磷酸盐指南

International society of geriatric oncology (SIOG) eco es Cole of Jules B it, Natio and land Bone pain treatment of dental problems by a dental team is recommended before bisphosphonates. In elderly cancer patients with bone metastases, the use of bisphosphonates to prevent skeletal-related events (SREs) warrants special consideration, due to physiologic decline and comorbidities that require the use of several concomitant renal insufficiency (creatinine clearance <60 mL/min) as a re- sult of age-related kidney function decline and may be at par- ticular risk from renal toxicity. Furthermore, they may have underlying renal impairment related to their disease (espe- cially multiple myeloma).1 Concomitant medications for E U R O P E A N J O U R N A L O F C A N C E R 4 3 ( 2 0 0 7 ) 8 5 2 –8 5 8 ava i lab le at www.sc iencedi rec t .com : w * Corresponding author: Tel.: +32 2 541 3303; fax: +32 2 541 3311. Clinical practice recommendations Elderly SIOG Renal safety Physicians should choose the most appropriate bisphosphonate. Safety precautions are particularly important in elderly patients. Further research is needed in this population. � 2007 Elsevier Ltd. All rights reserved. 1. Introduction drugs. Many elderly patients have impaired renal function or Article history: Received 18 September 2006 Received in revised form 6 December 2006 Accepted 8 December 2006 Available online 26 January 2007 Keywords: Bisphosphonates Bone metastases A society of geriatric oncology (SIOG) task force reviewed information from the literature (in PubMed) on bisphosphonates in elderly patients with bone metastases until December 2005. Additional pertinent data were obtained from the manufacturers. Bisphosphonates are recommended in the elderly with bone metastases to prevent skeletal-related events. Intravenous formulations are preferred for the treatment of hyper- calcaemia. It has been recognised that zoledronic acid, ibandronate and pamidronate can effectively contribute in relieving metastatic bone pain. Creatinine clearance should be monitored in every patient, and a less renally toxic agent should be used where evidence of similar efficacy is available. The assessment and optimisation of hydration status is rec- ommended. Due to the risk from osteonecrosis of the jaw, routine oral examination and clinical practice r of bisphosphonat Jean-Jacques Bodya,*, Rob Rene Rizzolie, Matti Aapr aUniversite´ Libre de Bruxelles, Institut bWeston Park Hospital, Sheffield, UK cINSERMU.664, Lyon, France dRehabilitation and Palliative Care Un eUniversity Hospital, Geneva, Switzerl fClinique de Genolier, Geneva, Switzer A R T I C L E I N F O 0959-8049/$ - see front matter � 2007 Elsevi doi:10.1016/j.ejca.2006.12.006 E-mail address: jj.body@bordet.be (J.-J. Bo mmendations for the use in elderly patients manb, Philippe Clezardinc, Carla Ripamontid, ordet and CHU Brugmann, Brussels, Belgium nal Cancer Institute of Milan, Italy A B S T R A C T Review journal homepage er Ltd. All rights reserved dy). ww.ejconl ine.com . treatment of the primary cancer, such as some chemothera- pies,2 also have potential nephrotoxic side effects. Tolerability issues associated with intravenous (i.v.) bis- phosphonates include infusion-site reactions, renal functions deterioration and osteonecrosis of the jaw (ONJ). Although exceptional, elderly patients are at higher risk to develop re- nal impairment due to reduced hydration, overuse of non-ste- roidal anti-inflammatory drugs (NSAIDs) for analgesic purposes, and concomitant treatment with antihyperten- sives, antidiabetic drugs and lipid-lowering agents. The objective of this publication is to provide clinical prac- tice recommendations for physicians on the indications and safe use of various bisphosphonates in elderly cancer pa- tients with bone metastases. At the time of writing, there were no randomised studies of elderly patients available on which to base recommendations; therefore, data from the available phase III and phase II studies of commonly pre- cases of life-threatening tumour-induced hypercalcaemia where the benefit outweighs the potential risk. Renal function monitoring is currently recommended prior to each dose. In patients receiving pamidronate for bone metastases, who show evidence of renal deterioration, pamidronate treatment should be withheld until renal function returns to within 10% of the baseline value.5 Caution is warranted when pamidro- nate is used with other potentially nephrotoxic drugs. 2.1.1.2. Clinical trial data 2.1.1.2.1. Breast cancer and multiple myeloma. Randomised studies of i.v. pamidronate have shown efficacy for the pre- vention of SREs in patients with metastatic bone disease due to breast cancer and multiple myeloma.6–8 In these stud- ies, pamidronate was generally well-tolerated, with few renal adverse events. Deterioration of renal function has been reported follow- nt idro ed sio .v. e om mu a; E U R O P E A N J O U R N A L O F C A N C E R 4 3 ( 2 0 0 7 ) 8 5 2 –8 5 8 853 scribed bisphosphonates and elderly subanalyses were considered. 