts. Patients with CIPN indicated that they experienced tingling, burning, numbness, “pins and needles,” and shock-like or painful sensations bilaterally in the feet and/or hands. Patients indicated that of all chemotherapy-related adverse events, CIPN was one of the least expected and most distressing and disabling.[11], [12] and [14] Upper-extremity neuropathy interfered with dressing, cooking, sewing, household work, and leisure. Problems with dressing included difficulty putting on undergarments or jewelry. Neuropathy in the lower extremities caused problems with walking (“I walk like I'm drunk,” “I feel clumsy”) and was accompanied by problems with balance, ambulation (hiking, running, biking, and standing for long periods), and driving.[11] and [12] Among breast cancer patients on paclitaxel, peripheral neuropathy was considered to be more incapacitating than bone pain because it affected daily functioning, whereas bone pain generally did not.12
The symptoms of CIPN not only resulted in physical distress and loss of functional ability but also affected emotional health and social interactions. Patients expressed that they were often ill-prepared to cope with CIPN symptoms. The functional impairments (ie, inability to pursue daily activities) affected patients' mood and often made patients feel dependent, disabled, and helpless. Subjects reported social isolation when they could not drive, walk, or stand for periods of time.11
Patients also expressed difficulty in describing symptoms, which were often described as “funny,” “strange,” or “weird.” Without the ability to communicate symptoms to their doctors, some patients expressed a feeling of frustration that their doctors did not take their symptoms seriously.11 Patients also felt disappointment about their lack of understanding of the significance of some CIPN-related symptoms over others and the prolonged duration for symptom resolution.[12], [13] and [14]
Nevertheless, patients generally could keep CIPN “in the background,” although it could be “annoying,” “distracting,” and “unpleasant.”11 Despite the many disruptions associated with CIPN, patients expressed reluctance in discontinuing chemotherapy and generally adapted and “learned to live with” their CIPN.[11], [12] and [14] As observed by Calhoun and colleagues,15 who conducted a patient preference study of chemotherapy toxicity states, patients appear to be willing to tolerate more toxicity in expectation of better chemotherapy outcomes.
Patient Preference Studies
Four patient preference studies echoed sentiments expressed in the qualitative studies regarding apprehension about chemotherapy-induced neurotoxicities. In general, the patient preference studies reported that peripheral neuropathy was viewed as worse than a number of other chemotherapy-induced toxicities. In a study in which ovarian cancer patients rated selected toxicities on a visual analog scale where 0.0 reflected the worst chemotherapy scenario and 1.0 reflected an ideal chemotherapy scenario, “peripheral neuropathy” was rated as 0.45 and was considered worse than alopecia, pancytopenia, and fatigue.16
Another study that included ovarian cancer patients used the time trade-off technique to assess preferences for different health states representing five different levels of severity each for neurotoxicity, nephrotoxicity, and ototoxicity. Whereas the two more mild levels of these toxicities were rated similarly, the patients consistently rated the three moderate to severe levels for neurotoxicity as worse than those for nephrotoxicity and ototoxicity. Patients with previous toxicity experience rated all toxicity scenarios worse than those without any previous experience.15
Similarly, Dranitsaris17 elicited rankings from the Canadian general population with respect to the importance of reducing the chance of febrile neutropenia, neurotoxicity, and renal toxicity. The general population felt that it was more important to reduce the chance of neurotoxicity versus renal toxicity. In a more recent study, Dranitsaris and colleagues18 assessed the perspectives of oncology pharmacists and nurses who served as proxies for patients regarding grade 2/3 motor neuropathy, grade 2/3 sensory neuropathy, grade 3/4 neutropenia, and grade 3/4 anemia. Of these four toxicities, the clinicians rated motor neuropathy and sensory neuropathy the most unpleasant. The clinicians preferred docetaxel in place of paclitaxel, the former being associated with smaller chances of sensory neuropathy and motor neuropathy but not neutropenia or anemia. Based on qualitative feedback, the respondents explained that they had long-term concerns about neuropathy because it could not be effectively managed but that neutropenia and anemia were short-term, treatable events.18
PRO Measures for CIPN Evaluation
Generic PRO measures focus broadly on functional status and can also be used to compare physical and mental health functioning across patient populations. However, they may not be sensitive enough to capture impacts of specific health conditions. This lack of sensitivity to disease-specific impacts has been observed in a number of oncology studies with respect to the occurrence of CIPN. Specifically, the generic measures the European Organization for Research and Treatment in Cancer—Quality of Life Questionnaire (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy (FACT)—General typically do not detect differences between treatment groups, although the incidence and severity of neurotoxicity may differ significantly as measured using National Cancer Institute Common Toxicity Criteria (NCI-CTC) or other criteria.[6], [19], [20] and [21] The lack of sensitivity of generic measures to treatment group differences in CIPN impacts likely is attributable to insufficient numbers experiencing neurotoxicity-related impediments to daily functioning and/or to the imprecision of these measures.[19] and [20]
However, CIPN-specific measures or items do show sensitivity to treatment differences in CIPN occurrence and impacts. Seven PRO measures have been used to specifically assess CIPN outcomes (Table 1).
