Should bisphosphonates be part of the standard therapy of patients with multiple myeloma or bone metastases from other cancers? An evidence-based review

PURPOSE: To review objectively the evidence for the use of bisphosphonates for the reduction of skeletal events or the management of pain due to multiple myeloma or bone metastases from other types of cancer. METHODS: MEDLINE was searched from 1976 onwards using the MeSH terms "exp diphosphonates/," "exp bone neoplasms/," "exp multiple myeloma/," and "bone metastases" as text words. Bibliographies of reports on these topics and major medical and scientific journals were searched. Experts in the field were approached. The question was defined and the evidence stratified in a hierarchical manner according to classification of study design. There were sufficient studies to enable the use of randomized trials only to address the questions. Effectiveness was defined and the evidence reviewed in a systematic manner. RESULTS AND CONCLUSION: Eighteen randomized trials were identified. No meta-analyses are available. There is level I evidence (defined as an appropriately conducted randomized clinical trial with a statistically significant result) for the use of bisphosphonates to reduce both skeletal events and pain in multiple myeloma and in breast cancer patients with metastatic bone disease. There is also level I evidence for their use as part of a pain management program for bone metastases from carcinoma of the breast, lung, and prostate, and for symptomatic myeloma. The bisphosphonates appear to be well tolerated.     

Current use of bisphosphonates in oncology. International Bone and Cancer Study Group

PURPOSE: The purpose of this article is to review the recent data on bisphosphonate use in oncology and to provide some guidelines on the indications for their use in cancer patients. DESIGN: The group consensus reached by experts on the rationale for the use of bisphosphonates in cancer patients and their current indications for the treatment of tumor-induced hypercalcemia and metastatic bone pain in advanced disease and for the prevention of the complications of multiple myeloma and of metastatic bone disease are reviewed. RESULTS: Bisphosphonates are potent inhibitors of tumor-induced osteoclast-mediated bone resorption. They now constitute the standard treatment for cancer hypercalcemia, for which we recommend a dose of 1,500 mg of clodronate or 90 mg of pamidronate; the latter compound is more potent and has a longer lasting effect. Intravenous bisphosphonates exert clinically relevant analgesic effects in patients with metastatic bone pain. Regular pamidronate infusions can also achieve a partial objective response by conventional International Union Against Cancer criteria and enhance the objective response rate to chemotherapy. In breast cancer, the prolonged administration of oral clodronate 1,600 mg daily reduces the frequency of morbid skeletal events by more than one fourth, whereas monthly pamidronate infusions of 90 mg for only 1 year in addition to chemotherapy reduce by more than one third the frequency of all skeletal-related events. The use of bisphosphonates to prevent bone metastases remains experimental. Last, bisphosphonates in addition to chemotherapy are superior to chemotherapy alone in patients with stages II and III multiple myeloma and can reduce the skeletal morbidity rate by approximately one half. CONCLUSION: Bisphosphonate use is a major therapeutic advance in the management of the skeletal morbidity caused by metastatic breast cancer or multiple myeloma, although many questions remain unanswered, notably regarding the optimal selection of patients and the duration of treatment.     

The effect of repeated strontium-89 chloride therapy on bone pain palliation in patients with skeletal cancer metastases

One hundred and eighteen patients with painful skeletal metastases of malignant diseases (predominantly prostate, breast and lung cancer) were treated with 150 MBq of strontium-89 chloride (Metastron, Amersham, UK) intravenously. The results were evaluated according to a score considering pain relief, mobility, analgesic intake and general feeling. In only five patients (4.2%) was no improvement observed; mild improvement was noted in 48 (40.7%), and substantial or complete improvement in 56 (47.5%) and 9 (7.6%), respectively. The mean painless period after a single 89SrCl dose was 3.3 +/- 2.28 months (in patients with prostate, lung, breast and other types of cancer it was 3.65 +/- 2.11, 3.29 +/- 1.27, 3.08 +/- 0.48 and 3.44 +/- 1.36 months, respectively). During a 3-year study, 89SrCl treatment was successively repeated up to 5 times in some patients (total number of Metastron applications was 256) who benefited from the first Metastron administration and did not show signs of myelosuppression. Even after repeated treatment, relief was consistent and the duration of the period without pain increased (in particular in patients with breast cancer, in whom the period of relief was prolonged from 3.08 +/- 0.48 months after the first dose to 5.33 +/- 2.36 months after the fifth 89SrCl administration). The increased painless period was not observed after repeated treatment in the patient group comprising miscellaneous types of cancer, and the degree of improvement was less apparent. During the course of successive 89SrCl treatments, transient signs of myelosuppression indicated by a decrease in white cell and thrombocyte counts of at least 25% were observed 10 times after Metastron administration (twice in two patients), i.e. in 3.9% of all 89SrCl administrations; these transient haematological changes of moderate grade were closely connected with Metastron administration. Palliative treatment of metastatic skeletal pain with 89SrCl improves the quality of life in most patients suffering from prostate, lung and breast cancer and may be safely repeated with the same benefit and without significant myelosuppression. The beneficial effect of 89SrCl treatment seems to be less pronounced in other types of cancer with painful skeletal metastases.     

