A diverse range of PRO measures has been used to assess pain and its impact among patients with bone metastases, with little consistency in measurement approach across studies. Based on this review, there appears to be no consensus on a strategy for assessing pain in patients with bone metastases. Furthermore, presentation of measures in the published articles often lacked clear description, information on measurement properties, citations, or a consistent approach to naming the instruments and method of administration. Given this lack of measurement consistency and clarity, it is difficult to directly compare findings across studies in order to understand the relative potential for pain relief offered by the various bisphosphonates and other treatments. Comparisons across studies using different outcome measures would require calculating effect sizes for each measure [67
], an approach which is based on the assumption that different measures are truly assessing the same construct. The lack of measurement consistency across clinical trials is similar to the inconsistent methods clinicians use to assess pain in clinical settings, as reported by patients in a recent large international survey [68
The results of this review raise questions regarding instrument development and validation. It is frequently recommended that PRO instruments be psychometrically evaluated in the population under investigation [69
]. However, none of the pain measures reviewed for this study (Table ) were developed specifically for patients with bone metastases, and none of the articles mentioned instrument validation conducted within this population. Similarly, none of the HRQL/function measures (Table ) are specifically targeted towards this population. As a result, it is not possible to know whether these instruments are capturing the aspects of pain and its impact that are most relevant and important to patients with bone metastases. Furthermore, the measurement approaches in these studies frequently do not meet the standards for PRO development and validation set forth in the FDA guidance document [15
A first step toward improving measurement of pain in patients with bone metastases would be to establish the content validity of frequently used instruments from the patient's perspective [71
]. This process would require qualitative interviews in which patients are asked about the relevance of the items to their condition, as well as the clarity and comprehensiveness of each item. These interviews could help determine whether single items, which are commonly used, are sufficient for capturing pain among these patients. Although there is support for reliability and validity of single-item pain intensity measures, pain is known to have qualities beyond the single dimension of intensity, with descriptors such as tingly, deep, sharp, or dull [31
]. Consequently, a thorough assessment of pain associated with bone metastases may require a multidimensional instrument assessing the range, types, frequency, duration, location, and impact of bone pain. It is possible that the pattern of a patient's ratings across all of these dimensions could influence treatment decisions.
Several PRO instruments have recently been developed specifically for use in patients with bone metastases. For example, a bone metastases module has been drafted to supplement the European Organization for Research and Treatment of Cancer (EORTC) Core Questionnaire [6
]. This new module includes 22 items assessing symptoms, functional interference, and psychosocial domains. Furthermore, the FACIT system now has a questionnaire called the Functional Assessment of Cancer Therapy-Bone Pain (FACT-BP), which was recently developed to assess bone pain and its effects on quality of life. In an initial validation study, this 16-item questionnaire demonstrated good internal consistency reliability, construct validity, and sensitivity to change [74
]. A related questionnaire designed to assess treatment satisfaction and convenience in this population was also examined in this validation study. None of these new condition-specific measures were used in clinical trials of bisphosphonates meeting criteria for inclusion in the current review. However, the FACT-BP is being used in clinical trials, and results will likely be published in the future. If these condition-specific measures are widely adopted, they may substantially improve outcomes assessment in future trials of treatments for bone metastases.
Even as new condition-specific measures are developed and implemented, it is likely that previously existing PRO measures of pain will continue to be used in many trials of treatments for bone metastases. There are four steps authors can take when drafting manuscripts to enhance clarity. First, we recommend explicitly stating when a measure is patient-reported rather than clinician-reported. Second, clear and accurate terminology should be used to identify and describe concepts. For example, there is a difference between the terms “PRO measure” and “quality of life (QOL) measure.” PRO implies that the measure is completed directly by patients, whereas QOL refers to the content of a measure, indicating that it was designed to capture quality of life. Despite this distinction, the literature in this field includes examples of researchers erroneously referring to any PRO measure as a QOL measure, even if the measure does not assess QOL [75
]. Third, all PRO measures should be clearly named and/or described so that readers can understand exactly how pain was assessed in each study. For example, VAS and NRS measures should be clearly described, and when measures have multiple versions, the version number should be specified. Fourth, validated PRO measures should be implemented according to instructions from instrument developers, and any deviations from the instrument's intended use and scoring approach should be specified. We also recommend avoiding the use of unusual item subsets or the creation of new composite scores derived from multiple measures. These idiosyncratic approaches are not validated, and they are difficult to interpret. Together, these four steps will enhance clarity and consistency of results, while facilitating interpretation of findings and comparisons across studies.
Several limitations of the current review should be acknowledged. First, this review focused only on studies of bisphosphonate treatment because this is the most commonly administered pharmaceutical treatment for patients with bone metastases. Therefore, we cannot comment on PRO measures used to assess pain related to other treatments such as radiotherapy. Second, the literature search conducted for this review only located articles that mentioned “pain” in the abstract or title. There may be published trials of bisphosphonates that included measures of pain, but did not explicitly mention pain in the title or abstract. Such articles are not included in the current review. Third, this review did not include a thorough search for the complete psychometric validation history of each instrument. It is possible that some of these measures could have been validated in the target population, although this was never mentioned in any of the articles included in this review. Fourth, this review focused on identifying and describing measures, rather than reporting the results of each study. Therefore, we cannot comment on which measures were most likely to reflect change in patients' conditions.
Findings of the current review suggest that pain is often a key outcome of trials examining treatment for bone metastases. However, results also highlight the measurement challenges for the field as new treatments are introduced and evaluated. Future research is needed to develop instruments specifically for assessing pain in patients with bone metastases, while validating previously existing measures for use in this population. In recent years, the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) has led to some consensus among leading researchers on the optimal measurement strategies for assessing chronic pain in clinical trials [29
]. These efforts have provided a multidisciplinary expert consensus on recommended measures and interpretation of PRO results. The inconsistencies revealed by the current review suggest that a similar effort focusing on assessment of pain associated with bone metastases would be a helpful first step toward improving the evaluation of treatments for these patients. With improved assessment tools, it may be possible to identify treatments targeting specific types of pain experienced by patients with bone metastases.