With the exception of the SCIN, the measures also include questions inquiring about activity limitations, such as instability when walking or difficulty buttoning buttons. However, whereas the FACT neurotoxicity scales and modified PNS include two to three questions on activity limitations, the CIPN-20 and CIPNS-32 include at least 10 of these items, such as difficulty opening a jar, holding a pen, climbing stairs, standing for long periods, and washing. The PNQ includes an activity limitations checklist which the respondent completes if he or she records a “moderate to severe” (grade D) or “severe” (grade E) response option (“none” [grade A], “mild” [grade B], and “moderate” [grade C] responses indicate no interference with daily activities).[2] and [23] With respect to emotional impacts, the CIPNS-32 inquires about the bothersomeness of the symptoms and the Assessment of Peripheral Neuropathy (APN) assesses only how bothersome symptoms have been during the past week. However, there are few data available on the measurement properties of the CIPNS-32 and the APN.[24] and [25]There is some indication that the impact of CIPN is multidimensional. For example, in an analysis of PNS data, a principal component factor analysis yielded a two-factor solution comprising “hand neuropathy” and “foot neuropathy.”26 In a psychometric analysis of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group—Neurotoxicity (FACT/GOG-Ntx) scale, Huang and colleagues27 divided the items into four subscales: sensory, motor, hearing, and dysfunction. The four items of the Ntx scale related to sensory neuropathy contributed the most to CIPN-related treatment differences. Nevertheless, most of the measures simply combine all items into an overall score, even those that comprise both symptom and activity limitation items.
The PRO measures vary with respect to development status. Except for the PNQ, the content of all the measures was informed in some way by patient input (this information is unknown for the CIPNS-32 and APN). However, patient assessment of content validity through cognitive debriefing interviews has only been reported for the PNS and CIPN20. When assessed for the measures, internal consistency reliability (Cronbach's alpha) is greater than 0.70, which is acceptable for making group comparisons. None of the measures reports test–retest reliability estimates.22
The CIPN20 is being developed following the steps recommended in the Food and Drug Administration (FDA) PRO Guidance, and it currently is being field-tested in a large, randomized clinical trial.[1] and [28] The FDA PRO Guidance recommends conducting one-on-one interviews and/or focus groups with patients for item generation, performing cognitive interviews to obtain feedback on the measure from patients, and performing a psychometric validation study when developing a new instrument. A personal communication with the authors of the CIPNS-32 revealed that no additional information on psychometric properties was available. The PNQ has been used to assess the impact of chemotherapy among adjuvant breast cancer patients.29 In this study, the PNQ appeared to detect more severe grades of sensory neuropathy compared to the NCI-CTC.29
Among the neurotoxicity measures, the FACT neurotoxicity scales have been most widely used in randomized controlled trials. The scales evaluate the impact of treatment on CIPN as an outcome on three specific areas of functioning—sensory, motor, and auditory—and have frequently demonstrated sensitivity to treatment effects.[7], [30], [31], [32], [33] and [34] For example, Land and colleagues34 used the FACT/GOG-Ntx-12 scale in colon cancer patients treated with fluorouracil, leucovorin, fluorouracil + oxaliplatin (OF) or leucovorin + oxaliplatin (OL). The mean scores for patient-reported neurotoxicity on the FACT-Ntx scale were significantly worse in the oxaliplatin arm throughout the 18-month period of the study (P < 0.001). Time to neuropathy resolution was significantly longer in the oxaliplatin group and continued beyond 2 years in more than 10% of patients.34
Moreover, neurotoxicity-specific measures like the FACT Ntx scales have been shown to be more sensitive than laboratory- and physician-based measures in detecting CIPN.[3], [10] and [35] For example, in a study of amisfostine for treatment of CIPN, the FACT/GOG-Ntx scale was more sensitive than the vibration perception threshold and NCI-CTC in detecting CIPN.35 In another randomized controlled trial comparing whole abdominal irradiation and doxorubicin–cisplatin in advanced endometrial cancer, the APN was found to be more sensitive than the FACT-G in detecting changes related to CIPN.24
Customized items to assess CIPN have also shown sensitivity to treatment effects and the ability to capture the occurrence of CIPN over the long term. For example, Bezjak et al.36 used one CIPN-specific item about “sensation in fingers or toes” in addition to the EORTC QLQ-30 to evaluate the quality-of-life impact of a cisplatin-based regimen among ovarian cancer patients. The study found significant treatment group differences in the CIPN item at every follow-up, although differences in the global or physical, emotional, social, and role function domains of the EORTC-QLQ-30 were not significant. In addition, the brief SCIN was found to be particularly useful for capturing lingering long-term toxicities of cisplatin and bleomycin among testicular cancer patients.[37] and [38]
Discussion
The impact of CIPN is unanticipated by patients and underestimated by clinicians. CIPN symptoms often linger well after termination of treatment, sometimes leading to prolonged functional impairments and suboptimal quality of life. Key physical impacts of CIPN include symptoms such as tingling, numbness, and pain in the hands and feet and activity limitations such as difficulties with walking, cooking, dressing, bathing, hobbies, and driving. Patients, often reluctant to discontinue chemotherapy, live with CIPN symptoms and express helplessness, anxiety, and frustration for not being able to manage CIPN-related disabilities and disappointment that clinicians often fail to appreciate its impact on everyday life. The disconnect between physicians' and patients' perceptions of CIPN was noted in several studies and is attributable, in part, to the lack of comprehensive and easily interpretable tools to measure CIPN.
