Clinical benefit in patients with metastatic bone disease: results of a phase 3 study of denosumab versus zoledronic acid.

BACKGROUND: Patients with metastatic bone disease are living longer in the metastatic stage due to improvements in cancer therapy, making strategies to prevent the aggravation of bone disease and its complications, such as skeletal-related events (SREs) and pain, increasingly important. PATIENTS AND RESULTS: In this phase 3 trial in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma, denosumab reduced the risk of radiation to bone by 22% relative to zoledronic acid (P = 0.026), prevented worsening of pain and pain interference (2-point increase in Brief Pain Inventory score; P < 0.05 versus zoledronic acid), and reduced the frequency of a shift from no/weak opioid analgesic use to strong opioids (P < 0.05 versus zoledronic acid at months 3-5). Denosumab delayed the time to moderate-to-severe pain compared with zoledronic acid in patients with mild or no pain at the baseline (P = 0.04), supporting early treatment. Health-related quality-of-life scores were similar in both groups. The number needed to treat to avoid one SRE for denosumab was 3 patient-years versus placebo and 10 patient-years versus zoledronic acid. CONCLUSION: The use of denosumab was associated with better prevention of the complications of metastatic bone disease secondary to solid tumors or multiple myeloma versus zoledronic acid.

Minimal clinically meaningful differences for the EORTC QLQ-C30 and EORTC QLQ-BN20 scales in brain cancer patients.

BACKGROUND: We aimed to determine the smallest changes in health-related quality of life (HRQoL) scores in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core 30 and the Brain Cancer Module (QLQ-BN20), which could be considered as clinically meaningful in brain cancer patients. MATERIALS AND METHODS: World Health Organisation performance status (PS) and mini-mental state examination (MMSE) were used as clinical anchors appropriate to related subscales to determine the minimal clinically important differences (MCIDs) in HRQoL change scores (range 0-100) in the QLQ-C30 and QLQ-BN20. A threshold of 0.2 standard deviation (SD) (small effect) was used to exclude anchor-based MCID estimates considered too small to inform interpretation. RESULTS: Based on PS, our findings support the following integer estimates of the MCID for improvement and deterioration, respectively: physical (6, 9), role (14, 12), and cognitive functioning (8, 8); global health status (7, 4*), fatigue (12, 9), and motor dysfunction (4*, 5). Anchoring with MMSE, cognitive functioning MCID estimates for improvement and deterioration were (11, 2*) and for communication deficit were (9, 7). Estimates with asterisks were <0.2 SD and were excluded from our MCID range of 5-14. CONCLUSION: These estimates can help clinicians evaluate changes in HRQoL over time, assess the value of a health care intervention and can be useful in determining sample sizes in designing future clinical trials.

The contribution of pain in determining the health status of cancer patients with bone metastases: A secondary analysis of data from three Phase III registration trials.

BACKGROUND: We aimed to provide a simple, descriptive health-status profile for cancer patients with bone metastases, based on the EuroQol EQ-5D, a tool commonly used to measure health utility scores, and to evaluate its association with the Brief Pain Inventory (BPI), a legacy pain-assessment tool. Although pain is one of five health-status dimensions measured by the EQ-5D, our understanding of how pain relates to the other EQ-5D dimensions is limited. METHODS: We derived data from 5500 patients with bone metastases who completed the EQ-5D and BPI. Regression analyses examined how BPI severity and interference scores correlated with EQ-5D utility scores and how BPI items associated with EQ-5D items, for the entire sample and by disease-type subgroup. RESULTS: Regardless of cancer site, the percentage of patients reporting moderate/severe problems in each of the five EQ-5D dimensions were pain/discomfort, 78%; usual activities, 58%; mobility, 55%; anxiety/depression, 57%; and self-care, 26%. BPI pain interference explained more of the variability in the EQ-5D utility scores than did pain severity (R2  = 41% vs. 34%). BPI worst pain, average pain, pain now, interference with general activity, and interference with work significantly predicted EQ-5D pain/discomfort, with odds ratio estimates <1. CONCLUSIONS: Pain/discomfort was the worst-rated dimension of the EQ-5D in this population, but the relationship of this item to BPI pain severity was modest, suggesting that the single pain item of the EQ-5D may be of limited utility in studies for which pain is an endpoint. SIGNIFICANCE: Health-status dimensions include more than pain. We examine the contribution of pain severity and pain-related functional interference in determining the health status of cancer patients with bone metastases. The pain dimension from a health-status measure may be an inadequate metric in clinical trials/clinical practice when pain is an important outcome.