2. Prevention of SREs Table 1 outlines dosing regimens, administration times and indications for some commonly used bisphosphonates. 2.1. Intravenous bisphosphonates 2.1.1. Pamidronate 2.1.1.1. Recommendations for use. The infusion rate of pamidr- onate should never exceed 60 mg/h (1 mg/min). In patients with myeloma and pre-existing renal disease (serum creati- nine <265 lmol/L or <3.0 mg/dL) ASCO guidelines recommend no specific change in dosage, infusion time, or interval,3 although it is probably advisable to increase the treatment interval.4 Pamidronate dose adjustment is not necessary in mild (creatinine clearance 61–90 mL/min) to moderate renal impairment (creatinine clearance 30–60 mL/min).5 Pamidro- nate should not be administered to patients with severe renal impairment (creatinine clearance <30 mL/min) unless in Table 1 – Commonly used bisphosphonates for the treatme Clodronate (Bonefos�;Ostac�) Pam (Ar Formulation Oral tablet or i.v. infusion (rarely used) i.v. Infu Administration time (i.v.) 2–4 h >2 h Dosing regimen Oral 1600 mg/day, range 800–3200 mg/day (maximum); i.v. 900 mg every 3–4 weeks 90 mg i weeks Indication MBD from breast cancer; multiple myeloma; HCM MBD fr cancer; myelom MBD =metastatic bone disease; HCM = hypercalcaemia of malignancy; i. ing long-term treatment with pamidronate in patients with multiple myeloma.5 However, a study has shown that long- term pamidronate treatment in 22 elderly patients (median age 73 years) with bonemetastases was effective andwell-tol- erated.9 There were two cases (9%) of mild reversible renal insufficiency (creatinine 1.7 and 1.6 mg/dL). 2.1.2. Zoledronic acid 2.1.2.1. Recommendations for use. Special care should be ta- ken to monitor renal function in the elderly.10 Pre-existing re- nal insufficiency11 and multiple cycles of zoledronic acid and other bisphosphonates (e.g. pamidronate) are risk factors for subsequent renal deterioration with zoledronic acid.11–14 Zoledronic acid dose adjustments are required for patients with mild to moderate renal impairment depending on base- line creatinine clearance: >60 mL/min = 4 mg; 50–60 mL/ min = 3.5 mg; 40–49 mL/min = 3.3 mg; 30–39 mL/min = 3.0 mg.15 Zoledronic acid is not recommended in patientswith se- vere renal impairment (<30 mL/min). Renal monitoring guide- lines in the prescribing information for zoledronic acid recommend that serum creatinine be measured before each dose and suggest that treatment be withheld in patients with renal deterioration.15 Factors such as dehydration or the of metastatic bone disease nate ia�) Zoledronic acid (Zometa�) Ibandronate (Bondronat�) n i.v. Infusion Oral tablet or i.v. infusion P15 min 1 h very 3-4 4 mg i.v. every 3–4 weeks 6 mg i.v. every 3–4 weeks Oral 50 mg/day breast ltiple HCM MBD from breast, prostate, lung or other solid tumours; multiple myeloma; HCM MBD from breast cancer; HCM v. = intravenous. concomitant administration of other nephrotoxic agents should be identified and managed if possible. 2.1.2.2. Clinical trial data 2.1.2.2.1. Breast cancer, multiple myeloma, all solid tumours. 158) of patients were P65 years in the placebo group, com- pared with 25% (39/154) of patients in the ibandronate 6 mg group. At 2 years, deterioration was similar between ibandro- nate and placebo (9% versus 6% with placebo; Fig. 118). These data may suggest that ibandronate has renal tolerance com- cti e >7 854 E U R O P E A N J O U R N A L O F C A N C E R 4 3 ( 2 0 0 7 ) 8 5 2 –8 5 8 The superiority of zoledronic acid compared with pamidro- nate has been demonstrated by a multiple-event analysis in breast cancer patients.16 The efficacy of 4 mg i.v. zoledronic acid for the prevention of SREs has been demonstrated in phase III trials of patients with breast cancer, multiple myelo- ma, hormone-refractory prostate cancer (HRPC) and other so- lid tumours.17 In patients with breast cancer, or with solid tumours, the safety of zoledronic acid was reported to be sim- ilar to pamidronate or placebo. In patients with HRPC, renal function deterioration occurred in 16/92 (17.4%) patients who received 4 mg zoledronic and in 10/78 (12.4%) patients who received placebo.15 A sub-analysis of renal function deterioration was con- ducted in patients aged 670 years and >70 years from the phase III study. The differences between age groups were sim- ilar for 4 mg zoledronic acid and 90 mg pamidronate (Table 2). Within the limits of the data, the elderly kidney is no more sensitive to the nephrotoxic effect of zoledronic acid than the younger kidney.18 2.1.3. Intravenous ibandronate 2.1.3.1. Recommendations for use. In a multivariate analysis, age was not found to be an independent factor of any phar- macokinetic parameters studied.19 No dosage adjustment is necessary for patients with mild or moderate renal impair- ment where creatinine clearance is P30 mL/min. Below 30 mL/min creatinine clearance, the dose for prevention of SREs in patients with metastatic breast cancer should be re- duced to 2 mg every 3–4 weeks, (1-h infusion) to maintain drug exposure levels. Approved product labelling for ibandro- nate in the European Union recommends monitoring renal function only according to clinical assessment of each patient at the discretion of the physician. There are no dosing restric- tions for ibandronate in patients who are receiving concomi- tant nephrotoxic cancer therapies. 