Patient-reported outcome instruments used to assess pain and functioning in studies of bisphosphonate treatment for bone metastases

A total of 49 studies were located that included patient-reported measures of pain to assess outcomes of bisphosphonate treatment for bone metastases. Sample sizes of the individual studies (excluding secondary and pooled analyses) ranged from 10 to 1,648 patients. The most common treatment under investigation was zoledronic acid, which was examined in 22 of the studies. Other bisphosphonate treatments included clodronate (6 studies), etidronate (1 study), ibandronate (8 studies), and pamidronate (15 studies). Three of the pamidronate studies included another bisphosphonate as a treatment comparator. Trial designs varied across the studies reviewed, with designs ranging from open-label, single-center studies to randomized, double-blind, multi-center controlled trials.

All 49 studies are listed in Table 1, grouped according to 12 categories of pain measures. The first four measures are multi-item scales: (1) the Brief Pain Inventory (BPI), (2) Wisconsin Brief Pain Questionnaire (BPQ), (3) McGill–Melzack Pain Questionnaire, and (4) a questionnaire from Guy's Hospital Assessment of Response Study. The next four categories of measures are reported by the original authors as “visual analogue scales”: (5) VASs with a specified length, (6) ten-point VASs, (7) five-point VASs, and (8) unspecified VASs. Then, four additional groups of measures are presented: (9) single-item scales that are not labeled by the original authors as VASs, (10) scores derived by multiplying pain severity and pain frequency, (11) composite scores involving combinations of bone pain with other constructs, and (12) a face scale. Table 1 includes descriptions of each measure, quoted from the articles included in the current review.

The BPI was the most common formally developed and named instrument used for assessing pain. This questionnaire was developed by the Pain Research Group of the WHO Collaborating Center for Symptom Evaluation in Cancer Care [32]. The original development article states that “depending on the patient, it can be self-administered or used in a clinical interview, [and] the form of administration has little effect on the outcome.” The BPI was adapted from the Wisconsin Brief Pain Questionnaire for use with cancer patients to assess intensity and interference of pain. Both short and long form versions of the BPI include questions about pain location, severity, relief, and interference. The four pain severity items ask patients to rate their worst, least, average, and current pain (i.e., “pain right now”) over the past week (in the long form of the BPI) or 24 h (in the short form) using a 0–10 NRS (0 = no pain or 10 = pain as bad as you can imagine). The seven pain interference items ask the patients to rate the degree to which pain limits their functions using a 0–10 NRS (0 = no interference or 10 = interferes completely). A total of 13 studies used part or all of the BPI, including 11 studies using an English version and two studies using the Greek version. Among the 11 English studies, there was variation in the items that were used. For example, some studies focused on a composite of the four pain scores (worst, least, average, and current pain), while other studies appear to have used a smaller subset of these items, but this information was not always presented clearly. Seven of the studies using the BPI did not specify that the instrument was completed by patients, and some studies erroneously described the response options as “1 to 10” or “ten-point scale” [33, 34], when there are actually 11 response options ranging from 0 to 10. In addition, one of the studies appears to have used the worst pain item as a single-item NRS measure [33]. Furthermore, it is likely that most or all of these studies were using items from the most recent version of the BPI, which the instrument developer calls the short form [35]. However, few of the studies specified which version of the instrument was used.

Three additional multi-item scales were each used in only one study. The Wisconsin Brief Pain Questionnaire was administered in a study by Berenson et al. [36], although minimal details were provided regarding the characteristics or administration of the instrument. This measure was designed to be a self-administered assessment of pain associated with cancer and other diseases [37]. It assesses constructs similar to those subsequently included on the BPI, as described above. The McGill–Melzack Pain Questionnaire was used in a study by Ernst et al. [38], which administered only the six-point Present Pain Intensity scale of this instrument, ranging from no pain to excruciating pain. The study identified in the current review did not include other items of this instrument, such as those for which patients are instructed to select words that best describe their pain experience [39, 40]. Finally, Berruti et al. [25] administered a brief unnamed questionnaire, but provided minimal description and an incorrect citation as explained in Table 1.