Symptom burden in patients undergoing autologous stem-cell transplantation.

Patients who undergo autologous peripheral blood stem cell (PBSC) transplantation experience multiple symptoms that adversely affect quality of life. We assessed symptoms during the acute phase of autologous PBSC transplantation to determine the severity of individual symptoms and to determine overall symptom profiles in 100 patients with multiple myeloma or non-Hodgkin's lymphoma. Study subjects completed the blood and marrow transplantation module of the M. D. Anderson Symptom Inventory before hospitalization, during conditioning, on day of transplantation, at nadir (the time of lowest white blood cell count) and on day 30 post-transplantation. Additional symptom, quality-of-life and medical status measures were collected. Symptom means were mild at baseline, intensified during conditioning, peaked at nadir and decreased by day 30. At nadir, the most severe symptoms for the entire patient sample were lack of appetite, fatigue, weakness, feeling sick, disturbed sleep, nausea and diarrhea. Cancer diagnosis was a significant predictor of changes in symptoms over time. The patterns of fatigue, pain, sleep disturbance and lack of appetite were significantly different for patients with multiple myeloma as compared with patients with non-Hodgkin's lymphoma.

Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three-times-weekly dosing.

PURPOSE: To prospectively evaluate the effectiveness, safety, and clinical benefits of once-weekly epoetin alfa therapy as an adjunct to chemotherapy in anemic cancer patients. PATIENTS AND METHODS: A total of 3,012 patients with nonmyeloid malignancies who received chemotherapy were enrolled onto this multicenter, open-label, nonrandomized study conducted in 600 United States community-based practices. Patients received epoetin alfa 40,000 U once weekly, which could be increased to 60,000 U once weekly after 4 weeks dependent on hemoglobin response. Treatment was continued for a maximum of 16 weeks. RESULTS: Among the 2,964 patients assessable for efficacy, epoetin alfa therapy resulted in significant increases in hemoglobin levels, decreases in transfusion requirements, and improvements in functional status and fatigue as assessed by the linear analog scale assessment (energy level, ability to perform daily activities, and overall quality of life) and the anemia subscale of the Functional Assessment of Cancer Therapy-Anemia questionnaire. Improvements in quality-of-life parameters correlated significantly (P <.001) with increased hemoglobin levels. The direct relationship between hemoglobin and quality-of-life improvement was sustained during the 16-week study period, which is similar to findings of large community-based trials of three-times-weekly dosing. Once-weekly epoetin alfa was well tolerated, with most adverse events attributed to the underlying disease or concomitant chemotherapy. CONCLUSION: The results from this large, prospective, community-based trial suggest that once-weekly epoetin alfa therapy increases hemoglobin levels, decreases transfusion requirements, and improves quality of life in patients with cancer and anemia who undergo concomitant chemotherapy. Based on the results of this study, the clinical benefits and the adverse event profile of once-weekly epoetin alfa therapy in community-based practice are similar to those observed in the historical experience with the three-times-weekly dosage schedule.

Motor performance after unilateral hemisphere damage in patients with tumor.

Hemispheric asymmetry of sensory-motor control has been hypothesized on the basis of clinical and experimental data, but discrepant data indicate asymmetry may vary with task requirements. To examine this possibility, the performance of normal controls and patients with right or left hemispheric tumors were compared on a variety of motor tasks of varying complexity. Group differences were significant only for the two most complex of six tasks; since these two tasks differ in quality (proximal steadiness and distal dexterity), it is unlikely that quality differences are crucial. On these tasks, the group with left hemisphere damage demonstrated bilateral impairment while the right hemisphere group's deficits were contralateral to lesion site. These results support previous data and Liepmann's hypothesis of hemispheric asymmetry of sensory-motor control. Task complexity and the more specific hypothesis of sensory-motor sequencing are important factors influencing hemispheric asymmetry of control.

Cancer-related symptoms.

