Annals of Oncology Advance Access originally published online on September 28, 2007
Annals of Oncology 2008 19(3):420-432; doi:10.1093/annonc/mdm442
reviews |
Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel
1 Institut Multidisciplinaire d'Oncologie, Clinique de Genolier, Genolier, Switzerland
2 Malmö University Hospital, Department of Urology, Malmö, Sweden
3 CHU Brugmann & Institut J. Bordet, Université Libre de Bruxelles, Brussels, Belgium
4 Academic Unit of Clinical Oncology, Weston Park Hospital, Sheffield, UK
5 MD Anderson International, Madrid, Spain
6 Hospital de Santa Maria, Faculdade de Medicina de Lisboa, Lisboa, Portugal
7 Department of Medical Oncology, Perugia Hospital, Perugia, Italy
8 AZ Sint-Augustinus Cancer Center, Wilrijk, Belgium
9 Department of Surgery, Medical University of Vienna, Vienna, Austria
10 University of Washington, Seattle Cancer Care Alliance, Seattle, WA, USA
11 Department of Gynaecology, Philipps University Marburg, Marburg, Germany
12 Department of Breast Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
13 Gynaecology and Obstetrics Clinic, University of Kiel, Kiel, Germany
14 Milton S. Hershey Medical Center, Hershey, USA
15 Department of Medical Oncology, Centre Hospitalier A. Boulloche, Montbéliard Cedex, France
16 Department of Oncology, University of Calgary, Calgary, Alta, Canada
17 Service of Bone Diseases, University Hospital, Geneva, Switzerland
18 Centre Hospitalier de l'Université de Montréal, Montréal, Canada
19 Senologie-Zentrum Ostschweiz, Kantonsspital St Gallen, St Gallen, Switzerland
* Correspondence to: Dr M. Aapro, IMO Clinique de Genolier, Route du Muids 1, 1272 Genolier, Switzerland. Tel: +41-22-366-91-34; Fax: +41-22-366-91-31; E-mail: maapro{at}genolier.net
 |
Abstract |
|---|
 Top Abstract introductionuse of BP in...breast cancerprostate cancerlung cancerrenal cell carcinoma and...choice of administration routeadherence to and persistence...initiation, dosing and duration...use of bone markers...elderly patientsmanaging QoL with BPpain control and BPconcomitant BP therapy given...AE associated with BP...prevention of CTIBLfuture uses of BPsummary of panel recommendationsfundingAcknowledgementsReferences |
|---|
Bisphosphonates (BP) prevent, reduce, and delay cancer-related skeletal complications in patients, and have substantially decreased the prevalence of such events since their introduction. Today, a broad range of BP with differences in potency, efficacy, dosing, and administration as well as approved indications is available. In addition, results of clinical trials investigating the efficacy of BP in cancer treatment-induced bone loss (CTIBL) have been recently published. The purpose of this paper is to review the current evidence on the use of BP in solid tumours and provide clinical recommendations. An interdisciplinary expert panel of clinical oncologists and of specialists in metabolic bone diseases assessed the widespread evidence and information on the efficacy of BP in the metastatic and nonmetastatic setting, as well as ongoing research on the adjuvant use of BP. Based on available evidence, the panel recommends amino-bisphosphonates for patients with metastatic bone disease from breast cancer and zoledronic acid for patients with other solid tumours as primary disease. Dosing of BP should follow approved indications with adjustments if necessary. While i.v. administration is most often preferable, oral administration (clodronate, IBA) may be considered for breast cancer patients who cannot or do not need to attend regular hospital care. Early-stage cancer patients at risk of developing CTIBL should be considered for preventative BP treatment. The strongest evidence in this setting is now available for ZOL. Overall, BP are well-tolerated, and most common adverse events are influenza-like syndrome, arthralgia, and when used orally, gastrointestinal symptoms. The dose of BP may need to be adapted to renal function and initial creatinine clearance calculation is mandatory according to the panel for use of any BP. Subsequent monitoring is recommended for ZOL and PAM, as described by the regulatory authority guidelines. Patients scheduled to receive BP (mainly every 3–4 weeks i.v.) should have a dental examination and be advised on appropriate measures for reducing the risk of jaw osteonecrosis. BP are well established as supportive therapy to reduce the frequency and severity of skeletal complications in patients with bone metastases from different cancers.
