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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 placebo. 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. Forty-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 mm, respectively, from baseline, but were not significantly different from changes following placebo. The average change in DMED was -6.4 (SE = 2.9) following clodronate and was +24.6 (SE = 14.9) following placebo (p = 0.03). In the blinded choice of which agent resulted in improvement in pain, 26 (57%) patients chose clodronate, 12 (26%) chose placebo, and eight (17%) had no preference (p = 0.0021). For the investigators who also made a blinded selection, clodronate was chosen in 30 (65%) patients, placebo in ten (22%) patients, and no difference was apparent in six (13%) (p < 0.0001). 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.

Background: The short elimination half-life of metoclopramide necessitates frequent administration for optimal relief of nausea. This study compares a newly developed controlled release preparation of metoclopramide (CRM) and immediate release metoclopramide (IRM) with respect to efficacy, safety, and pharmacokinetics in patients with chronic nausea associated with advanced cancer., Methods: Thirty-four patients with advanced cancer with nausea lasting more than 1 month and with no evidence of involvement of the gastrointestinal tract, peptic ulcer or gastritis, brain metastases, or metabolic abnormalities were randomized, in a double-blind cross-over study, to receive 40 mg of CRM every 12 hours or 20 mg of IRM every 6 hours for 3 days. Nausea, food intake, and side effects were assessed four times daily. On Day 3, sequential venous samples were taken (12 patients) to determine plasma metoclopramide concentrations., Results: In 29 evaluable patients, the intensity of nausea on Day 3, measured by a 0-100-mm visual analogue scale and 0-3 categoric scale was 15 +/- 17 and 0.6 +/- 0.6 after IRM, versus 8 +/- 9 (P = 0.033) and 0.4 +/- 0.5 (P = 0.055) after CRM, respectively. Visual analogue scale nausea scores recorded by time of day and by day for the 3 treatment days were significantly lower for patients who received CRM compared with those who received IRM (P = 0.047 and P = 0.043, respectively), but categoric nausea scores were not significantly different between treatments by time of day and by day across the 3 treatment days. No differences were observed in caloric intake or side effects between treatments. In a pharmacokinetic analysis, the CRM/IRM ratio for area under the curve0-12 (microgram x hours x L-1), Cmax (microgram/L), and Tmax (hours) was 100%, 98%, and 2.3 fold, respectively., Conclusion: Controlled release metoclopramide is safe and effective in managing chronic nausea in patients with advanced cancer. Future studies should focus on characterizing this syndrome more clearly and on determining the optimal dose of metoclopramide and the effects of drug combinations that have proven to be useful in managing chemotherapy-induced emesis (i.e., metoclopramide plus corticosteroids).

After a baseline symptom and laboratory assessment, 24 patients with metastatic bone disease and pain were randomized to receive either a 4-hr intravenous infusion of 2-dichloromethylene bisphosphonate (Cl2MDP), 600 mg in 500 mL of normal saline, or a 4-hr placebo infusion, 500 mL of normal saline. The administration was double blind. After 1 wk, the assessment was repeated and the patients were crossed over to the alternate treatment. After 1 more wk, a final assessment and blinded choice by the patient and investigator took place. Of the 21 evaluable patients, 12 (57%) chose the Cl2MDP and 4 (19%) chose the placebo; 5 (24%) patients did not have a specific preference (p = NS). The investigator chose the Cl2MDP in 14 (67%) cases, placebo in 6 (29%) cases and was unable to discern a difference in 1 (5%) case (p less than 0.05). The patients and investigator made similar selections in 16 (76%) instances. On the visual analogue scale assessments, a significant decrease in pain scores was observed following the Cl2MDP infusion (p less than 0.01) and an increase in activity scores was also demonstrated (p less than 0.01). No significant difference in the daily oral morphine equivalent analgesic requirement was demonstrated for either arm. No difference in clinical and laboratory parameters of toxicity was evident between the placebo and Cl2MDP arms of the trial. Our preliminary findings suggest that Cl2MDP is safe, and has analgesic properties that may prove to be useful in the management of metastatic bone pain.

