A Randomized, Controlled Trial of Intravenous Clodronate in Patients with Metastatic Bone Disease and Pain

Transcription

1 Vol. 13 No. 6June 1997 Journal of Pain and Symptom Management 319 Original Article A Randomized, Controlled Trial of Intravenous Clodronate in Patients with Metastatic Bone Disease and Pain D. Scott Ernst, MD, FRCP(C), Penny Brasher, PhD, Neil Hagen, MD, FRCP(C), Alexander H. G. Paterson, MD, FRCP, R. Nell MacDonald, CM, MD, FRCP(C), FRCP(Edin), and Eduardo Bruera, MD Tom Baker Cancer Centre (D.S.E., P.B., N.H., A.H.G.P.), Calgary, and Cross Cancer Institute (R.N.M., E.B.), Edmonton, Alberta, Canada Abstract To evaluate the effectiveness of intravenous clodronate in ameliorating refractory bone pain in patients with metastatic bone disease, 60 patients with established osseous metastases and persistent bone pain were randomized to receive either clodronate (600 mg or 1500 mg in 500 ml of normal saline) or 500 ml of saline as. After 2 weeks, the patients were crossed over to receive the alternate treatment. After another 2 weeks, each patient and investigator made a blinded choice. Daily visual analogue scales (VAS) and analgesic diaries were recorded throughout the study period. For~-six patients were evaluable (77%). A treatment X period interaction was identified in the VAS and daily morphine equivalent dose (DMED) scores. First period analysis of the VAS scores for general pain, pain at rest, and pain upon movement demonstrated an average reduction of 13, 14, and 24 ram, respectively, from baseline, but were not significantly different from changes following. The average change in DMED was -6.4 (SE = 2.9) fouowing clodronate and was (SE = 14.9) following (p = 0.03). In the blinded choice of which agent resulted in improvement in pain, 26 (57%) patients chose clodronate, 12 (26%) chose, and eight (17%) had no prejkrenee (p = O. 0021). For the investigators who also made a blinded selection, clodronate was chosen in 30 (65%) patients, in ten (22%)patients, and no difference was apparent in six (13%) (p < ). Intravenous clodronate appeared to have analgesic effect in patients with refractory bone pain due to metastatic bone disease. The optimal dose and duration of effect require further evaluation, particularly in patients with stable disease and persistent bone pain. J Pain Symptom Manage 1997;13: U.S. Cancer Pain Relief Committee, Key Words Clodronate, bone pain, metastatic bone disease, osseous metastases Introduction Skeletal metastases occur commonly with advanced malignant disease, and resultant Address reprint requests to: D. Scott Ernst, MD, Tom Baker Cancer Centre, Street Northwest, Calgary, Alberta, Canada T2N 4N2. Accepted for publication: September 20, complications, such as pathological fractures, hypercalcemia, and bone pain, contribute significantly to the morbidity of the underlying neoplastic process. The prevalent cancers of the breast, lung, and prostate constitute 80% of symptomatic bone metastases. 1 In those patients with predominantly osseous involvement, survival may be protracted, but quality U.S. Cancer Pain Relief Committee, /97/$17.00 Published by Elsevier, New York, New York PII S (97)

2 320 Ernst et al Vol. 13 No. 6June 1997 of life is negatively impacted by the sequelae of the bone disease. Symptomatic treatment includes opioid analgesics, nonsteroidal antiinflammatory agents, local radiotherapy, orthopedic stabilization, and immobilization. Nonetheless, in some patients, the control of the bone pain is suboptimal because of doselimiting side effects of various treatment modalities. 2'~ The presence of incident pain, pain accentuated with movement, can be particularly refractory to nonspecific therapeutic maneuvers.4 Clodronate (dichloromethylene bisphosphonate) is a member of a novel class of bone resorption inhibitors, bisphosphonates, which have been in increasing clinical use over the past 10 years. "~ These synthetic analogues of pyrophosphate resist enzymatic hydrolysis and are rapidly absorbed by the bone mineral matrix. Clodronate acts principally to block osteoclastmediated bone resorption without interference with mineralization. 6'v The bisphosphonates have become the agents of choice in the management of hypercalcemia of malignancy. Initial normalization of the serum calcium can be achieved in 80%- 90% of patients, particularly when osteolysis is the primary underlying pathogenic mechanism. s'9 When clodronate was used to treat hypercalcemia, it was observed that some patients also experienced improvement in their bone pain. ~ '11 Initial uncontrolled studies suggested an analgesic benefit in patients with multiple myeloma, prostate, and breast cancer Although a dose-response relationship was not definitively established, bisphosphonates, particularly when administered intravenously, appeared to induce a clinically significant analgesic effect In 1992, we reported the first controlled study primarily evaluating the analgesic effect of intravenous clodronate in normocalcemic patients with refractory bone pain. is With a 600 mg dose of clodronate, blinded patient and investigator selections, and patient-generated visual analogue scores (VAS) of pain and activity levels suggested a beneficial effect on the control of the patients' bone pain. The study sample was small, however, and treatment was limited to a single dose of clodronate. Subsequently, two controlled randomized studies of oral clodronate in patients with multiple myeloma and metastatic prostate cancer have been reported and showed a significant reduction in pain with clodronate. 