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Advances in Treating Metastatic Bone Cancer |
Author's Affiliation: Department of Symptom Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Requests for reprints: Charles S. Cleeland, Department of Symptom Research, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 221, Houston, TX 77030. E-mail: ccleeland{at}mdanderson.org.
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Abstract |
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 Top Abstract What Needs to be...Measuring Pain and Its...Concurrent Symptoms and...Innovative Trends in Pain...Trial Design: Important...Open DiscussionReferences |
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Numerous guidelines for the management of cancer pain have been endorsed by governmental organizations, professional associations, and the WHO. Research studies evaluating the WHO guidelines for cancer pain relief (7, 8) indicate that most patients obtain good pain relief when the WHO protocol for oral analgesic medications is followed (9). Other pain management therapies can provide pain control when oral analgesics are not effective. Especially when pain is caused by bone disease, a wide variety of nonanalgesic therapies are available to mechanistically treat the source of pain. These treatments include radiation therapy, radionuclides, interventional methods of stabilization (such as kyphoplasty and orthopedic intervention), and the use of bisphosphonates for regularization of bone metabolism.
Despite the availability of effective pain treatments, multiple studies document undertreatment of pain in cancer patients (1, 10, 11). A study completed by the Eastern Cooperative Oncology Group surveyed more than 1,300 outpatients with recurrent or metastatic cancer (1). Sixty-seven percent of the patients had pain or were being treated for pain with daily analgesics. Among the patients with pain, 42% were prescribed analgesics that were less potent than those recommended by WHO guidelines or other cancer pain management guidelines. In a more recent study, 60% of patients in a multicenter clinical trial did not receive analgesics of the potency recommended by current guidelines. There was considerable variation among the study sites, with inadequate treatment ranging from 15% to 67% (12).
Pain must be appreciated to be adequately treated, and pain of which the severity is underestimated will not be treated aggressively enough. One of the most important predictors of undertreatment of pain in the Eastern Cooperative Oncology Group study was the discrepancy between patient and physician in their estimates of pain intensity (1). Physicians typically underestimate the level of pain that patients reported on standardized questionnaires, especially when pain is severe. Inadequate pain assessment is a critical barrier to good pain control for patients with cancer. In another Eastern Cooperative Oncology Group survey, physicians completed a survey designed to assess their knowledge and practice of cancer pain management (4). The physicians ranked a list of potential barriers to pain management to indicate those that hindered pain treatment in their practice settings. The most frequently identified barrier was inadequate pain assessment: 76% of the physicians rated poor assessment as one of the top four barriers to good pain management. Patient reluctance to report pain, closely related to inadequate assessment, was the next most frequently cited barrier. A more recent survey of physicians in the Radiation Therapy Oncology Group found that poor pain assessment and patient reluctance to report pain continue to be identified as top barriers to optimal pain management (13). A first step toward reducing inadequate pain control in clinical practice is adequate assessment of cancer pain using validated pain measurement instruments.
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What Needs to be Assessed in Pain Clinical Trials |
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TopAbstractWhat Needs to be...Measuring Pain and Its...Concurrent Symptoms and...Innovative Trends in Pain...Trial Design: Important...Open DiscussionReferences |
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The need for common assessment approaches is well illustrated by the need to make comparisons among the multiple methods that can be used to treat bone pain. The ideal treatment for bone pain would provide good pain relief, be free of treatment-related adverse effects, reduce pain-related interference with activities and other pain-related symptoms (impaired mood, disturbed sleep, increased fatigue), act quickly (especially important for patients with a short life span), have a durable effect, reduce the need for opioid analgesics (because of the adverse effects of these drugs), and be reasonably priced. Finally, the patient's satisfaction with the treatment is an important consideration.
Of course, no treatment methods currently available can satisfy all these criteria. However, these criteria outline what types of information might be expected from a clinical trial (or more probably a set of clinical trials) of a treatment for bone pain, and the remainder of this article will discuss how self-report measures of pain and other symptoms, symptom interference with patient function, and related adverse effects can be combined with appropriate trial design to provide this type of information.