Nursing science in German--current status and future prospects

Metastatic bone disease is a frequent cause of morbidity in advanced cancer patients with a subsequent high incidence of skeletal complications (fractures, hypercalcemia, spinal cord compression) and severe pain. The osteolytic process is mainly characterized by an osteoclastic activity of bone resorption and inflammatory activity provoked by various cytokines and prostaglandins. Bisphosphonates represent a new class of drugs with inhibitory activity on bone resorption and on inflammatory processes which revealed themselves to be efficacious in a series of clinical conditions such as tumour-induced hypercalcemia, Paget's disease, osteoporosis and metastatic bone disease. The aim of this review of the literature is to show the analgesic efficacy of the different bisphosphonates in phase III studies carried out on patients with metastatic bone disease. Medline and Cancerlit database from January 1984 to February 1998 have been considered. From the analysis of the published studies it appears that bisphosphonates and, in particular, intravenous Disodium Pamidronate, are not only able to slow down the progression of the disease and to reduce the onset of skeletal complications but also have an analgesic effect and the possibility of improving the quality of life, above all in patients with osteolytic metastases due to breast cancer and multiple myeloma. Bisphosphonates represent a further valid therapy to add to an already consolidated list of therapies such as radio, chemo and endocrine therapy, analgesic drugs, orthopaedic and physiatric in the pain management of patients with bone metastases. These drugs meet with the patients' compliance, are well-tolerated as well as having a good cost/efficacy profile. It still remains to be seen if the newer and more potent bisphosphonates such as Ibandronate and Zoledronate can be administered differently from the intravenous route such as by mouth or by patch which are readily accepted by the patient and, moreover, if these more potent drugs are able to prevent or delay the onset and/or the progression of bone metastases.     

The concept of rehabilitation of cancer patients

The scope of supportive care and cancer rehabilitation is very wide and heterogeneous. In this review we focus on nutritional aspects, sexual and gonadal function, psychological rehabilitation, treatment of cancer pain, and rehabilitation of patients with bone metastases. The anorexia-cachexia syndrome is a particularly frequent manifestation of cancer that profoundly affects body image and significantly impairs quality of life of cancer patients. However, enteral feeding through nasogastric tubes, gastrostomies, or jejunostomies is an efficient method for providing long-term enteral nutrition at home and for contributing to complete rehabilitation after cancer therapy. Recent effort has focused on nutritional pharmacology and on the optimalization of the use of appetite-stimulating drugs, such as progestational agents. The psychological components of cancer, anticancer therapy, and quality of life have now been widely recognized and studied. Effective pharmacological and psychotherapeutic interventions help patients and their family to better adjust to the chronic stress of cancer, but more specific determinants of psychological morbidity should be developed. In particular, the safe and efficient use of the most recent classes of antidepressants and anxiolytics should be urgently studied. More than 90% of cancer patients present one or more pain syndromes during their illness. The adequate use of drugs is the cornerstone of treatment. The development on new molecules and new routes of administration opens interesting perspectives for cancer pain control. Bone metastases are the source of considerable morbidity. Intravenous bisphosphonates have been successfully used for the treatment of the symptoms of metastatic bone disease, especially bone pain. Moreover, monthly pamidronate infusions in addition to chemotherapy reduce the mean skeletal morbidity rate by more than one third and contribute to the rehabilitation of cancer patients with bone metastases from breast cancer or with multiple myeloma.     

