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Bone-targeted agents in the treatment of lung cancer:

Bone-targeted agents in the treatment of lung cancer: 582178 TAM0010.1177/1758834015582178Therapeutic Advances in Medical OncologySilva research-article2015 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Bone-targeted agents in the treatment 2015, Vol. 7(4) 219 –228 DOI: 10.1177/ of lung cancer © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ Shobha C. Silva, Caroline Wilson and Penella J. Woll journalsPermissions.nav Abstract: Over a third of patients with lung cancer will develop bone metastases during the course of their disease, resulting in symptoms of pain and immobility, and skeletal- related events (SREs) such as fracture, hypercalcaemia, surgery or radiotherapy to bones, and malignant spinal cord compression. These reduce quality of life and increase mortality. Preclinical research has identified the interactions between tumour cells and bone that are key to tumour cell survival and associated osteolysis. These data have led to the development of drugs to prevent osteoclast-mediated bone breakdown, such as zoledronic acid and denosumab, which are now licensed for use in patients with bone metastases from solid tumours. Both zoledronic acid and denosumab reduce the risk of SREs and increase time to first SRE, with minimal side effects. In addition, denosumab improved survival in patients with lung cancer compared with zoledronic acid. Ongoing trials are testing whether these drugs can prevent the development of bone metastases from lung cancer. New bone-targeted agents showing promise in breast and prostate cancer include radium-223, cabozantinib and Src inhibitors. These agents require further evaluation in patients with lung cancer. Keywords: denosumab, skeletal-related events, survival outcomes, vicious cycle, zoledronic acid Correspondence to: Introduction mediators including parathyroid-like related hor- Penella J. Woll, BMedSci, Lung cancer is the commonest cause of death mone, interleukin 1 and tumour necrosis factor, MBBS, PhD, MRCP Academic Unit of Clinical from cancer worldwide. Over a third of patients which promote the maturation of osteoclasts result- Oncology, Weston Park with advanced lung cancer develop bone metasta- ing in increased bone resorption. Hypercalcaemia Hospital, Whitham Road, Sheffield S10 2SJ, UK ses during the course of their illness [Coleman, leads to debilitating symptoms, including fatigue, p.j.woll@sheffield.ac.uk 1997], presenting a significant morbidity burden. nausea and constipation. It is a poor prognostic fac- Shobha C. Silva, MBBS, These morbidities include bone pain, hypercal- tor, with a life expectancy of a few months [Ralston MRCP Caroline Wilson, PhD, caemia, pathological fractures, spinal cord com- et al. 1990; Clines and Guise, 2005]. MRCP pression and bone marrow infiltration. Weston Park Hospital, Sheffield, UK Pathological fractures occur most commonly in Bone pain is the most common type of cancer- weight-bearing bones (long bones, vertebrae), related pain [Mercadante, 1997] with both and are more likely if the bone metastases are mechanical and neurogenic components, requir- large, lytic and involve the cortex [Coleman, ing a combination of pharmacological (nonsteroi- 2006]. The sequelae of fractures include pain, dal anti-inflammatory drugs, opioid analgesics, reduced mobility, hospitalization, deterioration in gamma-aminobutyric acid (GABA) analogues, quality of life, and requirement for interventions corticosteroids) and nonpharmacological therapies including surgery and radiotherapy. (surgical stabilization, palliative radiotherapy, nerve blocks, transcutaneous electric nerve stimulation), Malignant spinal cord/cauda equina compression is a in addition to systemic anticancer treatments. medical emergency, typically characterized by back pain, followed by weakness and, less com- Hypercalcaemia is related to direct induction of local monly, sensory loss, with bladder and bowel dys- osteolysis by tumour cells, as well as to chemical function being late findings. Early diagnosis and http://tam.sagepub.com 219 Therapeutic Advances in Medical Oncology 7(4) Table 1. Frequency of SREs in 250 patients with prompt intervention with surgery, vertebroplasty NSCLC and other solid tumours (Rosen et al. 2004). or radiotherapy are crucial to avoiding irreversi- ble neurological sequelae [Martenson et al. 1985; Skeletal complication Number of events (%) Kim et al. 1990]. Radiation to bone 86 (34) Pathological fracture 55 (22) Bone marrow infiltration can lead to pancytopenia, Surgery to bone 13 (5) putting patients at risk of infection and bleeding. Spinal cord 10 (4) It can also compromise other anticancer treat- compression ments, such as cytotoxic chemotherapy. Hypercalcaemia 9 (4) Any SRE 120 (48) The morbidities associated with bone metastases (often referred to as skeletal-related events, SREs) NSCLC, non-small cell lung cancer; SRE, skeletal- have major impacts on patients’ quality of life and related event. present a significant economic burden. For