A trial with pain reduction as an outcome has several recognized obstacles to overcome. First, the severity of pain and the degree of pain relief can only be obtained by subjective report obtained from the patient, as opposed to more "objective" findings such as reduction of skeletal events (a common end point in bisphosphonate trials). Even so, patient self-report has often been discounted as too variable and too affected by personality factors to be used as an outcome measure. Second, pain can be affected by many other factors besides the treatment under examination. A patient with bone metastases, for example, is liable to have pain from preexisting comorbidities (e.g., arthritis) or other aspects of their cancer or treatment (e.g., therapy-related neuropathic pain). Pain may also arise from destruction or distortion of soft tissue in areas adjacent to the bone lesion. It is often impossible for patients to differentiate pains coming from multiple sources. Every attempt to verify the mechanistic basis of the pain needs to be made. Finally, pain related to bone destruction is liable to be aggravated by activity level and to be at its worst only when challenged by activity.
Despite these obstacles, those whose major focus is to treat pain have become comfortable with self-report from analgesic studies as the primary clinical trial outcome variable. Those whose focus is treatment of cancer, however, are less likely to be comfortable with "pain" as a primary outcome.
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Measuring Pain and Its Impact: Self-report Measures |
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TopAbstractWhat Needs to be...Measuring Pain and Its...Concurrent Symptoms and...Innovative Trends in Pain...Trial Design: Important...Open DiscussionReferences |
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Pain assessment needs to be done via validated pain questionnaires administered at appropriate times during the trial. Although several measures of pain and its relief are available for clinical trial use, we will focus here on the Brief Pain Inventory (BPI; ref. 17), a short scale that measures both pain severity and functional interference caused by pain. The BPI is probably the most widely used pain questionnaire in trials that examine agents for the relief of both cancer pain and noncancer pain.
The BPI uses a numerical rating scale to capture both the severity of pain and the interference of pain with function (Fig. 1 ). Patients rate the severity of their pain at its "worst," "least," and "average" in the last week using an 11-point numerical rating scale with anchors of "no pain" and "pain as bad as you can imagine." They are also asked to rate their pain "now," at the time they complete the BPI. Using an 11-point numerical rating scale with anchors of "does not interfere" and "completely interferes," the BPI similarly assesses to what extent pain interferes with mood, walking, general activity, work, relations with others, sleep, and enjoyment of life. The BPI also asks patients to mark the location of their pain on a body drawing and includes other questions about pain treatment and the extent of pain relief. The BPI provides a list of descriptors to help the patient describe pain quality. A short form of the BPI is frequently used for regular pain assessment in clinical and research settings. The BPI short form uses a time reference of "in the last 24 hours" rather than "in the last week."
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Thus, the implementation of cancer pain treatment guidelines necessitates the categorization of pain intensity. Mild, moderate, and severe pain can be defined as ranges of patient responses to a numerical rating of pain at its worst on an 11-point scale. The ranges for each category of pain severity are based on the degree of interference with function associated with each category. Both pain severity and pain interference can be obtained from the BPI (18).
Mild pain (1-4 worst pain) will most often call for a mild analgesic (acetaminophen or a nonsteroidal anti-inflammatory medication). Mild pain typically causes the least interference with function. Studies have shown that patients with mild pain, in terms of functional and affective interference, are more like patients with no pain than those with moderate or severe pain, both of which substantially disrupt function (18, 19). Because pain from bone metastases is rarely totally eliminated without significant adverse effects from opioids, especially at rest (20), reducing pain to the mild range may be a reasonable target for treatment or for a clinical trial. For instance, patients who end a trial with pain of 
4 or 3 might be classified as trial "responders," allowing for a responder analysis of the data (12). Moderate pain (5-6 worst pain) and severe pain (7-10 worst pain) mandate aggressive analgesic intervention.
To fully understand the effect of a treatment for pain, additional measures are often added at certain points throughout the trial. A recent consensus on analgesic trial measurement suggested several measurement domains that need to be considered for inclusion in the trial (21). In addition to reported reduction in pain severity and improvement in pain relief, it is important to measure the effect of the treatment on other symptoms, which may increase if they are adverse effects of the treatment or decrease if they are linked to pain. Along with standard ratings of adverse events, a multiple symptom rating scale, such as the Rotterdam Symptom Checklist (22) or the M.D. Anderson Symptom Inventory (23), might be used for this purpose. An improvement in physical function might be expected with treatment and should be reflected in a decrease in the ratings of the interference items of the BPI. Some trials may include a specific measure of affective status, such as one of the versions of the Profile of Mood States (24).