19'9 The primary purpose of the current study was to confirm the analgesic efficacy of two doses of intravenous clodronate in patients with metastatic bone disease and refractory pain, and to evaluate the impact on subjective baseline and incident pain measurements. Me~o~ Patients Sixty patients with metastatic cancer and radiographically demonstrated bone metastases were recruited to the trial from the pain referral services and general oncology wards at the two participating centers. All patients had refractory bone pain characterized by persistent discomfort despite the use of opioid analgesics titrated to the maximum tolerated dose, concomitant use of nonsteriodal anti-inflammatory agents, and local radiotherapy to the painful sites. No changes in chemotherapy or hormonal therapy, or local radiotherapy had been instituted within 4 weeks prior to study entry. All patients had normal measurements of serum sodium, potassium, chloride, calcium, phosphate, and creatinine. Patients with a previous history of congestive heart failure, renal insufficiency, or benign focal bone disease were specifically excluded. Patients had no clinical evidence of cognitive impairment. After obtaining informed, written consent, each patient underwent a baseline evaluation that consisted of the characterization of each painful site and the determination of the Edmonton pain stage by the investigator, m Each patient completed a baseline set of 150-ram visual analogue scales that assessed general pain, pain at rest, pain with movement, level of activity, nausea, depression, anxiety, drowsiness, appetite, and general wellbeing. 22 Patients were entered into the trial on stable analgesic regimens, which generally included regular administration of opioid analgesics with provision for breakthrough doses of opioids as required. No adjustments in the analgesic regimen could be made during the 3 days prior to study entry.

3 Vol. 13 No. 6June 1997 Clodronate and Metastatic Bone Disease 321 Study Design The study was a two-period crossover trial. Patients were randomized to receive either an intravenous infusion of clodronate (600 mg or 1500 mg) followed by, or followed by clodronate (600 mg or 1500 mg), respectively. The randomization was performed by random block assignment with the sealed drug-order allocations located in the pharmacies of each center. Patients were not stratified in accordance with clinical variables or center location. Patients, nursing staff, and investigators were blinded to the assignment until the completion of the study. All intravenous infusions were delivered over 3 hr. Each dose of clodronate was given in 500 ml of normal saline, and infusions consisted of 500 ml of normal saline alone. Fourteen days after the first infusion, the patients were reassessed by the investigators and received the crossover treatment of clodronate or in accordance with the randomization. After an additional 14 days, the final assessment was completed. The patients were asked which, if any, of the two infusions most correlated with an improvement in pain. The investigators, also blinded, chose which of the infusions appeared to correlate with a clinically apparent amelioration in the patient's pain. Following the final assessment, the dose and order of the clodronate was revealed. If the patient appeared to have benefitted from the clodronate, further infusions at the same dose were provided every 2 weeks until no further clinical benefit was apparent. Patients were instructed in the daily completion of analgesic diaries and were encouraged to utilize the breakthrough doses, if needed, recording dose and time in the diaries. They were not specifically advised to reduce their regular analgesic requirements if they were experiencing some improvement in pain during the study period. Daily morphine equivalent doses (DMED) were calculated for each patient while on study and included the additional analgesic requirements from breakthrough dosing. Evidence for toxicity was monitored throughout the study by patient, medical staff, and nursing staff assessments, and by weekly measurements of the complete blood count, and serum electrolytes, including calcium and creatinine. Table 1 Patient Characteristics n % Age (years) Mean, 63 Range, Primary site Breast Prostate Unknown primary 5 8 Multiple myeloma 4 7 Renal cell 3 5 Lung 3 5 Other 6 10 Number of painful sites Daily equivalent PO morphine dose (nag) Mean, 451 Range, Daily number of breakthrough doses Mean, 3.1 Range, 0-7 Statistical Methods For the analysis of the VAS and DMED, the baseline value was