Key words: bisphosphonates, bone, cancer, CTIBL, metastases, SRE
|
introduction |
|---|
|
TopAbstractintroductionuse of BP in...breast cancerprostate cancerlung cancerrenal cell carcinoma and...choice of administration routeadherence to and persistence...initiation, dosing and duration...use of bone markers...elderly patientsmanaging QoL with BPpain control and BPconcomitant BP therapy given...AE associated with BP...prevention of CTIBLfuture uses of BPsummary of panel recommendationsfundingAcknowledgementsReferences |
|---|
Bisphosphonates (BP) reduce and delay skeletal morbidity and the resulting complications of osteoporosis and skeletal morbidity due to metastatic bone disease (MBD). BP have therefore been used for >15 years to improve the outcome of patients with bone metastases from solid tumours. In recent years, a wealth of publications on BP efficacy and safety was generated, providing a rationale for guidelines on the use of various BP compounds in solid tumours, particularly with respect to administration route, dose optimization, initiation, duration, and monitoring of therapy.
This paper offers clinical recommendations on the role of BP in the metastatic and nonmetastatic settings, reflecting consensus of an interdisciplinary expert group based on a concise review of available evidence. The recommendations were drafted at a consensus meeting followed by reviews of manuscript drafts circulated within the panel. These recommendations should be understood as an auxiliary tool for supporting and informing individual clinicians’ decisions regarding choice and implementation of BP therapy in patients with solid tumours.
BP effectively inhibit osteoclast-mediated bone resorption [1], thus providing the rationale for their use for skeletal protection in osteoporosis [2] as well as in various stages in the natural history of solid tumours [1]. BP compounds are remarkably variable in structure and resulting physicochemical and biological properties [1], including potency[3]. The newer, nitrogen-containing bisphosphonates (N-BP) such as ibandronate (IBA), pamidronate (PAM), risedronate (RIS), and zoledronic acid (ZOL) are several orders of magnitude more potent than earlier generation BP such as etidronate, tiludronate and clodronate (CLO). While non-N-BP are incorporated into adenosine triphosphate (ATP)-containing compounds, thus inhibiting cell function [4], N-BP interfere with cell signalling and block the prenylation of small signalling proteins (e.g. Ras, Rho) which are essential for cell function and survival [5, 6]. Farnesyl pyrophosphate synthase was proposed as main enzymic target of N-BP [5]; however, more recent reports indicate that the main biological activity of N-BP is directed against protein geranylgeranylation [6]. Non-N-BP induce production of a unique ATP analogue that can directly induce apoptosis [3]. The variability in structure and potency (Figure 1 as electronic supplement) has substantial biological and clinical implications [1].
|
MBD is commonly seen with various cancer types, including frequent ones such as those of the breast and prostate. Accordingly, bone metastases affect a multitude of patients with advanced disease (e.g. >60% of patients with metastatic breast cancer [7]). They often lead to skeletal complications, such as pain, pathological fractures requiring surgery and/or radiation to bone, spinal cord compression, or hypercalcaemia of malignancy [8–10], many of which are associated with life-altering morbidity and can negatively impact survival times. Pathologic fractures are the most common skeletal events, reflecting the fragility of patients’ bones and the burden of bone pain. Many patients will have to receive radiation to bone as treatment for bone pain and in order to prevent complications. Moreover, skeletal events are associated with a loss of mobility and social functioning, a decrease in quality of life (QoL) [11–13], and with a substantial increase in medical costs [14].
To date, BP are the key treatment option for reducing, delaying and preventing skeletal complications associated with bone metastases, thus maintaining and restoring patient's mobility and function and reducing pain [15]. Health economic studies on BP indicate that they are a cost-effective treatment considering drug costs, QoL benefits (especially due to bone pain reduction), and incidence and costs of skeletal complications [16–18]. The choice of BP for a given clinical setting should be evidence based.
In nonmetastatic, early-stage cancer, BP were shown in clinical trials to be effective in preventing cancer treatment-induced bone loss (CTIBL) due to hormone deprivation therapy [19–21]. Moreover, some evidence that they may prevent bone metastasis [22, 23] has resulted in a large trial program investigating this hypothesis.
It is finally recommended to consider the use of calcium (1 g/day) and vitamin D3 (800 IU/day) whenever BP are used.