patients with lung cancer and bone metastases, a retrospec- tive analysis in the USA showed the lifetime SRE cost per patient to be US$12,000 [Delea et  al. interacting with RANK. The ratio between 2004]. Placebo treatment arms of clinical trials of RANKL and OPG produced by osteoblasts antiresorptive agents in bone metastases have pro- controls RANKL-stimulated osteoclast activity vided evidence of the frequency of SREs in non- [Dougall et al. 1999; Kong et al. 1999]. small cell lung cancer (NSCLC) and other solid tumours, demonstrating that 48% of patients with When metastatic tumour cells arrive in bone, they bone metastases experience SREs and highlighting localize to areas that are highly vascular, particu- the need for preventive treatments (Table 1) larly trabecular bone [Holen, 2012], where they [Rosen et  al. 2004b; Coleman 2004]. Moreover, interact with osteoblasts and osteoclasts. The the development of bone metastases and SREs presence of tumour cells in bone disrupts the increases the risk of death and reduces median sur- RANKL:OPG coupling mechanism, as osteo- vival time (Table 2). clasts are stimulated by tumour-secreted parathy- roid-related protein (PTHrP), which increases The impact of bone metastases on morbidity and local production of RANKL [Kingsley et  al. mortality has been increasingly recognized over 2007]. The increase in osteoclast bone resorption the past 20 years and has led to interest in under- releases growth factors such as transforming standing the pathophysiology and pharmacologi- growth factor β, which are stored in bone matrix cal treatment of bone metastases from solid and further increase tumour secretion of PTHrP tumours. The remainder of this review will focus [Mourskaia et  al. 2009]. Other tumour-secreted primarily on the two drugs that are licensed for factors such as bone morphogenetic proteins acti- use in America, the UK and Europe for patients vate osteoblasts directly, which subsequently with bone metastases from solid tumours: zole- release more RANKL and less OPG to initiate dronic acid and denosumab. osteoclast differentiation [Dai et al. 2005]. These interactions create what is termed ‘the vicious cycle’ of bone metastasis [Mundy, 1997], a Bone-targeted agents in preclinical models tumour-induced self-propagating breakdown of Bone is a dynamic organ that is constantly remod- bone (Figure 1). elled. The balance between bone formation by osteoblasts and resorption by osteoclasts is criti- Both zoledronic acid and denosumab have been cal to prevent pathological excess of either pro- shown in vitro and in vivo to disrupt this vicious cess that could alter bone volume and architecture. cycle, primarily by their effect on osteoclast- One such coupling mechanism involves the recep- mediated bone resorption. Zoledronic acid is tor activator of nuclear factor κβ (RANK) and an intravenous-administered nitrogen-containing osteoprotegerin (OPG) (Figure 1). RANK ligand bisphosphonate and is the most potent of the (RANKL) is secreted by osteoblasts and binds to bisphosphonates [Russell et  al. 2008], binding RANK on the surface of preosteoclasts to pro- avidly to the bone surface, with a half life in mote differentiation into osteoclasts. This is pre- serum of about 2 hours [Lin, 1996]. The drug is vented by osteoblast secretion of OPG, which incorporated into the hydroxyapatite matrix binds and inactivates RANKL preventing it from and is taken up by osteoclasts during the 220 http://tam.sagepub.com SC Silva, C Wilson et al. Table 2. Effects of bone metastases and SREs on survival in lung cancer. Author Type of study Population (n) and Outcome tumour type Bauml et al. Single 376 NSCLC Bone metastases were an [2013] centre retrospective independent adverse prognostic analysis factor for survival. Saad [2007] Retrospective analysis of >3000 solid tumours Pathological fracture increased pooled data from RCTs including lung cancer death by 20% in all tumours of zoledronic acid except lung cancer* Tsuya [2007] Retrospective analysis 259 NSCLC ⩾1 SRE reduced median survival by half (366 days to 187 days) Hirsh et al. Retrospective analysis of 507 solid tumours Development of SREs reduced [2008] a phase III study including lung cancer median survival by half *The reason for this exception was thought to be due to the short median survival of lung cancer patient. In addition, nearly 70% lung cancer patients already had an SRE at study entry. NSCLC, non-small cell lung cancer; RCT, randomized controlled trial; SRE, skeletal-related event. Figure 1. The vicious cycle of bone metastases. Once tumour cells arrive in bone they interact with the bone forming osteoblasts (Ob) and bone-resorbing osteoclasts (Oc). Tumour cells secrete factors that stimulate Oc, that is, parathyroid-related protein (PTHrP). The increase in osteoclast bone resorption releases growth factors such as transforming growth factor β (TGFβ) which are stored in bone matrix which further increase tumour secretion of PTHrP. Other tumour-secreted factors such as bone morphogenetic proteins (BMPs) activate osteoblasts