Patient satisfaction scales. Recent recommendations for the conduct of clinical trials with pain as an outcome include having measures of both patient satisfaction and patient disposition (e.g., do the patients wish to continue treatment after the trial is ended?). Satisfaction scales are usually one or two items that have participants rate their satisfaction with the treatment. Satisfaction questionnaires may ask patients to rate how satisfied they are with their pain treatment on a five-point scale from "very satisfied" (1) to "very dissatisfied" (5; ref. 25). The scores are then classified into "adequate" (1-3) or "inadequate" (4-5) treatment. Alternatively, patients may be asked to indicate whether they believed the treatment improved their pain by rating their pain as "the same," "better," or "worse." The follow-up question relates to the first answer: if better, then how much better, "a lot," "some," or "a little"; or if worse, then how much worse, "much worse," "some," or "a little." Disposition can be covered by the end-of-trial question, "If possible, would you continue taking this medication for pain relief?"
Despite a growing consensus that global measures of treatment satisfaction should be included in clinical trials (21, 26, 27), little research that clarifies the meaning or validity of such measures has been done. Jensen et al. (28) reported the validity of global satisfaction ratings as assessing something other than pain intensity or change in pain intensity and therefore supported the use of such measures, as recommended by experts in the field of pain assessment in clinical trials (21). The predictors of satisfaction in the context of an analgesia clinical trial included treatment regimen, age, worst pain experienced, pain interference with functioning, morphine equivalent dose taken, and number of opioid-related symptoms (e.g., nausea and fatigue). All of these were associated with satisfaction with the overall performance of the study medications at day 1. These findings indicate that the study participants considered more than one factor when estimating their satisfaction with the study medications and that the changes produced by the treatment (e.g., decreased pain and opioid-related symptoms) mediated, in part, the effects of treatment on treatment satisfaction.
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Concurrent Symptoms and Treatment Adverse Effects |
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TopAbstractWhat Needs to be...Measuring Pain and Its...Concurrent Symptoms and...Innovative Trends in Pain...Trial Design: Important...Open DiscussionReferences |
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A checklist of potential concurrent symptoms, such as the M.D. Anderson Symptom Inventory, can be used to assess the presence and intensity of symptoms (23). The M.D. Anderson Symptom Inventory consists of a core list of symptoms that are common across all cancer diagnoses and treatments, plus modules of additional symptoms that can be included for patients who are at risk for symptoms not highly prevalent in oncology patients in general (e.g., because of a particular cancer or treatment regimen). The core M.D. Anderson Symptom Inventory consists of 13 symptoms: pain, fatigue, nausea, sleep disturbance, emotional distress, shortness of breath, lack of appetite, drowsiness, dry mouth, sadness, vomiting, difficulty remembering, and numbness or tingling. Each symptom is rated on a 11-point scale, with 0 being "not present" and 10 being "as bad as you can imagine."
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Innovative Trends in Pain Assessment |
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TopAbstractWhat Needs to be...Measuring Pain and Its...Concurrent Symptoms and...Innovative Trends in Pain...Trial Design: Important...Open DiscussionReferences |
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Trial Design: Important Considerations |
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TopAbstractWhat Needs to be...Measuring Pain and Its...Concurrent Symptoms and...Innovative Trends in Pain...Trial Design: Important...Open DiscussionReferences |
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When pain is the primary outcome variable for a clinical trial, either between the agent under investigation or the agent and a comparator, several design features need to be considered. Once the instruments for assessment are determined, rules need to be established a priori that define the success or failure of the trial. Often, a regulatory authority such as the Federal Drug Administration will be involved in an agreement about the adequacy of these rules. In very large trials, marginal group differences may be statistically significant, although these differences may be of little or no clinical significance for patients. It is important to justify what a minimally important difference will be in the context of the trial. There are several methods of setting the minimally important difference, which are beyond the scope of this presentation, but one rule of thumb is that the difference between groups on pain severity at the end of trial should be in the range of half a SD of the pain scores of both groups at trial baseline (31). Alternatively, the minimally important difference might be set by change seen in prior trials with the same or similar painful conditions. Another alternative is to define a "responder" to the trial, with a responder being defined as having achieved a prespecified reduction in pain and the final test being the proportion of responders in each arm of the trial. With bone pain from cancer, few treatments will provide total relief or totally eliminate the need for analgesics, so the definition of a "responder" needs to be set realistically.
Some trials have used a composite end point, such as a specified reduction in pain coupled with a reduction in opioid analgesics. There are a few examples of successful trials using such end points, but they need to be approached with caution; often, as reviewed earlier, there is substantial practice-to-practice variation in prescription of analgesics, making stabilization or reduction of analgesics as an end point problematic.