Currently, there is no single comprehensive PRO scale to evaluate CIPN symptoms, severity, functional impairment, and psychosocial impacts, although several neurotoxicity PRO scales have demonstrated acceptable validity, internal consistency, and construct validity. Therefore, additional content validity assessment may be necessary if these measures are to be used to obtain labeling claims in the United States.
Of the neurotoxicity PRO scales, the FACT/GOG-Ntx scales have been used most often in randomized clinical trials and have demonstrated acceptable reliability, validity, and responsiveness.[32], [33] and [38] The Ntx scales were developed as modules for administration with their core measure, FACT-G. The EORTC-QLQ CIPN20 is under development and, given that it specifically focuses on peripheral neuropathy, may be more sensitive in measuring CIPN-related functional impairment compared to FACT scales.
A scale capturing emotional distress would be a useful addition to several of the existing CIPN measures, enabling a thorough evaluation of CIPN. Such a scale may be sensitive to treatment group differences in a clinical study. As observed by Bruner et al.,25 the APN, which measures bothersomeness, was more sensitive than the FACT-G in detecting changes in CIPN over time. The CIPNS-32 also inquires about bothersomeness of impacts, but unfortunately development information on this scale is not published.
Ultimately, the selection of an appropriate CIPN PRO measure will depend on the objective of the study and the future uses for the data; for example, if one is interested in assessing only the occurrence of CIPN, only a few items likely are required. If, on the other hand, one is interested in a comprehensive assessment of CIPN impacts, including assessment of functional and emotional impacts, one would need to develop a new measure or use a combination of available PRO scales. Dunlap and Paice39 have suggested that standardized instruments that evaluate peripheral neuropathy in those receiving chemotherapy should be multidimensional, addressing the nature, intensity, and time course of symptoms, as well as their effect on quality of life.
Key domains that likely should be captured within a comprehensive PRO measure of CIPN impacts include hand and foot symptoms, central nervous system symptoms, daily physical functioning/activities, emotional impacts such as frustration and anxiety, and work productivity.
However, to ensure that all important concepts are covered, it would be useful to conduct focus groups or one-on-one interviews with patients experiencing CIPN. Although the qualitative and preference studies report on patient experience of CIPN, additional research among CIPN patients would help us to understand the patient experience fully. Studies that evaluate the relative importance of functional impairments and patient strategies used to cope with these impairments are necessary. Such studies will not only help to identify constructs that are important to patients but can also be used to inform a conceptual model. Similarly, patient preference research that sheds light on the relative preferences of patients with previous experience of CIPN versus those suffering from CIPN for the first time or the disutility associated with CIPN and other side effects would help clinicians to optimize cancer treatment by incorporating the patient's view in clinical decision making.
Conclusion
In the larger context of treating carcinomas, CIPN may seem like a self-limiting and acceptable cost considering the benefits of chemotherapy. However, its impact on patients' HRQL and sometimes on overall treatment outcomes can be significant. The lack of effective pharmacological options makes CIPN symptom management challenging, and teaching patients effective coping skills becomes a large part of CIPN treatment. Often, physicians do not ask patients about neurological symptoms unless patients complain about them, and patients may also have difficulty understanding their own symptoms as attributable to CIPN. It is therefore essential to educate patients and provide them with language to express CIPN symptoms as well as teach coping mechanisms to effectively manage CIPN.
Physician-based measures such as NCI-CTC and laboratory-based measures such as nerve conduction studies often underestimate the severity of CIPN symptoms.[3], [37] and [39] Researchers note that the CIPN incidence and severity data should be collected from patient self-report questionnaires as studies show that physicians underreport the impact of CIPN on patients.[3], [37], [39] and [40] As newer chemotherapies with more neurotoxicities emerge, the evaluation of neuropathy is likely to gain greater importance in patient-reported outcomes.
This review underscores the need to use neurotoxicity-specific PRO measures to detect meaningful differences in CIPN HRQL impact between treatments and to obtain patient self-reports of CIPN symptoms to accurately account for the influence of CIPN on HRQL. Outcomes of CIPN are not measured in a uniform fashion. For consistent measurement of patient-reported outcomes of CIPN, first clinicians and researchers need to recognize that CIPN has a significant impact on patient's HRQL, use comprehensive scales with adequate patient input to evaluate those outcomes, and teach patients effective coping mechanisms
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