directly which subsequently release more receptor activator of nuclear factor κβ ligand (RANKL) and less osteoprotegerin (OPG), a RANKL decoy, to initiate osteoclast differentiation and hence further bone resorption. resorption process. Zoledronic acid inhibits bone, zoledronic acid has been shown to reduce farnesyl pyrophosphate synthase [van Beek et al. tumour-induced osteolysis, and to reduce 1999] preventing prenylation of small guano- tumour burden outside bone in subcutaneous sine-5-triphosphatease (GTPases), which are tumours from breast, lung and prostate [Holen responsible for many cellular functions in osteo- and Coleman, 2010]. Denosumab is a subcuta- clasts, thus inducing apoptosis and loss of cell neously administered human immunoglobulin membrane integrity [Coxon and Rogers, 2003]. G antibody that binds to and neutralizes RANKL In animal models of breast cancer metastases to in a similar way to OPG, with a serum half life of http://tam.sagepub.com 221 Therapeutic Advances in Medical Oncology 7(4) 46 days [Brown and Coleman, 2012]. In animal follow up, these benefits were sustained [Rosen models denosumab reduces tumour-induced et al. 2004b]. osteolysis and tumour progression in bone from breast, lung and prostate cancer, and it has been In phase II and III trials in patients with breast shown to decrease metastasis outside of bone cancer and bone metastases, denosumab was [Dougall et al. 2014]. shown to have similar efficacy to intravenous bis- phosphonates in reducing SREs but led to a greater reduction in bone turnover markers and Clinical evidence for prevention of SREs with significantly delayed the time to first on-study bone-targeted agents in lung cancer SRE [hazard ratio (HR) 0.77; 95% confidence The encouraging preclinical data demonstrating interval (CI) 0.66–0.89; p = 0.001] [Stopeck that both zoledronic acid and denosumab can et  al. 2010]. In a phase III trial in patients with modify the bone microenvironment and affect bone metastases from solid tumours (apart from skeletal and extraskeletal tumour growth led to breast and prostate) and multiple myeloma, eligi- clinical trials that have provided the evidence ble patients were randomized to receive deno- for licensing in the USA, the UK and Europe sumab or zoledronic acid. Of the 1776 patients for patients with bone metastases from solid recruited, 811 had lung cancer (702, 47% had tumours. The endpoints in clinical trials of NSCLC). Denosumab was found to be noninfe- bone-targeted agents vary and have included rior (trending to superiority) to zoledronic acid in survival outcomes [Rosen et  al. 2004b; Hirsh terms of delaying time to first on-study SRE (HR et  al. 2008; Henry et  al. 2011], SRE incidence, 0.84; 95% CI 0.71–0.98; p = 0.0007), with a 4.3 time to first SRE [Henry et al. 2011], changes in month improvement in time to first SRE (20.6 bone biomarkers [Lipton et  al. 2008] or symp- months in the denosumab group versus 16.3 tom outcomes including changes in reported months in the zoledronic acid group) [Henry pain or opioid use [Van Moos, 2010; Henry et al. 2011]. The authors also noted that the sub- et  al. 2011; Rosen et  al. 2004b]. Bone bio- cutaneous formulation was more convenient than markers that have been studied include markers the intravenous infusion required for zoledronic of bone formation such as bone alkaline acid. phosphatase (BALP), type I procollagen and markers of bone resorption such as serum and urine N-terminal telopeptide (NTX), which Clinical evidence for a survival benefit for have been shown to correlate with SREs and bone-targeted agents in lung cancer survival. Survival outcomes with bone-targeted agents in lung cancer have been evaluated in clinical trials Zoledronic acid is the only bisphosphonate that has assessing the role of these agents in patients with demonstrated long-term efficacy and safety in and without bone metastases. patients with lung cancer with bone metastases. Zoledronic acid has been shown to effectively reduce the risk of SREs in patients with meta- Bone metastases at trial entry static prostate cancer [Lipton et al. 2002], multi- Zoledronic acid, when used as a single agent, has ple myeloma and breast cancer [Berenson et  al. not been found to improve survival outcomes in 2001; Rosen et  al. 2001]. Rosen and colleagues patients with lung cancer and bone metastases. In analysed 773 patients with bone metastases from a phase III study of zoledronic acid (4 mg) or pla- solid tumours (of whom nearly half had NSCLC) cebo given 3 weekly for 9 months in 773 patients randomized to receive 4 mg or 8 mg of zoledronic with solid tumour (n = 378 NSCLC), neither acid or placebo. Due to concerns over renal toxic- time to progression of bone lesions (145 days ver- ity, the 8 mg arm was later discontinued. sus 109 days, p = 0.415) nor survival (202.5 days Zoledronic acid significantly reduced the risk of versus 183 days, p = 0.929) was significantly bet- all skeletal events (including hypercalcaemia) in ter in the zoledronic acid arm [Rosen et al. 2004b]. the 4 mg group compared with placebo (38% ver- A