Patients with cancer experience multiple symptoms including pain, dyspnea, fatigue, depression, and cognitive impairment. These symptoms impair patients' daily functioning and their quality of life. Symptoms that can be well managed are often undertreated. A major barrier to adequate symptom treatment is poor assessment. The use of simple measurement scales greatly improves the symptom assessment process, helps direct treatment choices, and provides information about the effectiveness of treatment. Recently, better methods for symptom assessment have been developed, including brief self-report tools for the assessment of multiple symptoms and interactive voice response systems for assessing symptoms at home. Symptom assessment can be linked to evidence-based or best practice guidelines to expedite optimal symptom treatment. Because patients with cancer receiving radiotherapy are seen in the clinic frequently, the radiation oncologist can play an integral role in a comprehensive approach that involves both the medical and radiotherapeutic treatment of cancer-related symptoms.

CSF beta-endorphin and the severity of pain.

Beta-endorphin-like immunoreactivity (i beta-EP) was measured in the CSF at myelography of 24 patients suspected of vertebral disk disease. Patients made several ratings of mood and pain for the 24 hours preceding myelography. Composite scores for pain, negative mood, and positive mood were derived by factor analysis. Pain Factor scores were negatively correlated with i beta-EP (r = -0.59, p less than 0.001), indicating a possible role for i beta-EP in the perception of the severity of pain. No significant correlation was shown between Positive or Negative Mood Factor scores and CSF i beta-EP. A physiologic indicator of pain severity is discussed.

Dimensions of the impact of cancer pain in a four country sample: new information from multidimensional scaling.

We investigated the question of how cultural and linguistic backgrounds affect relationships among ratings (reported by patients with metastatic cancer) of pain's interference with such functions as activity, mood, and sleep. Multidimensional scaling (MDS) was used to analyze ratings of pain interference from a sample consisting of four culturally and linguistically different groups from the US (n = 1106), France (n = 324), the Philippines (n = 267), and China (n = 146). Patients all completed the Brief Pain Inventory, a self-report measure of pain and its interference with function. For each of these samples, MDS solutions consistently revealed two interpretable dimensions. In all samples, one dimension represented affect and the other dimension represented activity. The dimensions were consistently interpretable across all four samples and across three levels of pain severity ('mild', 'moderate', and 'severe'). The dimensions were most prominent when pain was moderate, rather than mild (when little interference was produced) or severe (when all domains were highly interfered with). These dimensions may have utility in the study of the epidemiology of pain and of the effectiveness of pain treatment. They may also be useful in clinical assessment to describe different patterns of pain interference.

The Chinese version of the Brief Pain Inventory (BPI-C): its development and use in a study of cancer pain.

We describe the development of a Chinese version of the Brief Pain Inventory (BPI-C) and demonstrate its reliability and validity. We also report the use of the BPI-C in a three hospital study of cancer pain and its treatment. As with other language versions of the BPI, factor analysis of the BPI-C items results in a two factor solution that satisfies the criteria of reproducibility, interpretability and fit in a confirmatory setting. The first factor consists of the four pain severity scales, while the seven pain interference scales comprised the second factor. The BPI-C proved to be a reliable measure of both the severity and impact of pain in patients with cancer. Coefficient alpha for the pain severity and pain interference items were 0.894 and 0.915, respectively. The sample (N = 147) was gathered at three cancer treatment hospitals in Beijing. The patients from these hospitals reported higher levels of pain severity and pain interference compared with patients in similar studies done at the time (1991-1992) in the United States and France. This was in keeping with the finding that a larger proportion (67%) of the cancer patients in these Beijing hospitals were judged to have inadequate analgesia as assessed by the Pain Management Index (PMI), an estimate of adherence to the World Health Organization (WHO) guidelines for cancer pain management.

Effects of oral morphine on cold pressor tolerance time and neuropsychological performance.

We investigated the analgesic effects of escalating doses (0.214, 0.286, 0.357, and 0.429 mg/kg) of oral morphine on tolerance to painful cold pressor in a double-blind, active placebo-controlled (diphenhydramine) study in 45 normal volunteers. The highest dose of morphine administered is equivalent to the starting dose recommended by the Agency for Health Care Policy and Research for the management of cancer pain and acute postoperative pain. We assessed analgesia in terms of cold pressor tolerance time and self-reported ratings of pain intensity and unpleasantness. Subjects receiving the highest dose of oral morphine showed significantly higher tolerance time than subjects receiving diphenhydramine. Neither morphine or diphenhydramine significantly reduced ratings of pain intensity and unpleasantness. Neuropsychological testing revealed that the two highest doses of morphine impaired the episodic retrieval of a word list, but the same doses did not affect motor, perceptual, or attentional tasks.