We report an open, uncontrolled study designed to assess the effects of subcutaneous (SC) morphine on dyspnea of terminal cancer. Twenty patients with dyspnea caused by restrictive respiratory failure received an SC dose of morphine of 5 mg (5 patients who were not receiving narcotics), or equivalent to 2.5 times their regular dose (15 patients who were receiving narcotics for pain). Dyspnea (D) and pain (15 cases) were measured before the dose and every 15 min for 150 min after the injection using a visual analog scale 0-100. Respiratory rate (RR), respiratory effort (RE) (score 1-6), arterial saturation of O2 (SO2) and end-tidal PACO2 were determined before and 45 min after SC morphine. D, RR, RE, SO2, and PACO2 were 68 +/- 32, 32 +/- 7; 3.5 +/- 1.8, 87 +/- 10, and 31 +/- 12, respectively, before SC morphine, and 34 +/- 25 (P less than 0.001), 31 +/- 9 (P:NS), 3.2 +/- 1.9 (P:NS), 86 +/- 11 (P:NS), and 33 +/- 9 (P:NS), respectively, 45 min after SC morphine. Nineteen of 20 patients (95%) reported improved dyspnea after morphine. We conclude that morphine appears to improve dyspnea without causing a significant deterioration in respiratory function in terminal cancer patients. Double-blind placebo controlled studies are needed in this population.

This double-blind, cross-over trial was designed to assess the effects of megestrol acetate (MA) on cancer-induced cachexia. Forty consecutive malnourished patients with advanced non-hormone-responsive tumors receiving no antineoplastic treatment were randomized to receive MA 480 mg/day versus placebo for 7 days. During day 8, a cross-over was made until day 15. Appetite, pain, nausea, depression, energy, and well-being were assessed with a visual analog scale (0 to 100 mm) at 9:00 AM and 4:00 PM during days 6, 7, 13, and 14. Weight (W;kg), tricep skinfold (TS; mm), arm circumference (AC; cm), and calf circumference (CC; cm) were measured at days 1, 8, and 15. Caloric intake (CI; Kcal/day) was determined during days 6, 7, 13, and 14. In 31 evaluable patients, the percentual difference in appetite at 9:00 AM, appetite at 4:00 PM, energy, and well-being after MA was +15.1, +14, +3.2, and +5.2, versus -12 (P = 0.03), -5.1 (P = 0.015), -10 (P = 0.024), and -8.3 (not significant) after placebo. Percentual difference in W, TS, AC, and CC after MA was +0.2, +1, -0.1, and +0.4 versus -0.8 (P = 0.03), -0.8 (P = 0.001), -0.3 (not significant), and -0.5 (P = 0.04) after placebo. CI during MA was 3480 +/- 1574 (48-hour intake), versus 2793 +/- 1542 (P less than 0.001) during placebo. Patients and investigators blindly chose MA in 20 (66%, P = 0.023) and 28 cases (92%, P less than 0.001), placebo in eight and two cases, and made no choice in three and one cases, respectively. Toxicity consisted of mild edema and nausea in three and two cases, respectively. After mean follow-up of 27 +/- 13 days, on an open basis, an average increase in W and AC of 4.8 +/- 1.7 kg and 2.8 +/- 1.7 cm was observed, respectively. The authors conclude that MA is a powerful appetite stimulant with subjective and objective effects on nutritional status.