determined by averaging the values of the first 2 days of the study period. Because the expected effect was previously determined to become evident on days 3-10, the average VAS and DMED values for days 3-10 were similarly calculated. Changes from baseline for the and clodronate were then compared using analysis of variance. Observed frequencies of patient and investigator preferences were compared to those expected under the null hypothesis of no preference, using Chi-square goodness-offit tests. Results One patient voluntarily withdrew after randomization and prior to the first infusion. The clinical characteristics of the 59 randomized patients are provided in Table 1. The mean age was 63 years (range, years). For all patients, the mean equivalent daily dose of oral morphine was 451 mg (range, mg) and the baseline daily number of breakthrough doses of opioid analgesics was 3.1 (range, 0-7). All patients described bone pain; 32 (54%) patients had one or two painful sites, and 27 (46%) had three or more sites of bone pain. According to the Edmonton pain staging classification, 43 (75%) had Stage 3 (poor prognosis) pain, and this was primarily on the

4 322 Ernst et al. 1/ol. 13 No. 6J'une 1997 basis of a major incident component to the pain description. Upon entry, all patients had normal white blood and platelet counts, and normal serum sodium, potassium, calcium, phosphate, and creatinine. None of these biochemical parameters changed during the course of the study. No patients had clinical or biochemical evidence of hypocalcemia. No hypersensitivity reactions, including fever, were observed. No patients complained of an increase in gastrointestinal symptoms following either infusion of clodronate or. Preliminary analyses comparing the two doses of clodronate showed no dosage effect. Furthermore, no difference in clinical or biochemical parameters of toxicity was observed. Thus, for all subsequent analyses, the results fi-om both dosage arms are combined in the clodronate group. Forty-six patients were evaluable. One patient was excluded because of a dispensing error such that clodronate was given for both infusions. Five patients were unable to complete the study because the development of cognitive impairment prevented completion of the VAS and a reliable choice at the end of the study period. Three patients developed alternate non-osseous sites of pain due to progressive metastatic disease. Three patients were unable to complete the study because of concurrent development of significant but unrelated medical problems requiring hospitalization. One patient developed severe tendonitis in the foot and subsequently was unable to assess the effect of the infusions on the test site (hip pain). Two patients who were unable to complete all VAS and analgesic diaries, were able to provide the final assessment and choice, and therefore, were included in the analysis of preference. Patient and Investigator Selections At the conclusion of the study period, the patients were asked which, if any, of the two infusions correlated with the highest level of pain relief. If they could not distinguish a difference, the finding was recorded accordingly (see Table 2) Twenty-six of the 46 evaluable patients (57%) preferred clodronate, 12 (26%) patients preferred, and eight (17%) had no preference. The selection of clodronate was significantly favored (p = Table 2 Final Choice of Patient and Investigator No Clodronate Placebo preference Patient" Investigator b ~ Among those with a preference, p = 0.04; among all patients where each selection is equally likely, p = b Among those with a preference, p = ; among all patients where each selection is equally likely, p < ) If one considers only those 38 who expressed a preference, clodronate was still favored (68% versus 32%, p = 0.04). The investigators also selected which of the two infusions corresponded with a reduction in bone pain. Their decision was based on their clinical observations and perusal of the VAS and analgesic diaries. Clodronate was chosen in 30 of 46 evaluable patients (65%), was chosen in ten (22%), and no preference could be determined in six (13%) (p < If one considers only those 40 in whom a preference appeared evident, clodronate appeared to be beneficial (75% versus 25%, p = 0.002). Visual Analogue Scales Box and whisker plots were constructed for the VAS data 2~ and are illustrated in Figure 1. In order to combine the estimated treatment effects in the two groups [clodronate followed by, (C-P), or followed by clodronate, (P-C)], one must assume that the effect is the same in both groups, that is, that there is no treatment period interaction. However, evidence for a treatment period interaction for general pain scores (p = 0.08) and number of breakthroughs (p = 0.07) was identified. Marginal evidence also existed for a treatment period interaction for the two other pain measures and DMED score (p < 0.20). Because a carryover effect was observed, analysis of the VAS and DMED was restricted to a comparison of clodronate and in the first period only. In the clodronate group, the mean scores for general pain decreased from baseline by an average of 14.3 mm (SE = 4.0) for days Scores decreased a further 8 mm by days for a total average decrease of 22 mm (SE = 7.2). Decreasing general pain scores were also seen in the group, although the effect was