Another approach to trials where bone pain is an outcome is similar to studies that use skeletal-related events as an outcome. Patients with mild or no current bone pain, but who are at risk for developing bone pain, are enrolled. Stable bone pain (e.g., two or more assessments where moderate to severe pain is present) becomes an "event" defining "failure" of the agent for preventing bone pain. This design allows broader recruitment of patients and provides information about how long patients might be expected to be free of significant bone pain if they are treated.
Finally, timing of assessments is critical, especially when testing methods for the reduction of bone pain. Many of these patients have limited survival, and thus rapidity of onset is a major positive factor for a given treatment. Although not all measures need to be given frequently, daily use of pain severity scales and estimates of pain relief (in percentages), whether obtained by calls from research nurses, pain diaries, or one of the more recent electronic methods, can capture the onset of pain relief and help determine when the maximal effect of the treatment has been achieved.
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Open Discussion |
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TopAbstractWhat Needs to be...Measuring Pain and Its...Concurrent Symptoms and...Innovative Trends in Pain...Trial Design: Important...Open DiscussionReferences |
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Dr. Cleeland: Yes, those comparisons have been made. As you might expect, you are going to get significantly more interference from pain from the bone metastasis patients compared with a group with moderate to severe osteoarthritis.
Dr. Clohisy: The same thing is true in mice. If you give them different types of pain and then you look at the amount of narcotics that they need to get the same level of function, bone pain requires many more narcotics than arthritis pain or neuropathic pain.
Dr. Smith: If you were designing the next bisphosphonate trial of the bone-targeted therapy trials, is it preferable to have an event-driven analysis, as was done in many of the previous trials, or to take patients with pain and look at change in pain?
Dr. Cleeland: It's a lot easier to do the latter. I've been doing these event-related trials for a long time; you need large numbers of patients, and you have to wait a long time. The regulators, at least in the United States, are more interested in symptom-related primary outcomes as opposed to skeletal events. It's important to have pain as a primary outcome.
Dr. Bruland: Are you suggesting that targeting analgesics to bone might be a way of improving their effect by a selective action on the neurons themselves?
Dr. Cleeland: Yes, absolutely.
Dr. Cook: You mentioned the difficulty with the mortality in estimating the pain over time. This is more of a problem the sicker the patients are. It's difficult to interpret those means after, for example, 2 years of follow-up when you have a potentially small subset.
Dr. Cleeland: It's often difficult to interpret after 6 months of follow-up. One of the problems has been regulatory, because you have to show a sustained benefit. That's a battle that has to be fought with the Food and Drug Administration.
Dr. Cook: One strategy that people use in quality-of-life analyses is to give a utility to a particular score on a quality-of-life scale, accumulate those over time, and look at quality-adjusted life-years. Have you thought of that approach in the context of pain analysis?
Dr. Cleeland: Yes, we have. We work under a larger umbrella, which I call symptom burden, and we are trying to translate symptom burden into something like quality-adjusted life-years.
Dr. Weilbaecher: If we are just focusing on pain and not treating the cancer, we are missing the bigger picture. By using better bone pain parameters, could we look at the impact of these ancillary therapies on actual disease progression?
Dr. Cleeland: Yes, and symptoms as well. One of my soapboxes is to attach very simple multiple-symptom scales to treatment protocols so that we gather data. Bisphosphonates, for example, are multiaction agents with inflammatory components. Why aren't we tracking the symptoms of patients taking bisphosphonates so that we're learning something?
Dr. Coleman: The issue of standard response criteria is extremely important, and I wonder what it's going to take to get those defined. We have had the Unio Internationale Contra Cancrum criteria for 30 years. Why can't that happen for pain?
Dr. Cleeland: We're getting close.
Dr. Coleman: We want them to be simple.
Dr. Cleeland: We want them to be very simple. There is a disenchantment with this notion of global quality of life because it has surplus meaning. We are trying to use the term "symptom burden." However, it is difficult to get people to agree on what a reduction in symptom burden is, but not impossible, because we have done it with pain.
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Footnotes |
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Presented at the First Cambridge Conference on Advances in Treating Metastatic Bone Cancer, a symposium held in Cambridge, Massachusetts, October 28-29, 2005.
Received 4/21/06; revised 6/29/06; accepted 6/30/06.
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References |
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TopAbstractWhat Needs to be...Measuring Pain and Its...Concurrent Symptoms and...Innovative Trends in Pain...Trial Design: Important...Open DiscussionReferences |
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