Cancer pain management by radiotherapists: a survey of radiation therapy oncology group physicians.

PURPOSE: Radiation Therapy Oncology Group (RTOG) physicians were surveyed to determine their approach to and attitudes toward cancer pain management. METHODS AND MATERIALS: Physicians completed a questionnaire assessing their estimates of the magnitude of pain as a specific problem for cancer patients, their perceptions of the adequacy of pain management, and their report of how they manage pain in their own practice setting. RESULTS: Eighty-three percent believed the majority of cancer patients with pain were undermedicated. Forty percent reported that pain relief in their own practice setting was poor or fair. Assessing a case scenario, 23% would wait until the patient's prognosis was 6 months or less before starting maximal analgesia. Adjuvants and prophylactic side effect management were underutilized in the treatment plan. Barriers to pain management included poor pain assessment (77%), patient reluctance to report pain (60%), patient reluctance to take analgesics (72%), and staff reluctance to prescribe opioids (41%). CONCLUSIONS: Physicians' perceptions of barriers to cancer pain management remain quite stable over time, and physicians continue to report inadequate pain treatment education. Future educational efforts should target radiation oncologists as an important resource for the treatment of cancer pain.

Hyperkinesis and food additives: testing the Feingold hypothesis.

Teacher ratings, objective classroom and laboratory observational data, attention-concentration, and other psychological measures obtained on 36 school-age, hyperactive boys under experimental and control diet conditions yielded no support for the Feingold hypothesis. Parental ratings revealed positive behavioral changes for the experimental diet; however, they seemed primarily attributable to one diet sequence. Parents' behavioral ratings on ten hyperactive, preschool boys indicated a positive response to the experimental diet; again, laboratory observations showed no diet effect.

Whole head mapping of magnetic fields following painful electric finger shock.

Painful intracutaneous electric finger shock was delivered to the fifth digit of the non-dominant hand of five healthy volunteers. Whole head evoked magnetic field maps were collected and cortical localizations were calculated using local sphere equivalent current dipole fits. MRI scans were used to identify the anatomical structures where magnetic field sources were located. Anatomically, sources were identified bilaterally in the primary somatosensory region and SII-Insula regions. Additionally, frontal operculum sources were observed contralaterally in two subjects. Temporally, an initial contralateral SI activation at 40-60 ms was followed by several SII-Insula responses over the next several hundred milliseconds (ms). These SII-Insula responses were often interspersed with additional activations of the SI region. These later responses were observed in both hemispheres.

Special aspects of cancer pain management in a Chinese general hospital.

China is still faced with a challenge in cancer pain management. The purposes of this study are to assess the current status of cancer pain management, and physicians' attitudes in China towards cancer pain management. The survey was done in a Chinese general hospital; 427 physicians and 387 cancer pain patients participated. The survey consisted of questionnaires to evaluate cancer pain management and physicians' knowledge of, and attitudes towards, cancer pain management. A total of 43% of patients with cancer pain and 51% with bone pain felt that they had been inadequately treated. The physicians rated the main reason for not using opioid drugs as the strong and difficult to control side-effects. The four main barriers to optimal management of cancer pain were: inadequate pain assessment; excessive state regulation of the prescribing of opioids; inadequate staff knowledge of pain management; and lack of access to powerful analgesics. To conclude: In China, there are some special aspects of cancer pain management, including physicians' concern about using opioid drugs, fear of being unable to manage adverse effects of opioids, and inadequately treated bone pain.

Unaided use of pain descriptors by patients with cancer pain.

A large sample of cancer patients in pain were instructed to describe their pain using their own words. Data were collected from patients representing several primary sites. A total of 129 distinct words were used by patients to describe their pain, with each patient using an average of 1.8 words. Ten words accounted for 67% of total word usage. Grouping words by response dimension revealed a predominant use of sensory descriptors, with the majority of these comprising the category "dullness." Patients divided by high and low self-reported worst pain differed significantly across several sensory categories and in the use of evaluative words. Comparisons made between patients grouped by primary site were significant only for the use of dullness adjectives. Patients with ovarian cancer used the greatest number of dullness words. No differences were found in word usage for patients with varying pain etiologies. The results point to the need to use word descriptor lists routinely in clinical and research settings. They also suggest that cancer patients' self-reported pain intensity can be inferred from word descriptors.