5 Vol. 13 No. 6June 1997 Clodronate and Metastatic Bone Disease ~00 O 0 doys; Clodronote days: I4 Clodror'~te -g c~ & 50 "~_ 50 0 d oy~;: Clodronate cloys: I Clodronate A B 150 Fig. 1. Box and whisker plots of visual analogue scale data for (A.) general pain; (B.) pain at rest; and (C.) pain with movement. The horizontal line within each box represents the median; the upper and lower box edges represent the 75th and 25th percentiles, respectively; and the whiskers extend over the range of the data fi N ~ 50 C do~: Clodtonote d~: o14 p~cebo Ciodronate not as large. At days 11-14, scores were an average of 13.2 mm (SE = 7.5) below baseline. The difference between clodronate and was not statistically significant (p = 0.51). Similar results were seen for VAS scores for pain at rest and pain with movement. The decreases in the clodronate group were approximately twice as large as those seen in the group (pain at rest 14 versus 8.5, pain with movement 24 versus 15) but the differences were not statistically significant (p = O. 78 and p = 0.22, respectively). Analgesic Requirements Of the 22 patients who first received clodronate, the DMED decreased from baseline in 13 (59%), increased in five (23%), and remained unchanged in four (18%). In the 17 patients who first received the, only six (35%) had a reduction in DMED, nine (53%) had an increase, and two (12%) remained unchanged. The average change in DMED for clodronate was -6.4 (SE = 2.9) and for was (SE = 14.9). The difference was statistically different ('p = 0. 03).

6 324 Ernst et al. Vol. I3 No. 6June 1997 Discussion All patients entered into the trial had advanced disease and pain that was refractory to usual medical management and local radiotherapy. Opioid intolerance was a major factor in providing suboptimal pain control and led to the consideration of alternative or adjunctive methods of improving pain control. The Edmonton Pain Staging System stratifies patients according to known prognostic factors for pain control, such as mechanism of pain, presence of incident pain, previous opioid exposure, and opioid tolerance. Forty-three patients (75%) were classified as poor prognosis (Stage 3), primarily because of the presence of incident pain, a finding characteristic of bone pain. According to the negative predictive value of the Edmonton system, most of these patients would be expected to have poor pain control. ~4 Furthermore, tile low performance status and poor survival (<3 months) would suggest that these patients had a higher likelihood of being refractory to interventions for their pain control. The results of this trial indicate that clodronate was chosen by most patients and would suggest that the adjunctive analgesic benefit may be even more pronounced in patients with less advanced disease and more favorable bone pain syndromes. The crossover design of this study was utilized in order to allow each patient to serve as his or her own control. 25 Each patient had a unique pain experience and had varying degrees of metastatic bone disease. In contrast to a parallel design that compares effects between patients, the crossover study can be more sensitive to treatment differences as the comparison is based upon differences within patients. Because each patient serves as his or her own control, the crossover design can achieve the same statistical power as the parallel design with fewer patients. The utility of the crossover design is lessened, however; if a patient's disease becomes unstable or if period or carryover effects are demonstrated. In a previous cross-over study and several Phase 2 analgesic studies, the duration of the analgesic effect produced by clodranate appeared to be limited to less than 14 days. l '13'ls However, in this study a carryover effect was evident in the VAS pain scores and limited further analysis to the first period, thereby reducifig the power to detect a signifi- cant difference. A carryover or period effect was not evident in the blinded selections made by patients or the investigators. In spite of the limited number of patients in the first period analysis, the analgesic requirements appeared to be reduced overall in the clodronate group. The analgesic consumption was considered a secondary end point, and patients were not specifically instructed in how and when to alter their analgesics. Rather, the patients' principle instructions were in the use of breakthrough doses should their baseline requirements be insufficient for pain control. Because a wide range of DMED existed in this heterogenous group of patients, the absolute differences become less meaningful. However, an overall reduction in analgesic requirements appears in evidence. No trends were apparent in the number of breakthrough doses, although all additional breakthrough doses were incorporated into the DMED calculations for each patient. Were the VAS measurements valid in this cohort of patients? M1 patients had advanced disease and were receiving opioids. Although cognitive function was evaluated by clinical assessment at study entry, a significant number of patients were withdrawn before study completion because of cognitive impairment. This is consistent with the findings of other investigators that as many as 85% of patients receiving terminal care develop cognitive impairment, zt-zs and 20% of such patients who enter clinical trials have subclinical evidence of cognitive impairment. 