The most common approach for assessing pain intensity, which was used in 24 studies, was to administer a single-item scale such as VAS, NRS, and VRS measures (these three types of single-item measures are defined above in the “Methods” section). Most articles did not explicitly state that these scales were completed by the patient, but it is likely that they were patient-completed in all cases. There was substantial variation in descriptions and citations of these single items. In four studies, the VAS was described in terms of a specific length (e.g., 10 cm or 100 mm), while the most frequently used single-item was a 0–10 NRS. Two studies mentioned that a VAS was used to assess pain, but did not provide any description of the VAS. Less than half of the studies using a single-item provided a citation for the scale, and there was great variation in the citations among the articles that did provide a reference. One of the single-item scales combined two constructs, requiring patients to simultaneously rate pain and analgesic use [27]. In sum, although it was common to use a single-item for pain assessment, there was substantial variation in the type of single-item used, strategy for implementation, citation, and clarity with which the measure was described. Furthermore, no studies mentioned that the single-item measure was validated for use in the target population.

Several studies derived a single pain score from a combination of multiple scores. For example, five studies included a pain score that was computed by multiplying severity and frequency of pain. Three of these five studies cite a pamidronate clinical trial published by Theriault et al. [41] when discussing this approach. However, Theriault and colleagues do not provide a citation or details for the origin of this scoring system. Two additional studies included a pain rating as one component of a composite score that also incorporated analgesic consumption and performance status or overall health [26, 28]. In addition, one study conducted by Viatale et al. [42] computed a pain score by adding scores from a 100-mm VAS for pain to a Trial Outcome Index, which was the “sum of the physical and functional domains of the FACT-G.” In this study, the authors referred to the VAS as the “Huskisson” VAS, but did not provide a citation for this VAS. Huskisson published several articles on the measurement of pain using visual and graphic methods [43‐45]. His publications suggest that VASs “provide the patients with a robust, sensitive, reproducible method of expressing pain severity” [44]. For the current review, we were unable to locate a specific VAS called the “Huskisson VAS.” It is possible that Vitale et al. [42] developed a new VAS according to Huskisson's principles and called it the Huskisson VAS.

Finally, one study used an approach called a “face scale,” which involved assessing patients' bone pain based on choosing a face that most reflected their current mood [46]. This face scale appears to be similar to items from the Functional Health Assessment Charts used in the Dartmouth Primary Care Cooperation Project (COOP Project) [47].

Of the 49 studies using a PRO measure to assess pain, 19 studies included at least one PRO assessing functional status or HRQL. These studies are listed in Table 2, grouped according to the seven measures used: (1) European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30), (2) EORTC Breast Cancer Module (QLQ-BR23), (3) Functional Assessment of Cancer Therapy-General (FACT-G), (4) EuroQol EQ-5D (EQ-5D), (5) Prostate Cancer-Specific Quality of Life Instrument (PROSQOLI), (6) the Edmonton Symptom Assessment System (ESAS), and (7) linear analog scale assessment of quality of life. The EORTC QLQ-C30 and the FACT-G were the most commonly used HRQL and functional status measures, while the other five measures were each used in only a single study. Table 2 includes descriptions of each measure, quoted from the articles included in the current review.

Seven studies administered the EORTC QLQ-C30, which was developed to evaluate the quality of life of patients participating in international oncology trials [48]. The EORTC QLQ-C30 was designed to be relevant to a broad range of cancer patients. It may be administered along with separate questionnaire modules designed for specific cancer types or treatments (although only one study in the current review administered one of these supplemental modules, discussed below). This measure includes 30 items which contribute to five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea and vomiting), a global health scale, and a quality of life scale. In the most recent version (version 3.0), the first 28 items are rated on a four-point Likert scale (1 = not at all or 4 = very much), and the last two items are rated on a seven-point Likert scale (1 = very poor or 7 = excellent) [49]. Among the seven studies administering the EORTC QLQ-C30, there were differences in how the questionnaire was used. Two studies analyzed only the physical functioning domain of this questionnaire, while another study described only the functional scales without indicating whether the other scales were also administered. The study by Mañas et al. [50] does not specify which version of the EORTC QLQ-C30 was used, but describes a series of “yes/no questions,” which is suggestive of version 1.0 before response options were modified to the four-point Likert scales used in subsequent versions. Six of the seven studies did not specify which version was administered, and four of the studies did not mention whether the instrument was completed by patients.