The charts of 200 consecutive patients with cancer pain admitted to a major teaching hospital in Edmonton, Canada (n = 100) and in Buenos Aires, Argentina (n = 100) were reviewed to assess the differences between North American (NA) and South American (SA) facilities in patterns of treatment of pain and other symptoms. Criteria for eligibility and methods were identical in both hospitals. Characteristics of patients (age, sex, primary tumor, reason for admission) and attending staff were similar between both hospitals. Mean daily equivalent doses of parenteral morphine (mg) were 44 +/- 26 and 9 +/- 10 in NA and SA, respectively (p less than 0.001). Patients in NA, received narcotics every 4 hr and on a regular basis more frequently than in SA. The types of narcotics and the use of adjuvant drugs were significantly different between NA and SA. Nonpharmacologic treatments, antiemetics, and laxatives were more frequently used in NA. These results suggest that there are significant differences in symptomatic management of advanced cancer between institutions in NA and SA.

We reviewed the charts of 48 consecutive patients treated by our Palliative Care Team (PCT) during 1984 and compared these results with 50 consecutive patients treated during 1987. The composition of the PCT did not change between 1984 and 1987. The median equivalent daily dose of parenteral morphine (MEDD) before referral, after initial treatment by the PCT, and at the maximum prescribed by the PCT were 43 mg, 48 mg, and 96 mg in 1984, respectively, versus 60 mg (p less than 0.03), 60 mg (p less than 0.03), and 120 mg (p less than 0.12) in 1987, respectively. Seventeen of 43 patients were receiving mild narcotics in 1984 versus 7 of 48 patients in 1987 (p less than 0.01). Parenteral narcotics were used initially in 2% of patients in 1984 versus 46% of patients in 1987 (p less than 0.001). Poor pain control after the initial treatment was observed in 42% of patients in 1984 versus 26% in 1987 (p less than 0.01). Our results suggest that patients are being treated more aggressively by their physicians before referral to the PCT in 1987, that our PCT is using more aggressive initial treatment than in 1984, and that, notwithstanding these changes, there is still a significant proportion of patients in whom pain cannot be controlled before death. These results suggest that more research is necessary to better define intractable pain syndromes and develop adequate treatments for them.

Previously untreated patients with myeloma were randomized to initial treatment with melphalan and prednisone (and to cyclophosphamide or carmustine if relapse or progression occurred)(Group A, 125 patients), melphalan, cyclophosphamide, carmustine and prednisone in alternating (Group B, 123 patients) or concurrent (Group C, 116 patients) schedules. The groups were similar with respect to known prognostic factors. Response rates and survival were also similar. We were unable to identify a subgroup of patients who responded or survived better on melphalan-cyclophosphamide-carmustine and prednisone than on melphalan and prednisone. We conclude that the combination of the four drugs is not better than melphalen and prednisone for inducing responses or prolonging the survival of patients with myeloma. Myelomas producing only gamma chains have a poorer prognosis (P greater than 0.001) than IgG, IgA, or kappa myeloma. Acute leukemia has developed in 14 patients. The actuarial risk of developing acute leukemia, has increased rapidly to 17.4 per cent at 50 months.

Sixty-one consecutive patients with advanced breast cancer (defined as metastatic disease) and 20 normal age- and sex-matched controls were admitted to a prospective study designed to assess muscle electrophysiology. Nutritional status, lean body mass, and ultrasonographic measurement of the triceps brachialis, sternomastoid, and adductor pollicis muscles were determined in patients and controls. In addition, tumor mass and performance status were determined in the patient group. Electrophysiology of the adductor pollicis muscle was assessed during isometric voluntary maximum effort and during electrical stimulation via the ulnar nerve (80-120 V, 50-100 msec). Nutritional status, lean body mass, and ultrasonographic measurements of the triceps brachialis, sternomastoid, and adductor pollicis were not significantly different between patients and controls. Maximum strength after supramaximal stimulation at 50 Hz was 34 +/- 15 N in patients, versus 40 +/- 9 (P less than .01) N in controls. Relaxation velocity was 336 +/- 149 N/sec in patients, versus 507 +/- 251 (P = .02) N/sec in controls. Fatigue (% of initial strength after 30 sec of stimulation) was 67% +/- 22% in patients, versus 79% +/- 17% (P = .03) in controls. Muscle electrophysiology did not correlate with tumor mass or performance status. It was concluded that patients with advanced breast cancer have abnormal muscle electrophysiology that is not due to abnormal nutritional status or decreased muscle mass. More research is needed to better characterize this disorder and to better define its cause.