99 As a result, the ability to obtain consistent and valid subjective measures can be limited, and alternative methods of subjective assessment require further development. In this population of debilitated patients who require high doses of opioids, the incidence of cognitive dysfunction would be expected to be much greater; this underscores the importance of objective measures of cognitive function at study entry. Because of the carryover effect, the analysis of the VAS was limited to the first period, and the study design did not have sufficient statistical power to demonstrate differences in pain scores between clodronate and. Interestingly, for those patients receiving the clodronate in the first phase, the VAS pain scores had not returned to baseline by day 14 and scores continued to increase, consistent with

7 Vol. 13 No. 6June 1997 Clodronate and Metastatic Bone Disease 325 progressive pain. These patients' underlying disease was similarly unstable during the 28-day duration of the study. The validity and reproducibility of VAS scores have been established when they are completed daily and with appropriate instruction and supervision. 3 'sl Throughout the study period, the patients were encouraged to complete the VAS at the same time each day. Due to practical limitations, however, patients did not receive daily reinforcement of the VAS completion. Consequently, many patients did have some difficulty in the daily completion of the all VAS scores, which may have contributed to the finding that the VAS scores did not fully support their final choice of agents. The final choice of patients reflects the overall level of satisfaction from the intervention and therefore, is the primary outcome measure. The selection allows the patient to effectively weigh the relative benefit of the study agent with the impact of the adverse effects. The investigator selection reflects the perceived clinical benefit to the patient. In this study, the blinded selections of both the patients and investigators appeared to support the overall positive effect of clodronate in reducing bone pain. The benefit was apparent regardless of the order of the and clodronate infusions, and was obtained despite the carryover effect apparent in the VAS scores. These observations underscore the importance of incorporating a multiplicity of efficacy parameters into trial designs for patients with complex symptom control problems. The design of controlled studies of cancer pain offers many challenges. Accurate assessment of the complex and interacting factors that determine the adequacy of pain control must be addressed, and the distinction between changes in pain control and changes due to malignant disease progression must be made. Impairment in cognitive function, limited life expectancy, the requirement for controls, and the potential interactions with other interventions contribute further to the complexity of evaluating any intervention in these patients. Although two doses of clodronate were tested in the study, no apparent effect on analgesic response was observed. The pursuit of a dose-response relationship may be better served by an alternative design that incorporates dose escalation in patients who achieve an initial response. The duration of response also proved problematic in this trial, in that a carryover effect extending beyond 2 weeks appeared to occur in some patients. This was not evident in our earlier trial, which evaluated a 600-mg infusion of clodronate using a similar design, is Patients had a variety of underlying malignant diseases, and, hence, the nature of the underlying bone disease may have differed. Controlled trials of adjuvant clodronate therapy have been performed in patients with breast cancer, prostate cancer, and multiple myeloma. Reductions in bone pain were observed in these trials, although they have not been seen in other primary disease sites. 19'2 '32 Recently, Coleman et al. reported that patients with increased bone resorption appeared to respond more frequently to pamidronate infusions. 3s Biochemical markers of bone turnover, such as urinary calcium and hydroxyproline to croatinine ratios, and pyridoline cross-links, may prove predictive for response to bisphosphonate therapy. In spite the limitations of this study, intravenous Clodronate appeared to have an analgesic effect in patients with refractory pain, with or without opioid intolerance. The determination of a dose-response relationship and the magnitude and duration of effect requires further evaluation. In future -controlled trials, the selection of stable patients with similar parameters of metastatic bone disease will provide additional opportunity to determine the role of clodronate in patients with refractory bone pain. References 1. Scher HI, Yagoda A. Bone metastases: pathogenesis, treatment and rationale for the use of resorption inhibitors. Am J Med 1987;82: Tong D, Gillick L, Hendrickson R. The palliation of symptomatic osseous metastases. Cancer 1982;50: Hanks GW. The pharmacological treatment of bone pain. Cancer Surv 1987;7: Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain 1990;41: Fleisch H. Bisphosphonates. Pharmacology and