2.1.3.2. Clinical trial data 2.1.3.2.1. Breast cancer and multiple myeloma. The efficacy and safety of i.v. ibandronate for the prevention of SREs are demonstrated in a phase III, placebo-controlled study of pa- tients with breast cancer and in an open-label 2-year exten- sion of this trial.17 Two-year assessments of time to serum creatinine increase also demonstrated renal safety compara- ble to placebo.17 In a subset analysis of the pivotal phase III study of i.v. ibandronate, time to renal function deterioration was investi- gated in patients aged P65 years. Twenty-two percent (35/ Table 2 – Percentage of patients who experienced renal fun pamidronate according to age Treatment Age 670 yr (%) Ag Zoledronic acid 4 mg 9.1 Pamidronate 90 mg 8.2 parable to placebo even when administered in the elderly, although this is unproven. 2.2. Oral bisphosphonates 2.2.1. Clodronate 2.2.1.1. Recommendations for use. Clinical trials have included patients over 65 years, and no adverse reactions specific to this age group have been reported. There are no special dos- age recommendations in the elderly. In patients with severe renal impairment (creatinine clearance 10–30 mL/min), the daily dose should be reduced to half the usual dose, i.e. 800 mg. Clodronate is contra-indicated in patients with creat- inine clearance <10 mL/min. 2.2.1.2. Clinical trial data 2.2.1.2.1. Breast cancer, multiple myeloma. Clinical trials of oral clodronate have established its efficacy in patients with breast cancer and multiple myeloma.19–22 Although oral clodronate has been available for many years, it may not be as effective as i.v. pamidronate.23 A high incidence of gastrointestinal adverse events and dif- ficulty swallowing the capsules/or large tablets commonly contributes to non-compliance with oral clodronate.24,25 2.2.2. Oral ibandronate 2.2.2.1. Recommendations for use. No dose adjustment is necessary in elderly patients, or in patients with mild or mod- erate renal impairment where creatinine clearance is P30 mL/min. Below 30 mL/min creatinine clearance, the recom- mended dose is 50 mg weekly to maintain drug exposure lev- els. Oral bisphosphonates should not be administered with food. Ibandronate tablets should be taken after an overnight fast (at least 6 h) and at least 30 min before the first food or drink of the day.26 2.2.2.2. Clinical trial data 2.2.2.2.1. Breast cancer. Oral ibandronate has been shown effective and well tolerated in two phase III trials, and in an open-label extension study, of patients with breast cancer.17 In these trials, 50 mg of oral ibandronate was well-tolerated with few gastrointestinal adverse events. No patients with- drew because of difficulties in swallowing the tablets.17 2.2.3. Approach in elderly patients Physicians should take care to choose the most appropriate bisphosphonate with the best safety profile. Head-to-head on deterioration with 4 mg i.v. zoledronic acid and 90 mg 0 yr (%) Difference between age groups (95% CI) 7.5 �1.6 (�10.1,6.9) 8.2 �0.1 (�8.6,8.4) A N trials of bisphosphonates would help to determine relative efficacy and safety profiles. Information on the cost-benefits of bisphosphonates also would aid with treatment choice. The panel recommends that bisphosphonates should only be given to patients with life expectancy 690 days for uncon- trolled pain. In terminally ill patients with hypercalcaemia, only selected cases should receive bisphosphonates, and this should be discussed first with the patients and/or their families. 3. Bisphosphonates for the palliation of metastatic bone pain Elderly patients may experience more pain than younger people, although they may be less likely to complain of it.27 The elderly suffer from different causes of pain because of polypathology.28 Bonemetastases are themost common cause of cancer-re- lated pain, especially in the advanced stage of disease. Pain caused by bone metastases is a serious clinical challenge. It has a relevant impact on the quality of life and performance status of patients, and causes disability, occurring at rest or typically during movement. 