|
use of BP in metastatic cancer |
|---|
|
TopAbstractintroductionuse of BP in...breast cancerprostate cancerlung cancerrenal cell carcinoma and...choice of administration routeadherence to and persistence...initiation, dosing and duration...use of bone markers...elderly patientsmanaging QoL with BPpain control and BPconcomitant BP therapy given...AE associated with BP...prevention of CTIBLfuture uses of BPsummary of panel recommendationsfundingAcknowledgementsReferences |
|---|
The skeleton is the preferred site of metastasis for many solid tumours. Across different solid tumour types the prevalence of MBD is highest in breast and prostate cancer (65%–75%) followed by thyroid (60%), lung (40%), and bladder cancer (30%–40%) [24]. As malignant bone lesions are characterized by a disordered bone metabolism, all patients with MBD are at risk of developing skeletal complications (Table 1). Skeletal complications are also associated with increased mortality [25]. Therefore, patients with MBD, irrespective of the cancer type, are in need of and should be considered for a therapy that effectively inhibits bone resorption. BP, mostly compared with placebo, have been proven to reduce and delay the occurrence of skeletal events [7] and control bone pain in patients with MBD [15, 26–28], thereby preserving mobility, social functioning, and QoL over the course of progressive metastatic disease [12, 13, 28]. BP efficacy has been quantified using various definitions of skeletal complications, measures, and methods for statistical analysis (Table 1). Moreover, sample size may influence the statistical significance of the outcome. This should be borne in mind when interpreting trial data.
|
|
breast cancer |
|---|
|
TopAbstractintroductionuse of BP in...breast cancerprostate cancerlung cancerrenal cell carcinoma and...choice of administration routeadherence to and persistence...initiation, dosing and duration...use of bone markers...elderly patientsmanaging QoL with BPpain control and BPconcomitant BP therapy given...AE associated with BP...prevention of CTIBLfuture uses of BPsummary of panel recommendationsfundingAcknowledgementsReferences |
|---|
Nearly 70% of breast cancer patients treated with placebo in controlled BP trials experience more than one skeletal-related event (SRE), and
50% have a pathological fracture >2-year period [29]. Experience of a pathological fracture increases the risk of death in breast cancer patients by 32% [25]. Several clinical trials using different measures of SRE as a composite end point have shown the benefits of BP to patients with advanced breast cancer (Table 2) [38]. Currently, four BP are approved for the treatment of MBD in breast cancer: oral CLO, oral or i.v. IBA, i.v. PAM, and i.v. ZOL. Meta-analysis of eight trials including women with advanced breast cancer and existing bone metastasis showed a 17% reduction in the risk of developing a skeletal event for patients on BP therapy [37]. Together with PAM, ZOL is the only i.v. BP demonstrating a statistically significant clinical benefit across multiple end points [26, 30, 36, 39]. The only head-to-head comparison of two BP in an appropriately powered phase III study was between ZOL and PAM [36]. In this study, the proportion of patients with at least one SRE was similar for ZOL and PAM; however, ZOL reduces the overall risk of developing any skeletal complications by 20% when compared with PAM [relative risk (RR) = 0.799; P = 0.025] [36, 40, 41]. In the subset of patients with lytic bone lesions, the greater efficacy of ZOL over PAM was demonstrated [41]. The efficacy of BP against bone pain was investigated by several trials and is shown for pooled studies of oral IBA (P = 0.001), i.v. IBA (P = 0.0006), oral CLO (P = 0.01), and PAM (P < 0.001) [15]. In a prospective placebo-controlled study, ZOL consistently reduced brief pain inventory composite pain scores at each evaluation carried out throughout a 12-month period (P < 0.05) [26]. Moreover, it has shown that oral IBA and i.v. ZOL can reduce bone turnover markers [42]; however current evidence does not support the use of bone markers as basis for clinical decision making.
|
On the grounds of efficacy data (which are difficult to interpret due to the lack of a multiple event analysis and suboptimal compliance) [33, 43], the panel recommends to offer an N-BP to breast cancer patients with MBD.
|
prostate cancer |
|---|
|
TopAbstractintroductionuse of BP in...breast cancerprostate cancerlung cancerrenal cell carcinoma and...choice of administration routeadherence to and persistence...initiation, dosing and duration...use of bone markers...elderly patientsmanaging QoL with BPpain control and BPconcomitant BP therapy given...AE associated with BP...prevention of CTIBLfuture uses of BPsummary of panel recommendationsfundingAcknowledgementsReferences |
|---|
Prostate cancer commonly metastasizes to bone; this can lead to significant skeletal morbidity. Although BP are known to reduce excessive bone turnover while preserving bone structure and mineralization in patients with breast cancer, in prostate cancer efficacy data differ (Table 3). ZOL significantly reduced the incidence of SREs by 36% [hazard ratio (HR) = 0.640; P = 0.002] and delayed the first SRE by >5 months (P = 0.009) [52] compared with placebo. ZOL also provided significant long-term reductions in bone pain compared with placebo [53].
|
In contrast, several randomized, placebo-controlled trials of early generation BP (etidronate (ETI), CLO, PAM) showed no statistically significant clinical benefit in patients with bone metastases from prostate cancer. Although results indicative of benefit were reported (Table 3), neither oral nor i.v. CLO showed statistically significant pain relief [45, 46, 55] or any significant improvement of symptomatic bone progression-free survival (P = 0.066) [46]. Also, PAM failed to demonstrate a significant overall treatment benefit compared with placebo in palliation of bone pain, improvement of QoL, or reduction of SREs [51] in patients with bone pain and disease progression after first-line hormonal therapy. In a small open-label, nonrandomized study (n = 25), i.v. IBA was shown to be effective for reducing pain from prostate cancer metastasized to bone [49]; efficacy in terms of reduction of skeletal events was not measured.