Thirty-two patients with chronic pain due to advanced cancer were treated with methylphenidate (10 mg with breakfast and 5 mg with lunch) for 3 days, versus placebo, in a randomized, double-blind, cross-over study designed to evaluate the capacity of methylphenidate to potentiate the analgesic effect of narcotics and/or to decrease sedation induced by narcotics. In 28 evaluable patients, the intensity of pain (visual analogue 0-100) and intake of extra doses of analgesics (number of doses/day) were 43 +/- 27 and 2.2 +/- 2.4 during methylphenidate, versus 55 +/- 24 (P less than 0.02) and 2.9 +/- 2.9 (P less than 0.002) during placebo, respectively. Activity and drowsiness (visual analogue 0-100) were 57 +/- 25 and 58 +/- 24 after methylphenidate, respectively, versus 41 +/- 26 (P less than 0.05) and 45 +/- 27 (P less than 0.02) after placebo. Upon completion of the study, the investigator and the patient chose methylphenidate blindly as a more useful drug in 23 cases (83%) and 20 cases (70%), respectively (P less than 0.02). No cases of severe toxicity were observed. We conclude that methylphenidate can increase the analgesic effect and decrease sedation of narcotics in this population.

To assess the influence of a pain and symptom control team on the pattern of prescription of pharmacologic and nonpharmacologic treatments for cancer pain, we reviewed the charts of 100 consecutive patients admitted to the Cross Cancer Institute during 1987 and 100 patients admitted during 1984. The average daily dose of parenteral morphine per patient was 44 +/- 26 mg in 1987 versus 34 +/- 38 mg in 1984 (p less than 0.05). In 1987 and 1984, only 31 and 22% of the analgesics were ordered around the clock respectively (P:NS). Approximately half of the patients in 1987 and 1984 were prescribed antiemetics and two-thirds of the patients were prescribed laxatives. Parenteral narcotics were prescribed subcutaneously in 0/52 cases in 1984 versus 21/63 cases in 1987 (33%, p less than 0.01). The pattern of prescription of narcotics by residents changed significantly during the last four weeks of rotation as compared to the first four weeks. We conclude that there have been some changes in the modality of treatment of pain that are probably due to changes in the pattern of prescription by the residents and continued improvement in assessment of pain by nurses. However, in several areas of treatment the impact of a pain and symptom control team remains minimal.

Fifty-six patients with chronic pain due to advanced cancer were treated with an sc infusion of morphone (34 patients) or hydromorphone (22 patients) using a portable disposable infusor. The infusion was maintained for 26 +/- 14 days. Twenty-five patients (45%) were discharged to the home for a mean period of 18 days (range, 2-138). The mean daily increase in dose was 2.6% +/- 1.4% of the initial dose. The sc site needed to be changed every 8 days (range, 2-31). Local toxicity consisted of infection in two patients (3%), chemical irritation in three (5%), and bleeding in one (2%). After 48 hours of treatment, 54 of 56 patients (96%) preferred the sc infusion to their previous parenteral treatment. We conclude that this is a safe and simple method for the administration of narcotics to inpatients and outpatients.

A sensitive and convenient electron-capture gas chromatographic procedure for analysis of MHPG in small volumes of urine is described. The method involves acetylation under aqueous conditions, extraction with an organic solvent and reaction with trifluoroacetic anhydride under anhydrous conditions. The resultant derivative is separated and quantitated on a gas chromatograph equipped with a fused silica capillary column and an electron-capture detector.