3.1. Pamidronate 3.1.1. Breast cancer, multiple myeloma, and prostate cancer The effect of i.v. pamidronate on pain from bone metastases Fig. 1 – Time to renal function deterioration with i.v. ibandronate (6 mg) and placebo in the patients aged P65 years of age with metastatic breast cancer.18 E U R O P E A N J O U R N A L O F C has been investigated in several randomised controlled trials. In patients with breast cancer or multiple myeloma, i.v. pamidronate (45 or 90 mg, every 3 or 4 weeks) was shown to significantly decrease pain and improve the quality of life.6,7,29 However, in a combined analysis of two placebo-con- trolled studies of men with prostate cancer, there were no significant or sustained differences in self-reported pain, analgesic use, or mobility between patients treated with pamidronate or placebo.30 3.2. Zoledronic acid 3.2.1. Breast cancer, HRPC and other solid tumours Decreases in pain scores from baseline were observed after 12 months in a study of zoledronic acid versus pamidronate in patients with advanced multiple myeloma and breast can- cer.17 In this study, analgesic scores either remained stable or were reduced. Pain scores were also reduced in two ran- domised studies of zoledronic acid versus placebo in patients with advanced breast cancer, and in patients with solid tu- mours (other than breast or prostate cancer) and pain at base- line.17 In a randomised, phase III study of patients with HRPC and bone metastases, patients receiving zoledronic acid re- ported fewer increases in pain and analgesic scores than those receiving placebo.17 The palliative effects of zoledronic acid to relieve bone pain have also been demonstrated in four non-blinded stud- ies in patients with metastatic bone disease due to various primary malignancies.31–34 3.3. Ibandronate 3.3.1. Breast cancer In three phase III studies, 6 mg of i.v. ibandronate (infused every 3 or 4 weeks) and 50 mg of daily oral ibandronate were shown to significantly reduce pain scores below baseline for up to 2 years.17 The mean increase in analgesic use was also lower in the ibandronate group compared with placebo (not significantly different).17 In an open-label, pilot study, intensive ibandronate treat- ment (4 mg infused over 2 h for 4 consecutive days, 16 mg to- tal dose) significantly reduced bone pain scores within 7 days (P < 0.001) in patients with opioid-resistant bone pain (from a variety of tumours; mainly breast).17 Pain reductions were sustained over the study period. 3.3.2. HRPC and urological cancer Although ibandronate is not registered for treating bone metastases from HRPC or other urological cancers, the effi- cacy and safety of loading-dose ibandronate (6 mg infused over 1 h on 3 consecutive days, 18 mg total dose) has been investigated in two, open-label, non-randomised, phase II tri- als. There was a significant reduction in the mean visual ana- logue scores for metastatic bone pain from baseline on Day 3 (both were P< 0.001), which remained below baseline through- out the remainder of the trials.17 There were no reports of re- nal adverse events. 3.4. Approach in elderly patients A multidisciplinary approach should be taken to the treat- ment of bone pain in elderly patients. Interventions may in- clude any combination of the following: analgesic drugs, chemotherapy and radiotherapy, hormone therapy, radionu- clide therapy, bisphosphonates, cementoplasty, kyphoplasty, surgical stabilisation and/or physiatric care. Bisphosphonates should not be considered as an alternative to analgesics. However, ibandronate, zoledronic acid and pamidronate have been shown to be useful in the management of metastatic bone pain. Depending on the situation in patients with severe pain, who are unable to move easily, it may be better to start treatment with an oral bisphosphonate at home (e.g. ibandr- onate or clodronate) in association with analgesic drugs and switch to an i.v. formulation and hospital treatment once mobility has improved or if compliance with oral ibandronate C E R 4 3 ( 2 0 0 7 ) 8 5 2 –8 5 8 855 becomes uncertain. However, the need to sit remaining upright for at least 30 min should also be considered in or by hypodermoclysis. 856 E U R O P E A N J O U R N A L O F C A N C E R 4 3 ( 2 0 0 7 ) 8 5 2 –8 5 8 administration route selection. Cost considerations should not generally affect the decision to administer the most appropriate therapy for each patient. 4. Bone markers as a clinical endpoint Bone marker levels appear to correlate with the severity of bonepain, and the extent of bonemetastases.35,36 Studieshave also shown that the collagen breakdown product N-terminal cross-linked type 1 collagen telopeptide (NTX) levels can pre- dict the occurrence of SREs in patients with bone metastases, and the response to bisphosphonate therapy.36–40 A 12-week, head-to-head, open-label trial of breast cancer patients with bonemetastases demonstrated similar effects of oral ibandro- nate (50 mg/day) and i.v. zoledronic acid (4 mg infused over 15 min every 4 weeks) on biochemical