Based on the available evidence demonstrating a significantly lower incidence of skeletal complications as well as durable pain palliation, the opinion of the panel is that ZOL is presently the BP treatment of choice for patients with hormone refractory prostate cancer metastatic to bone. And it has been published that SRE reduction is greatest in patients without pain, thus patients should probably not have to wait for symptoms before starting ZOL therapy in this setting [56, 57].
|
lung cancer |
|---|
|
TopAbstractintroductionuse of BP in...breast cancerprostate cancerlung cancerrenal cell carcinoma and...choice of administration routeadherence to and persistence...initiation, dosing and duration...use of bone markers...elderly patientsmanaging QoL with BPpain control and BPconcomitant BP therapy given...AE associated with BP...prevention of CTIBLfuture uses of BPsummary of panel recommendationsfundingAcknowledgementsReferences |
|---|
ZOL reduced the risk of developing an SRE by 31% (HR = 0.693, P = 0.003) in a double-blind, placebo-controlled, 21-month trial that included 773 patients with lung cancer and other solid tumours (except breast and prostate; 244 with non-small-cell lung cancer (NSCLC) and 36 with small-cell lung cancer) [58, 59]. Therefore, the panel recommends that lung cancer patients with bone metastases and a reasonable chance of benefiting (i.e. expected survival times, patients performance status, etc.) should be considered for ZOL treatment. Further prospective clinical trials are warranted to better define the role of BP in the treatment strategy of NSCLC, with particular emphasis on locally advanced stage IIIB disease after completion of chemo/radiotherapy.
|
renal cell carcinoma and other solid tumours |
|---|
|
TopAbstractintroductionuse of BP in...breast cancerprostate cancerlung cancerrenal cell carcinoma and...choice of administration routeadherence to and persistence...initiation, dosing and duration...use of bone markers...elderly patientsmanaging QoL with BPpain control and BPconcomitant BP therapy given...AE associated with BP...prevention of CTIBLfuture uses of BPsummary of panel recommendationsfundingAcknowledgementsReferences |
|---|
Renal cell cancer with lymph node metastases at primary diagnosis often metastasizes to bone and patients are at high risk of skeletal complications [60]. In 46 patients, ZOL reduced the risk of having a SRE by 58% (HR = 0.418; P = 0.010) and the incidence of SREs by 41% (HR = 0.590; P = 0.011). Occurrence of the first SRE was delayed by
1 year (424 days versus 72 days in the placebo group, P = 0.007) [58, 59]. ZOL is the only BP with data on reduction of SREs in other tumour types, such as thyroid cancer (n = 6), bladder cancer (n = 26), and 16 further types of solid tumours (n = 143) [58, 59]. In the subset ‘other tumours’, ZOL reduced the proportion of patients with SRE (33% versus 43%) and extended the median time to first SRE to 314 days compared with 168 in the placebo arm. Both outcomes did not reach statistical significance (P = 0.11 and P = 0.051, respectively) [59]. Some tolerability data have been reported for i.v. IBA in colorectal carcinoma [61], and a further study in different tumour types (n = 66) has shown decreased analgesic requirement for patients with CLO treatment [62].
The panel recommends that ZOL should be considered in all patients with bone metastases from renal cell carcinoma and other solid tumours as discussed above, based on an assessment of their expected survival time and an expectation of overall palliative benefit.
|
choice of administration route |
|---|
|
TopAbstractintroductionuse of BP in...breast cancerprostate cancerlung cancerrenal cell carcinoma and...choice of administration routeadherence to and persistence...initiation, dosing and duration...use of bone markers...elderly patientsmanaging QoL with BPpain control and BPconcomitant BP therapy given...AE associated with BP...prevention of CTIBLfuture uses of BPsummary of panel recommendationsfundingAcknowledgementsReferences |
|---|
Oral administration (CLO, IBA) is approved in patients with breast cancer, and should be considered for patients who cannot or do not need to attend regular hospital care. Oral administration requires precautionary measures to ensure absorption and—for some BP—to avoid gastrointestinal (GI) adverse event (AE) [63, 64]. The inconvenience and complexity of oral dosing requirements, the potential for adverse effects, especially when dosing recommendations are not followed, and very low absorption rates of oral BP even under ideal conditions, may contribute to poor outcomes [65].