In addition to administering the EORTC QLQ-C30, Wardley et al. [51] assessed quality of life using the Breast Cancer Module (QLQ-BR23). This condition-specific questionnaire was developed by the EORTC Study Group to be used in conjunction with the EORTC QLQ-C30. Developed according to the EORTC guidelines for module development, the QLQ-BR23 focuses on aspects of quality of life specifically related to breast cancer with 23 items assessing treatment modalities, body image, sexuality, and future perspective [52].

Nine studies administered the FACT-G, which was developed by Cella et al. [53] as a quality of life questionnaire for use in patients receiving cancer treatment. This questionnaire is part of the Functional Assessment of Chronic Illness and Therapy measurement system, which is a collection of HRQL questionnaires focusing on chronic illnesses [54]. Version 4 of the FACT-G (the most recent version) contains 27 items, which comprise four subscales (physical, social/family, emotional, and functional). Each item is rated on a five-point Likert scale (0 = not at all or 4 = very much) [53, 55]. Among the nine studies that administered the FACT-G, there was some variation in the way the subscales were used. Two studies indicated that only the functional and physical well-being subscales were analyzed. In one of these studies, Facchini et al. [56] calculated a Trial Outcome Index (TOI) by summing only the functional and physical subscales. This approach to calculating the TOI is not entirely consistent with recommendations from the instrument developers. The developers specified that the TOI can be calculated for use as an endpoint in clinical trials based on these two subscales as well as an “additional concerns” subscale from one of the Functional Assessment of Chronic Illness Therapy (FACIT) disease-, treatment-, or condition-specific scales [55]. In the other study, Mystakidou et al. [34] stated that the functional and physical subscales were used to calculate a “total physical and functional QOL score,” which also appears to be inconsistent with instructions from the instrument developers. Only three of the nine studies specified the version of the FACT-G that was used, and five studies did not specify that this questionnaire was completed by patients.

The large zoledronic acid trial published by Saad et al. [57] was the only study in this review to administer the EQ-5D. The EQ-5D is a generic preference-based health status instrument used in health economic relations. Patients report their functioning in five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression [58, 59]. Responses to these five items are used to derive the EQ-5D index score, which represents overall health. After completing the five dimension items, patients complete the EQ-5D VAS, on which they rate their current health on a scale ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).

Ernst et al. [38] used the nine-item PROSQOLI questionnaire, which was derived by Stockler et al. [60] from a longer version originally developed by Tannock et al. [61]. The original version was designed to assess the effects of systemic treatments in men with advanced hormone-resistant prostate cancer. The Stockler version consists of nine linear analog self-assessment scales assessing pain and quality of life, the six-point Present Pain Intensity (PPI) verbal scale from the McGill Pain Questionnaire, and an analgesic score. These nine linear scales are each 10-cm long, and the score is measured in millimeters with 100 representing best function or quality of life.

The small ibandronate trial published by Mancini et al. [62] was the only study in this review to use an item from the ESAS, which was developed and validated as a self-report symptom intensity measure for patients with cancer [63, 64]. The ESAS originally consisted of eight 100-mm VASs for pain, activity, nausea, depression, anxiety, drowsiness, appetite, and sensation of well-being. A ninth VAS for shortness of breath was subsequently added, and some versions also include an additional blank VAS for a symptom that can be added by the patient. The Mancini et al. [62] study only used the well-being item of the ESAS.

Lastly, one study administered a measure described as a “linear analog scale assessment (LASA) of quality of life” [65]. Linear analog self-assessments, also referred to in the literature as LASAs or linear analog scale assessments, use 100-mm lines with descriptors at each extreme [66]. Patients are asked to mark their current state along the line, and scores are measured in distance (e.g., centimeters or millimeters) to this mark from point 0. Mystakidou et al. [65] do not provide a citation or additional details for this measure.