Massive adrenal hemorrhage secondary to metastasis of lung cancer

Hemorrhagic adrenal metastasis from lung cancer is extremely rare, although adrenal involvement is common in widely disseminated cancer. We report a case of massive adrenal hemorrhage secondary to metastasis of lung cancer. A 47-year-old female was treated by left upper lobectomy and mediastinal lymph node resection for an adenocarcinoma with intrapulmonary metastasis in the left upper lobe. Eight months later, she presented with right flank and back pain, and abdominal ultrasonography and computed tomography showed a right solitary adrenal tumor with massive hemorrhage. The tumor was not resectable and partially responded to chemotherapy. A massive adrenal hemorrhage, secondary to metastasis of lung cancer, presents with nonspecific clinical signs and symptoms. In lung cancer patients with an acute flank or back pain, hemorrhagic adrenal metastasis should be considered in the differential diagnosis.     

Small intestine pathogens in AIDS: conventional and opportunistic

Cancer presents itself in numerous ways, adding to the complexity of any pain syndrome with which it is associated. Neuropathic pain, unlike many other pain syndromes, is difficult to treat even in the absence of cancer. The combination results in a heterogeneous group of patients with a complex set of symptoms. This makes the assessment of pain, classification of syndromes, and clinical study a challenge. If the disease is nonprogressive, general principles of care are essentially the same as in those without cancer. In patients with progressive disease and more refractory painful conditions, spinal anesthetic and neurosurgical therapies must often be considered. Under such circumstances, caregivers are forced to carefully balance uncertain benefits and risks, often without the luxury of time. More careful observation and controlled trials in these patients help facilitate this challenging process.     

Causes and treatment of bone pain of malignant origin

Pain relief has been one of the oldest and most important duties of the physician. There has been little change with regard to this obligation of all caregivers. One-third of patients with advanced cancer will develop clinically relevant skeletal metastases and chronic pain during the course of their disease. All physicians involved in the treatment of cancer patients should know the basic principles of pain treatment. These are described in the following article with special regard to bone pain of malignant origin. Correct assessment of pain intensity and frequency, as well as of the probable causes of pain, and the administration of adequate analgesic treatment should achieve satisfactory results in the vast majority of patients. Every physician should obtain detailed knowledge of the indications and adequate administration of pain-killing therapy as well as possible adverse effects and their successful treatment. It is important in particular to concentrate on a few nonsteroidal anti-inflammatory drugs (NSAIDs) as well as opiates. Knowledge of adequate doses, maximal recommended daily doses, pharmacological properties, important adverse effects and interactions is essential for success in the daily routine. Only by selecting 2 or 3 drugs from each step in the analgesic ladder (WHO) will the nonspecialised physician obtain sufficient experience for optimal analgesia. Physicians should also not hesitate to contact other specialists (medical oncologists, radiotherapists, neurosurgeons, anaesthesiologists and others) in order to maximise benefit for an individual patient.     

Bone metastasis with superimposed osteomyelitis in prostate cancer

The following case of a male patient with a history of prostate cancer suffering from pain and swelling in the right mandibular area illustrates the well-known diagnostic problem of a superinfected tumor. Orthopan tomography and CT showed no defects in bone structure or smooth tissue. Whole-body bone scanning showed increased tracer uptake in the mandibular bone and in several other locations in the skeletal system. Antigranulocyte immunoscintigraphy showed increased uptake over the right mandible, whereas the other metastatic sites were visualized as cold spots. A second CT scan depicted a sclerotic lesion with surrounding periostal reaction and soft-tissue swelling and was interpreted as osteomyelitis. Therefore, clinical symptoms, bone scanning, antigranulocyte immunoscintigraphy and follow-up CT resulted in a diagnosis of osteomyelitis, although open needle biopsy revealed the lesion to be prostate cancer metastasis with massive leukocytic invasion.     

Isolation and partial characterization of a broad specificity aminotransferase from Leishmania mexicana promastigotes

Previous studies have shown that intraspinal injection of quisqualic acid (QUIS) produces excitotoxic injury with pathological characteristics similar to those associated with ischemic and traumatic spinal cord injury (SCI). Significant changes in the functional properties of sensory neurons adjacent to the site of injury have also been observed in this model. Additionally, following QUIS injections, mechanical and cold allodynia, combined with excessive grooming behavior have been shown to be the behavioral correlates of these pathological and physiological changes. These behaviors are believed to be related to the clinical conditions of spontaneous and evoked pain following SCI. Given the therapeutic properties of adrenal chromaffin cell transplantation in conditions of neuropathic and cancer pain, it is proposed that the neuroactive substances released from chromaffin cells can alter or prevent the onset and progression of QUIS-induced behavioral changes. The effects of adrenal transplants were evaluated in 14 male Long-Evans rats that received intraspinal injections of QUIS. Pain behaviors, including the progression of excessive grooming behavior (n=8) and hypersensitivity to mechanical and thermal stimuli (n=6) were evaluated following transplantation. A 53% increase in mechanical thresholds was observed following adrenal transplants along with a 70% reduction in the area of skin targeted for excessive grooming. These behaviors were not affected in 11 animals receiving transplants of skeletal muscle. The effects of adrenal transplants on cold allodynia consisted of a stabilization of response latencies in contrast to the continued decrease in latencies, i.e., increased sensitivity, following transplants of skeletal muscle. The results are consistent with previous studies showing the therapeutic efficacy of adrenal chromaffin cell transplants in neuropathic pain, and support the use of this treatment strategy for the alleviation of chronic pain following spinal cord injury.     