Generally, i.v. administration (CLO, IBA, PAM, and ZOL) is preferable since it can help ensuring adherence and persistence compared with oral administration and can be combined with infusions of nonnephrotoxic chemotherapy or clinical monitoring of metastatic patients. Although i.v. administration is usually done in an outpatient clinic setting, delivery at the patient's home has been evaluated [13] and can be considered. Infusion time ranges from 15 min (ZOL, IBA) up to 2 h (PAM).
|
adherence to and persistence with BP therapy |
|---|
|
TopAbstractintroductionuse of BP in...breast cancerprostate cancerlung cancerrenal cell carcinoma and...choice of administration routeadherence to and persistence...initiation, dosing and duration...use of bone markers...elderly patientsmanaging QoL with BPpain control and BPconcomitant BP therapy given...AE associated with BP...prevention of CTIBLfuture uses of BPsummary of panel recommendationsfundingAcknowledgementsReferences |
|---|
Oral BP require regular intake, must be taken on an empty stomach and—in case of IBA—in an upright position. Therefore, all patients receiving oral BP need to be educated about the pivotal importance of adherence to and persistence with therapy. Both are known to be poor in patients self-administering oral BP for osteoporosis [66, 67], even with patient support [68], particularly with weekly or daily dosing [2, 66]. In the metastatic setting, there are also reports of low persistence [69, 70] that can be expected to jeopardize therapeutic efficacy. In a study assessing patient preference for either ZOL or PAM, 92% preferred ZOL because shorter infusions caused less disruption to their daily schedule [71]. Compliance with CLO in the adjuvant and metastatic setting has been reported to be acceptable [22].
|
initiation, dosing and duration of BP therapy in metastatic cancer |
|---|
|
TopAbstractintroductionuse of BP in...breast cancerprostate cancerlung cancerrenal cell carcinoma and...choice of administration routeadherence to and persistence...initiation, dosing and duration...use of bone markers...elderly patientsmanaging QoL with BPpain control and BPconcomitant BP therapy given...AE associated with BP...prevention of CTIBLfuture uses of BPsummary of panel recommendationsfundingAcknowledgementsReferences |
|---|
There is a paucity of data for optimal use of BP, mainly regarding initiation and treatment duration. To maximize the benefit of BP treatment, the panel recommended—in the absence of data—considering the start of therapy as soon as bone metastases are diagnosed by radiographic techniques, even if they are asymptomatic.
Dosing regimens of BP therapy for patients with bone metastases should follow the evidence generated in clinical studies. In patients with mild to moderate renal impairment [creatinine clearance (CrCl) 30–60 ml/min], regulations recommend lower doses of CLO and ZOL and longer infusion times for PAM, respectively [63, 64, 72, 73]. A recent label of IBA approved by European regulatory authorities allows a dosing regimen of 6 mg >60 min instead of 15 min when CrCl is 30–50 ml/min [74].
In patients with evidence of renal deterioration during treatment, i.v. BP should be withheld and only resumed when serum creatinine returns to within 10% of baseline [72]. However, in case of persistent renal deterioration, the panel agreed that either dose reduction or longer infusion time could be considered under close monitoring when clinical assessment indicates that BP therapy should not be discontinued. Because of the importance of continuing BP treatment to prevent further SREs, discontinuation of therapy should be limited to patients who cannot tolerate BP therapy.
Treatment with ZOL is contraindicated in patients with severe renal dysfunction (serum creatinine >265 µmol/l >3.0 mg/dl, CrCl <30 ml/min). In such cases, a reduced dose of 2 mg i.v. IBA >60 min can be used in patients with breast cancer, while there are no data for other tumours. Treatment with CLO is contraindicated in patients with CrCl <10 ml/min or serum creatinine >440 µmol/l.
Benefit of BP therapy with ZOL and IBA in breast cancer has been shown for a treatment duration of up to 2 years [36, 52, 59, 75]. Since the risk of SREs is going to continue, the expert panel—in the absence of supporting data—recommends continuation of therapy beyond 2 years but always based on an individual risk assessment. Specifically, it should not be discontinued once skeletal events occur, as controlled studies with ZOL show a significant reduction in the risk of subsequent skeletal events [52, 76]. In case of disease progression, the anticancer treatment should be adapted according to the patient's clinical situation. In patients with disease progression in the skeleton and pain despite the use of oral BP or PAM, change to ZOL or IBA can improve pain control [77, 78].