8 326 Ernst et al. Vol. 13 No. 6June 1997 use in the treatment of tumor-induced hypercalcemia and metastatic bone disease. Drugs 1991;42: Flanagan AM, Chambers TJ. Dichloromethylerie bisphosphonate (C12MBP) inhibits bone resorption through injury to osteoclasts that resorb C12MBP-coated bone. Bone Miner 1989;6: Miller SC, Jee WSS. The effect of dichloromethylene diphosphonate on bone and bone cell structure in the growing rat. Anat Rec 1979;193: O'Rourke NP, McCloskey EV, Vasikaran S, Eyres K, Fern D, Kanis JA. Effective treatment of malignant hypercalcemia with a single intravenous infusion of clodronate. Br J Cancer 1993;67: Bonjour JP, Rizzoli R. Treatment of hypercalcemia of malignancy with clodronate. Bone 1991;12: S19-$ Jung A, Chantraine A, Donath A, van Ouwenaller C, Turnill D, Mermillod B, Kitler ME. Use of dichloromethylene diphosphonate in metastatic bone disease. New EnglJ Med 1983;308: Jung A, van Ouwenaller C, Chantraine A, Courvoisier B. Parenteral diphosphonates for treating malignant hypercalcemia. Cancer 1981;48: Merlini G, Parrinello GA. Long-term effect of parenteral dichloromethylene bisphosphonate on bone disease of myeloma patients treated with chemotherapy. Hematol Oncol 1990;8: Adami S, Mian M. Clodronate therapy of metastatic bone disease in patients with prostatic carcinoma. Cancer Res 1989;116:6% Neri B, Gemelli MT, Sambataro S, et al. Subjective and metabolic effects of clodronate in patients with advanced breast cancer and symptomatic bone metastases. Anticancer Drugs 1992;3:8% Luzzani M, Vidili MG, Rissotto R, et al. Disodium clodronate in the treatment of pain due to bone metastases, lntj Clin Pharmacol Res 1990;10: Glover D, Lipton A, Keller A, et al. Intravenous pamidronate disodium treatment of bone metastases in patients with breast cancer. Cancer 1994; 74: Thurlimann B, Morani R, Jungi WF, P,,adziwill A. Pamidronate for pain control in patients with malignant osteolytic bone disease: a prospective dose-effect study. Support Care Cancer 1994;2: Ernst DS, MacDonald RN, Paterson AHG, JensenJ, Brasher P, Bruera E. A double-blind, crossover trial of intravenous clodronate in metastatic bone pain. J Pain Symptom Manage 1992;7: Lahtinen R, Laakso M, Palva I, Virkkunen P, Elomaa I. Randomized, -controlled multicentre trial of clodronate in multiple myeloma. Lancet 1992;340: Elomaa I, Kylmala T, Tammela T, et al. Effect of oral clodronate on bone pain: a controlled study of patients with metastatic prostatic cancer. Int Urol Nephrol 1992;24: Bruera E, Kuehn N, Miller MJ, et al. The Edmonton symptom assessment system: a simple method for the assessment of palliative care patients. J Palliat Med 1991;7: Duncan GH, Bushnell MC, Lavigne GJ. Comparison of verbal and visual analogue scales for measuring the intensity and unpleasantness of experimental pain. Pain 1989;37: Williamson DF, Parker RA, Kendrick JS. The box plot: a simple visual method to interpret data. Ann Intern Med 1989;110: Bruera E, Schoeller T, Wenk R, et al. A multicentre validation of the Edmonton staging system for cancer pain. J Pain Symptom Manage 1995: 10(5) : Hills M, Armitage R The two-period cross-over clinical trial, Clin Pharmacol 1979;8: Bruera E, Miller L, McCallionJ, et al. Cognitive failure in patients with terminal cancer: a prospective study. J Pain Symptom Manage 1992;7: Derogatis L, Morrow G, Fetting J, et al. The prevalence of psychiatric disorders among cancer patients. JAMA 1983;249: Massie MJ, Holland J. The cancer patients with pain: psychiatric complications and their management. Med Clin North Am 1987;74: Bruera E, Spachynski K, MacEachern T, Hanson J. Cognitive failure in patients in clinical trials. Lancet 1993;341: Cleeland C. Assessment of pain in cancer patients: measurement issues. In: Foley KM, Bonica JJ, Ventafridda V, eds. Advances in pain research and therapy, vol 16. Proceedings of the Second International Congress on Cancer Pain New York: Raven, 1990:4% Price DD, McGrath P, Raffi A, et al. The validation of a visual analog scale or ratio scale for pain. Pain 1983;17: Paterson AHG, Powles TJ, Kanis J, et al. Double blind controlled trial of oral Clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993;11: Coleman RE, VinholesJ, Abbey ME, Purhit OE Double-blind randomized trial of pamidronate for the palliative treatment of metastatic bone disease [Abstract]. ASCO Proceed 1996;15:528.