Fifty-six consecutive patients with pain due to cancer were admitted to a prospective study designed to test a clinical staging system for cancer pain. The system classifies patients in stage 1 (good prognosis) to stage 3 (poor prognosis) according to the mechanism of pain, characteristics of pain, previous narcotic exposure, cognitive function, psychological distress, tolerance and past history of drug addiction or alcoholism. During day 1 patients were staged after being seen by one of the investigators. Patients were treated for 21 days, when a final diagnosis of pain control was made. Eighteen of 22 patients in stage 1 achieved good pain control (82%) vs. 2/22 patients in stage 3 (10%; P less than 0.01). Sensitivity, specificity and negative predictive value of the system were 0.75, 0.86 and 0.80, respectively. We conclude that this is a simple and reliable system for clinical staging that can be used for clinical research and management of patients with cancer pain.

Reports have been made in important advances in the therapy of nonseminomatous germ cell tumors from specialized cancer therapy centers that treat a selected referred patient population. We herein examine the impact of these improvements on the total community of a large geographic area. Using the facilities of a comprehensive cancer registry and standardizing the treatment of nonseminomatous germ cell tumors from 1976 to the present, we have shown that there has been a marked improvement in the over-all survival of patients with these tumors in northern Alberta. During the 4-year interval the survival rates were 100 per cent for patients with stage I, 93 per cent for those with stage II and 83 per cent for those with stage III tumor. The over-all survival rate for patients with nonseminomatous germ cell tumors in this community presently is comparable to that of patients with pure seminomas. We have shown that aggressive, multidisciplinary treatment, developed in specialized centers, can significantly improve the outlook for all patients with nonseminomatous germ call tumors in a defined community.

Sixty-four consecutive patients with advanced breast cancer were included in a study designed to determine the prevalence of asthenia and its association with other clinical features. The Asthenia Score (AS, the average of four tests designed by our group to assess asthenia) was 59 +/- 9 for patients versus 88 +/- 7 for a group of 68 normal controls (p less than 0.001). Twenty-six patients (41%) scored below the tenth percentile of normal controls and were considered asthenics. AS was correlated with depression and the general severity index of the SCL-90 R test. No association was found between AS and nutritional status, lean body mass, tumor mass, anemia, or type of treatment. We conclude that asthenia is a frequent symptom in patients with advanced breast cancer, which, in our series, showed independent correlations only with psychological distress.

Four men with metastatic nonseminomatous testicular cancer, who had received combination chemotherapy, experienced transient gynecomastia. Serum hormone levels were measured during and after the resolution of the gynecomastia. These levels indicated toxic effects on Leydig's cells and germinal epithelium concurrent with raised serum estradiol levels in the absence of tumor. The gynecomastia may have been caused by Leydig's cell dysfunction or refeeding after substantial weight loss. This benign form of gynecomastia must be recognized to avoid unnecessary investigation and treatment.

Twenty-five patients with pain due to advanced cancer were randomized to receive patient-controlled sc injections (PCIs) of hydromorphone (HM) versus continuous sc infusion (CSCI) of HM by means of a Pharmacia 5200 pump. Each self-injection of HM during PCI was equivalent to 4 hours of CSCI. After 3 days, a crossover occurred, and patients received the alternate treatment for 3 days. During both phases of the study, patients could request extra doses of HM from their nurses. In 22 patients able to be evaluated, pain intensity (visual analogue, 0-100 mm) at 9:00 a.m. and 4:00 p.m. was 31 +/- 23 and 28 +/- 18 mm, respectively, on PCI versus 28 +/- 18 and 27 +/- 17 mm, respectively, on CSCI [P = not significant (NS)]. The total dose of HM was 168 +/- 197 and 181 +/- 234 mg on PCI and CSCI, respectively (P = NS). No significant difference was found in nausea, drowsiness, or number of hours of sleep. The total number of extra doses of HM was 6 +/- 7 on CSCI versus 2 +/- 3 on PCI (P = .007). At the end of the study, patients chose PCI and CSCI in seven and 10 cases, respectively (P = NS; 5 patients expressed no preference). We conclude that both methods were similar in regard to effectiveness and toxic effects in short-term hospital use.