|
use of bone markers in BP therapy |
|---|
|
TopAbstractintroductionuse of BP in...breast cancerprostate cancerlung cancerrenal cell carcinoma and...choice of administration routeadherence to and persistence...initiation, dosing and duration...use of bone markers...elderly patientsmanaging QoL with BPpain control and BPconcomitant BP therapy given...AE associated with BP...prevention of CTIBLfuture uses of BPsummary of panel recommendationsfundingAcknowledgementsReferences |
|---|
The use of bone markers for adjusting BP therapy and for the prediction of patients’ risk of bone metastasis is under investigation with ZOL (BISMARCK, OPTIMIZE). There is no prospective trial at this point which shows that bone markers are reliable for individual patients: they are only valid for a cohort of patients in respective studies. Currently, the panel does not recommend the use of bone markers in clinical routine [42, 79, 80, 81].
|
elderly patients |
|---|
|
TopAbstractintroductionuse of BP in...breast cancerprostate cancerlung cancerrenal cell carcinoma and...choice of administration routeadherence to and persistence...initiation, dosing and duration...use of bone markers...elderly patientsmanaging QoL with BPpain control and BPconcomitant BP therapy given...AE associated with BP...prevention of CTIBLfuture uses of BPsummary of panel recommendationsfundingAcknowledgementsReferences |
|---|
There are no specific limitations for the use of BP in the elderly. An International Society of Geriatric Oncology task force reviewed information from the literature on BP in elderly patients with bone metastases. They recommended that CrCl (because serum creatinine values can be misleading in the elderly) should be monitored in every patient, and an agent with best possible renal tolerability should be used where evidence of similar efficacy is available. The assessment and optimization of hydration status was recommended in this often dehydrated population [82].
|
managing QoL with BP |
|---|
|
TopAbstractintroductionuse of BP in...breast cancerprostate cancerlung cancerrenal cell carcinoma and...choice of administration routeadherence to and persistence...initiation, dosing and duration...use of bone markers...elderly patientsmanaging QoL with BPpain control and BPconcomitant BP therapy given...AE associated with BP...prevention of CTIBLfuture uses of BPsummary of panel recommendationsfundingAcknowledgementsReferences |
|---|
One goal of BP therapy in metastatic cancer is to keep patients functional and mobile for as long as possible, thus preserving their QoL and delaying its deterioration. Reduction and postponement of skeletal complications and the associated life-altering morbidity is essential for this purpose [11, 12, 83–86]. New tools for measuring QoL in routine practice are being developed and need to be validated in different countries.
|
pain control and BP |
|---|
|
TopAbstractintroductionuse of BP in...breast cancerprostate cancerlung cancerrenal cell carcinoma and...choice of administration routeadherence to and persistence...initiation, dosing and duration...use of bone markers...elderly patientsmanaging QoL with BPpain control and BPconcomitant BP therapy given...AE associated with BP...prevention of CTIBLfuture uses of BPsummary of panel recommendationsfundingAcknowledgementsReferences |
|---|
Adequate pain control is a key aspect of QoL maintenance in patients with bone metastases. Analgesic therapy should follow a stepwise escalation regimen as per World Health Organization guidelines [87]. Along with analgesics, BP therapy is a major factor contributing to the preservation of QoL in patients with progressive metastatic disease [11, 12, 28, 31, 50, 83, 88–92]. Controlled clinical studies have shown BP therapy, apart from its benefits in terms of skeletal morbidity, to reduce bone pain including opioid-resistant pain, and over the course of progressive disease to maintain it at lower levels compared with controls [15].
|
concomitant BP therapy given with anticancer therapy |
|---|
|
TopAbstractintroductionuse of BP in...breast cancerprostate cancerlung cancerrenal cell carcinoma and...choice of administration routeadherence to and persistence...initiation, dosing and duration...use of bone markers...elderly patientsmanaging QoL with BPpain control and BPconcomitant BP therapy given...AE associated with BP...prevention of CTIBLfuture uses of BPsummary of panel recommendationsfundingAcknowledgementsReferences |
|---|
A growing body of preclinical evidence from in vitro studies and animal models demonstrates that BP can reduce skeletal tumour burden and prevent metastasis to bone [93]. N-BP have been shown to exert anti-tumour effects in vitro through apoptosis induction and several other mechanisms [3, 94]. ZOL inhibits tumour cell adhesion to the extracellular matrix, invasion, and angiogenesis [3]. IBA prevented adhesion and spreading of tumour cells to bone and tumour cell invasion. These inhibitory effects were additive when IBA was given with paclitaxel or docetaxel. In animal models of tumour-induced osteolysis, IBA significantly reduced the development of osteolytic lesions [94]. ZOL and IBA were also shown to exert synergistic antitumour activity when combined with various other anticancer agents [95–99], with some evidence for higher in vitro efficacy with ZOL [99].