The assessment of cancer pain in north India: the validation of the Hindi Brief Pain Inventory--BPI-H.

The status of pain treatment for cancer patients in India is largely undocumented. Although many languages and dialects are spoken throughout the country, millions of persons in North India speak Hindi. This project developed and validated a Hindi version of the Brief Pain Inventory (BPI-H), a short measure of pain and pain interference that has been shown to be relatively free of cultural or linguistic influences. In the validation process, we were able to administer both the Hindi and English versions of the BPI to a sample of bilingual (Hindi and English) patients. The English and Hindi versions of the BPI were very similar in their psychometric properties, supporting the reliability and construct validity of the Hindi version. As with other language versions of the BPI, factor analysis of the BPI-H items results in severity and interference subscales. We followed the validation with an examination of the status of cancer pain management in a major northern Indian cancer center, based on 200 patients with pain who spoke only Hindi. Using a conservative measure of analgesic prescription adequacy (the Pain Management Index), three-fourths of Hindi-speaking cancer patients in this study were inadequately treated by World Health Organization (WHO) recommendations. The results of this study encourage the development of other forms of the BPI in the many languages of India, and the use of the instrument in studies of the epidemiology and treatment of cancer pain.

A preliminary study of the utility of the brief hospice inventory.

The increasing number of palliative care patients necessitates a simple, reliable instrument to routinely measure outcomes among hospice patients. We tested the utility of the Brief Hospice Inventory (BHI) to assess outcomes of hospice patients and estimations of patients' outcomes by nurse caregivers. In a prospective study, 145 home-based hospice patients were enrolled in the study from VistaCare Hospice. During the first week of admission, patients and nurse caregivers completed the BHI, which assessed patients' symptoms, satisfaction with care, and quality of life. Factor analysis supported a two-factor structure for the BHI for patients and caregivers, including a symptom subscale and quality of life subscale. Patients with severe symptoms showed improvement on the symptom subscale, but not the quality of life subscale, during the first 2 weeks after admission. The BHI shows utility in measuring hospice patients' symptom severity and quality of life over time.

Cancer pain in the marital system: a study of patients and their spouses.

Forty married patients with metastatic cancer, who were receiving opioid medication for cancer pain, were interviewed for this study. They were asked about their pain and its treatment, their beliefs regarding cancer pain, their concerns about opioid analgesics, their mood state, and the nature of their interaction with their spouse in relation to these issues. The spouses of these cancer patients were interviewed separately about the same issues. For example, patients who were concerned about medication side effects tended to suffer high levels of pain before requesting additional analgesics. Spouses are shown in this study to be an important support for the patient and an essential source of information regarding the patient's pain and its management. For example, although spouses were generally accurate in their estimates of the patients' pain levels, in the case of relatively stoic patients, who may underreport their pain levels, the spouses' estimates were higher than the patients'. The results also indicate that patients underestimate the distress their pain causes to their spouses and that spouses tend to downgrade their own support to the patients. Implications and limitations of these findings are discussed.

A brief cancer pain assessment tool in Japanese: the utility of the Japanese Brief Pain Inventory--BPI-J.

Despite recognition that pain management is an important component in the treatment of Japanese cancer patients, progress in this area has been slowed by the lack of an appropriate measure of pain. In a prospective, single-institution study, a Japanese translation of the Brief Pain Inventory (BPI-J) was administered to 121 patients to assess the intensity and impact of cancer-related pain. After an analysis of the instrument's reliability and validity, this study tested the utility of the new measure in an analysis of the adequacy of analgesic prescription. Results were compared with predictive models from studies using non-Japanese patient groups. Factor analysis of the BPI items resulted in two factors, pain severity and pain interference, showing consistency with other language versions of the tool. Coefficient alphas of greater than 0.80 for the items comprising these two subscales indicate a reliable self-report pain instrument. After establishing the validity and reliability of the BPI-J, we examined possible predictors of inadequate pain management in these Japanese cancer patients. Similar to studies done in other countries, women patients and those whose pain severity was underestimated by their physician were more likely to be undermanaged for pain. The results of this study support the utility of the Japanese BPI for studies of the epidemiology of cancer pain in Japan, as well as for the assessment of pain treatment outcome in Japanese-speaking patients.