Magnetic resonance imaging of subcutaneous diffuse neurofibroma

A 31-year-old woman presented with increasing pain and tenderness of a long-standing soft tissue mass on her back. MRI showed a network of interconnecting tubular areas, which were T1 isointense and T2 hyperintense relative to skeletal muscle, and displayed marked Gd-DTPA enhancement. The lesion was situated within the subcutaneous fat. Clinically and radiologically, this mass was considered to be a subcutaneous venous haemangioma. Histological examination of the excised mass showed a diffuse neurofibroma with ectatic vessels and entrapped adipose tissue. Similar MRI appearances of subcutaneous haemangioma and diffuse neurofibroma may result in failure to make the correct diagnosis and in inappropriate management.     

Participatory action-research for health

Patients' reluctance to report pain and to use analgesics are considered major barriers to pain management. To explore this problem, 270 patients with cancer completed a 27-item self-report questionnaire (BQ) that assessed the extent to which they have concerns about reporting pain and using pain medication. The 8 specific concerns included fear of addiction, beliefs that 'good' patients do not complain about pain, and concern about side effects. Patients also completed a measure of pain severity and pain interference (the BPI). The percentages of patients having concerns assessed by the BQ ranged from 37% to 85%. Those who were older, less educated, or had lower incomes were more likely to have concerns. Higher levels of concern were correlated with higher levels of pain. Based on their reports of pain medications used in the past week and on their reports of pain severity, patients were categorized as under-medicated versus adequately medicated. Those who were under-medicated reported significantly higher levels of concern. The data are discussed in terms of implications for research and practice.     

Connections between musculoskeletal complaints and personality

Modern research has demonstrated a weak association between level of muscle tension and experience of muscle pain. Anxiety and dysphoric over-responsiveness are the traditional psychogenic risk factors in muscle tension. Results from recent Norwegian research lend support to a more multidimensional causal understanding of muscle tension and of pain. Generally, personality factors were found to be a contributory cause of muscle pain of the neck and shoulders, whereas ergonomic load was found to be of greater significance for low back pain. Personality factors may induce patterns of skeletal muscle activation discrepant with characteristics of the skeletal muscle physiology: Preference for aerobic activities may develop through social learning, whereas the muscles may be genetically biased toward anaerobic activities. Furthermore, personality factors may be challenged by the work setting, and may result in mismatch that provokes muscle pain. Impatient expenditure of effort has appeared as a mediating personality risk factor among workers exposed to high ergonomic load, whereas dysphoric over-responsiveness mediated back pain primarily among staff exposed to high emotional load.     

A short (3-day) course of azithromycin tablets versus a 10-day course of amoxycillin-clavulanic acid (co-amoxiclav) in the treatment of adults with lower respiratory tract infections and effects on long-term outcome

The majority of patients with cancer experience significant pain during their illness. Most cancer pain can be readily managed with oral analgesic therapy. However, cancer pain is often under-treated because of poor communication between physicians and patients and inadequate training of physicians in pain management. A systematic pain-oriented history, pain intensity assessment physical exam, and diagnostic evaluation are needed to delineate the cause of pain. A therapeutic plan can then be tailored to the patient's needs, preferences, and severity of pain. This paper reviews the evaluation and treatment of cancer pain, with guidelines for initiating and monitoring non-opioid and opioid analgesic therapy.     