These preliminary data indicate that N-BP might have clinical antitumour effects by themselves or in combination with other anticancer treatments such as chemotherapy, hormone therapy, radiotherapy [100, 101], or monoclonal antibodies. However, special caution should be exerted when administering cytotoxic drugs that can be nephrotoxic, such as platinum salts, some antibiotics, and nonsteroidal anti-inflammatory drugs (NSAIDs). The panel indicated that nephrotoxic chemotherapy should not be administered on the same day as an i.v. BP to reduce the risk of renal toxicity.
|
AE associated with BP therapy for metastatic cancer |
|---|
|
TopAbstractintroductionuse of BP in...breast cancerprostate cancerlung cancerrenal cell carcinoma and...choice of administration routeadherence to and persistence...initiation, dosing and duration...use of bone markers...elderly patientsmanaging QoL with BPpain control and BPconcomitant BP therapy given...AE associated with BP...prevention of CTIBLfuture uses of BPsummary of panel recommendationsfundingAcknowledgementsReferences |
|---|
BP therapy for metastatic cancer is generally well tolerated, with a low rate of (AE) in clinical practice [102]. Patients should be instructed to recognize and report signs and symptoms indicating key AE, and both the occurrence and severity of AE should be monitored at each visit. Monitoring must include questioning for AE and appropriate evaluation of CrCl in patients receiving i.v. BP.
AE commonly associated with BP are generally manageable. Side-effects related to BP pharmacology include osteomalacia and (an AE associated with 1st generation but not observed with 2nd or 3rd generation BP) hypocalcaemia. AE unrelated to the anti-resorptive effect of BP include acute-phase reactions, GI problems, local reactions at the injection site, and more rarely nephrotoxicity and uveitis. Osteonecrosis of the jaw (ONJ) has been described in recent years in association with the use of BP.
‘Hypocalcaemia’ is typically observed in conditions of high bone turnover, such as in mixed or sclerotic lesions. Clinically relevant hypocalcaemia is very rarely observed and may be prevented with calcium and vitamin D3 from the start of therapy. A transient increase in ‘bone pain’ is seen mostly in patients with painful bone lesions associated with aggressive bone resorption treated with i.v. BP; it is usually mild and transient and can be managed with preventive or therapeutic analgesics. Transient ‘acute-phase reactions’ characterized by fever and myalgia occurs in 15%–30% of patients [103], generally after the first infusion of an N-BP, less frequently after the following infusions. They peak within 24–48 h and subside after 3 days [104]. They are no reason for treatment discontinuation and can be managed with preventive or therapeutic analgesics (e.g. paracetamol or ibuprofen (expert consensus, despite of this being an NSAID).
‘Nephrotoxicity’ characterized by elevation of serum creatinine level and potentially acute tubular necrosis with reversible or irreversible kidney damage may occur in patients receiving i.v. BP [105]. Grade 3 creatinine elevations have been observed in three (3.3%) of prostate cancer patients treated with 4 mg ZOL and in one (1.3%) receiving a placebo [54]. Renal effects are generally seen after rapid infusion leading to high BP concentrations in the blood and kidney. Medline reports on creatinine elevation were more frequent with ETI or CLO (8% and 5%, respectively) than with PAM (2%), alendronate (0%), or IBA (<1%) [106], the difference reaching statistical significance for ETI only. No significant difference in renal tolerability was seen in a pair wise comparison of PAM (90 mg i.v. >2 h) and ZOL (4 mg i.v. >15 min) in a large clinical trial in breast cancer [36]. ZOL can be safely administered with proper serum CrCl evaluation, in cancer patients previously treated with i.v. BP [107]. In a phase III trial of patients with MBD from breast cancer, 6 mg IBA infused >1–2 h had a renal safety profile comparable to that of placebo [108, 109]. Manufacturers’ recommendations for infusion times [63, 64, 72, 73] should be followed to minimize the potential for renal AE since Cmax determines the nephrotoxicity of BP. To avoid renal toxicity with i.v. BP, patients need to be adequately hydrated before treatment, and monitoring of serum creatinine is recommended [110].
GI problems with oral BP include mild gastric irritation, erosions, and diarrhoea, and rarely ulcers, perforations, and strictures. The more severe GI AE are uncommon with weekly dosing regimens. Patients should be instructed to comply well with the dosage prescriptions [fasting 
1–2 h before and 1 h after intake (except water), in the case of oral IBA upright position for 1 h after intake] [63, 64]. Local reactions at the injection site include phlebitis, pain, local swelling, and ulceration. ‘Uveitis’ is rare and usually resolves within 1–2 weeks of treatment cessation.
ONJ is an uncommon but potentially serious complication predominantly seen in patients receiving potent i.v. N-BP [111] including PAM, ZOL [112, 113] and IBA [114], observed mostly during treatment for multiple myeloma or breast cancer [102, 111]. ONJ was also seen in a few patients treated with oral alendronate and RIS for osteoporosis or Paget's disease [112, 115, 116], and was recently reported in one multiple myeloma patient treated with CLO [117]. The aetiology of ONJ is unclear but likely multifactorial [116]. Actinomyces has been found frequently in these lesions [118], indicating that osteomyelitis at sites of dental/jaw trauma may contribute to the condition. There is a strong association with dental pathology and interventions [102, 111, 112, 119, 120]. At least 60% of cases occur after dentoalveolar surgery to treat infection, and the remainder often involves patients with dentures [111]. The risk of experiencing ONJ seems to be time- and dose dependent [111]. Other potential risk factors include chemotherapy [114], glucocorticosteroids [102], and thalidomide [102].
Best practices for identifying, staging and managing ONJ in oncology patients on i.v. N-BP have been proposed [111, 116]. Preventive strategies aim at avoiding dental infection and dentoalveolar surgery. Before starting i.v. N-BP treatment, patients should have a dental examination and any treatment required [116]. They must be advised to keep good oral hygiene, have active oral infections treated, and sites at high risk for infection eliminated. Patients with dental problems other than ONJ should get the least invasive dental treatment. Until healing of invasive dental surgery, temporary discontinuation of BP therapy may be considered [116], although there are no data available on which to make a firm recommendation and the decision to stop or continue should be made on a case by case basis.
|
prevention of CTIBL |
|---|
|
TopAbstractintroductionuse of BP in...breast cancerprostate cancerlung cancerrenal cell carcinoma and...choice of administration routeadherence to and persistence...initiation, dosing and duration...use of bone markers...elderly patientsmanaging QoL with BPpain control and BPconcomitant BP therapy given...AE associated with BP...prevention of CTIBLfuture uses of BPsummary of panel recommendationsfundingAcknowledgementsReferences |
|---|
Patients receiving adjuvant anticancer treatment are at significant risk of CTIBL, including osteopenia and osteoporosis. Cytotoxic chemotherapy (CT) and hormone deprivation therapies can directly affect bone mineral density (BMD) and micro-architectural structure [121–127]. Aromatase inhibitors (AIs) or gonadotropin-releasing hormone agonists used in patients with breast or prostate cancer may result in a two- to 10-fold higher yearly bone loss compared with a healthy age-matched population [128–130]. Accelerated bone loss increases fracture risk and has long-term implications for QoL, costs, and even survival [131, 132]. Starting adjuvant endocrine therapy of early breast cancer with tamoxifen and switching to an AI after 2–3 years does not prevent a significant increase in fractures in spite of prior bone protective effect of tamoxifen [126].
In premenopausal women with CT-induced estrogen depletion and antiestrogen therapy, CLO and RIS, respectively, reduced bone loss significantly compared with placebo [133–135]. PAM stabilized bone loss in androgen-deprived patients with prostate cancer [130]. Alendronate is approved for the treatment of osteoporosis in men and 70 mg once weekly significantly increased bone mass at the spine and the total hip in men with nonmetastatic prostate cancer on androgen deprivation therapy [136]. To date, ZOL is the most intensively investigated BP in this setting and long-term data in CTIBL in large ongoing trials accruing several thousand patients in total [22, 137–139] have shown ZOL to prevent or slow bone loss during adjuvant endocrine therapy. In premenopausal patients treated with anastrozole and goserelin, ZOL prevented bone loss in lumbar spine and hip, regardless of endocrine therapy (P < 0.0001) [19]. When added to adjuvant letrozole in postmenopausal patients, ZOL (4 mg every 6 months) was most effective when initiated before osteoporosis or fractures occur [3.3%, 95% confidence interval (CI) 2.8% to 3.8%; P < 0.0001] [20, 21]. Patients treated with delayed ZOL (i.e. after a fracture or a T-score less than –2) experienced a reduction in spine and hip BMD [139]. Similarly, in nonmetastatic prostate cancer, ZOL (4 mg every 3 months or once a year [140]) increased BMD in the spine in the first year of androgen deprivation therapy, whereas BMD decreased in patients receiving placebo (7.8%, 95% CI 5.6% to 10.0%; P < 0.001) [141]. Prevention of bone loss has also been demonstrated with long-term (2–3 years) CLO therapy in the adjuvant setting [135, 142, 143]. These results are of particular importance in patients who are osteopenic at baseline.
The combination of ZOL with hormone deprivation therapy is well tolerated.