Knowledge and attitudes of health-care providers toward cancer pain management: a comparison of physicians, nurses, and pharmacists in the state of New Hampshire

The knowledge and attitudes toward cancer pain management of physicians, nurses, and pharmacists in the state of New Hampshire were examined through the use of a statewide survey. Many of the providers who completed the survey, and thus indicated that they treated patients with cancer pain on a regular basis, were not pain or oncology specialists. Most of these providers were quite well informed about the fundamentals of cancer pain management. Approximately 90% of providers in all three groups were not concerned about addiction among cancer patients. Yet, there was a small percentage of providers who responded in less than optimal ways to items dealing with opioid pharmacology, pain assessment, and the importance of pain relief. Comparison of responses among provider groups indicated that nurses were the most knowledgeable and pharmacists the least knowledgeable about pain assessment. Physicians were the most knowledgeable regarding opioid pharmacology but seemed the least committed to providing optimal pain relief. Further analysis identified a small group of physicians that included a disproportionately high percentage of family practitioners and surgeons who consistently responded in less than optimal ways to items dealing with the importance of pain relief. The results of this study indicate a continuing need for broad-based educational programs in cancer pain management and for new initiatives focused on practitioners who see relatively few cancer patients and may have difficulty accessing traditional educational programs.     

Glial fibrillar acidic protein in peripheral nerve tumors in rats

Cancer education merits a coordinated, vertical curriculum and an integrated planning strategy. It has become clear that it is as important to teach the techniques of supportive care in oncology as it is to teach the concepts of cancer biology, pathology, epidemiology, prevention, detection and aggressive treatments. Our aim is to determine whether the medical school and nursing school curricula give the students an introduction to the concepts of supportive care of the cancer patient. The spectrum of such supportive care encompasses a wide range of issues working towards a common goal of providing overall comfort with an emphasis on quality of life, and runs parallel with specific therapeutic strategies and associated problems. Do the graduate medical student and nursing student understand that cancer management is multidisciplinary and team-based? That the approach to pain management not only includes the administration of pain medications, but should also evaluate pain assessment and anesthetic, neurosurgical and behavioral approaches? That nausea and vomiting associated with chemotherapy can be ameliorated to a certain extent? That infections are common but algorithms exist for prevention and therapy? That certain metabolic complications are unique to cancer patients? That transfusions are vital procedures in patients with neoplasms undergoing aggressive treatments but are associated with certain risks and complications? That there are serious psychosocial, ethical and legal needs to be considered? To address these issues, the American Cancer Society Professors of Clinical Oncology, the American Cancer Society Professors of Oncology Nursing and the United States Cancer Center Directors were surveyed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Polyethylene wear of the Optifix cementless acetabular component after 5 years

We describe seven patients who developed symptoms including severe headache, circumoral paresthesia, and facial flushing during high-dose carmustine (BCNU) infusion as part of the preparative regimen for autologous peripheral blood stem cell (PBSC) transplantation for metastatic breast cancer. Five patients responded to pain medications, including partial and complete opiate receptor agonists. Premedication of subsequent doses of BCNU with corticosteroids, pain medications, or benzodiazepines lessened, but did not prevent the same symptoms from recurring. The incidence and mechanism of this toxicity are unknown, but this adverse syndrome should be considered when administering high-dose BCNU infusions.     

Strontium-89 for palliation of pain from bone metastases in patients with prostate and breast cancer

We have used strontium-89 chloride (89Sr) for the palliative treatment of metastatic bone pain. Seventy-six patients (50 males with prostate carcinoma and 26 females with breast cancer) were treated with 148 MBq of 89Sr. Sixteen patients were retreated, receiving two or three doses; the total number of injected doses was consequently 95. The Karnofsky performance status was assessed and pain and analgesia were scored on scales of 9 and 5 points, respectively. The efficacy of 89Sr was evaluated at 3 months of treatment. Three levels of response were considered: good - when there was an increase in the Karnofsky status and a decrease in the pain score (equal to or higher than 4) or analgesic score (equal to or higher than 1); partial - when there was an increase in the Karnofsky status and a decrease in the pain score (2 or 3 points) without significant changes in the analgesic score; no response - if no variation or deterioration in these parameters was observed. In prostate cancer patients, the response was good in 64% of cases and partial in 25%, and there was no response in the remaining 11%. In breast cancer patients, the response was good in 62% of cases and partial in 31%, and there was no response in the remaining 8%. Duration of the response ranged from 3 to 12 months (mean 6 months). In the patients who were retreated the effectiveness was as good as after the first dose of 89Sr. A decrease in the initial leucocyte and platelet counts was observed after the 1st month of treatment, with a gradual partial to complete recovery within 6 months. It is concluded that 89Sr is an effective agent in palliative therapy for metastatic bone pain in patients with prostate or breast carcinoma. If required, retreatment can be administered safely and with the same efficacy as is achieved by the first dose.