subgroup analysis, restricted to patients with sus 47%, p = 0.039) [Rosen et  al. 2003]. This NSCLC patients, suggested that high levels of the dose of zoledronic acid was also shown to increase biomarker urinary NTX at baseline predicted the median time to first SRE by more than 2 benefit from zoledronic acid and significantly months compared with placebo (p = 0.023). In decreased the relative risk of death 35% (relative an updated analysis after 21 months of treatment/ risk 0.650, p = 0.024) [Hirsh et al. 2008]. These 222 http://tam.sagepub.com SC Silva, C Wilson et al. Table 3. Ongoing trials of bone-targeted agents in lung cancer. Clinical Trial. Phase N Population Design Primary endpoint gov identifier NCT01951586 II 216 NSCLC 4-6 cycles of standard doublet Overall survival stage IV platinum-based chemotherapy +/- denosumab 120 mg every 3–4 weeks NCT02129699 III 1000 NSCLC 4-6 cycles of standard doublet Overall survival (Splendour) stage IV platinum-based chemotherapy +/- denosumab 120 mg every 3–4 weeks NCT01737216 II 100 4-6 cycles of standard doublet Progression-free Aged >70 platinum-based survival years, lung chemotherapy +/- zoledronicacid cancer 4 mg every 4 weeks/every 12 weeks until progression NSCLC, non-small cell lung cancer. data suggest that NTX is a useful biomarker and Absence of bone metastases at trial entry the survival benefits of zoledronic acid are great- A randomized trial in 437 patients with stage est in patients with a baseline high bone turnover, IIIA/B NSCLC without metastases evaluated the likely due to the increased risk of SREs in this use of zoledronic acid administered every 3–4 group and subsequent prevention by antiresorp- weeks for 24 months after completion of primary tive therapy. However, predicting which individ- therapy (including surgery, radiotherapy and ual patients will benefit from zoledronic acid is chemotherapy) without progression [Scagliotti not currently possible. et al. 2012b]. No significant differences were seen between zoledronic acid treated patients and con- More recently, denosumab has been shown to trols in progression-free survival (PFS) (9 months significantly improve survival in patients with versus 11.3 months respectively, p = 0.096), risk lung cancer and bone metastases in a subgroup of death (HR 1.17; 95% CI 0.86–1.59), or the analysis (n = 811) [Scagliotti et  al. 2012a] of a number of patients who developed bone metasta- large international phase III study comparing ses (6.6% versus 9%). Similar results were seen in denosumab (120 mg every 4 weeks) with zole- a smaller (n = 150) phase II study of zoledronic dronic acid (4 mg every 4 weeks) in solid tumours acid versus control in patients with stage IIIB/IV (excluding breast and prostate) [Henry et  al. NSCLC after primary therapy with docetaxel and 2011]. Denosumab increased overall survival carboplatin, with no difference between treatment compared with zoledronic acid (8.9 months ver- groups in time to progression or overall survival sus 7.7 months, p = 0.01). In NSCLC, the great- [Pandya et al. 2010]. These data suggest that zole- est benefit from denosumab appeared to be in dronic acid may decrease the formation of bone those patients with squamous cell carcinoma metastases, but as disease progression in patients with an increased survival of 2.2 months com- with lung cancer is primarily in extraskeletal sites, pared with zoledronic acid (HR 0.68, p = 0.035); there is no impact of the drug on survival out- however, the trend to increased survival was seen comes. No data are currently available on the use in all histological subtypes, including small-cell of denosumab to prevent the formation of bone lung cancer. Although a subgroup analysis, this metastases specifically from lung cancer. represents a large prospective randomized trial in NSCLC. Following on from these data, deno- The ability of osteoclast inhibitors to prevent the sumab was licensed for use in patients with estab- formation of bone metastases and improve survival lished bone metastases from solid tumours in in patients with solid tumours has been demon- America (2010) and Europe (2011). Ongoing strated in a large meta-analysis (23,000 patients) of trials of both zoledronic acid and denosumab on adjuvant trials of bisphosphonates in early breast survival outcomes in lung cancer will add to cancer. There was a significant decrease in bone existing data (Table 3). recurrence in the treated population compared http://tam.sagepub.com 223 Therapeutic Advances in Medical Oncology 7(4) with controls (6.9% versus 8.4%). In addition, with the first cycle with an incidence in meta- there was a nonsignificant trend to a reduction in static breast cancer and myeloma trials of 16– nonbone recurrence in postmenopausal women 38% [Rosen et  al. 2004a; Body et  al. 2007]. treated with zoledronic acid compared with con- Renal toxicity is dose and schedule dependent, trols (9%; 95% CI 5–19%), resulting in a signifi- but with the standard 4 mg dose infused over 15 cantly improved 10-year breast cancer mortality min the incidence is about 10–15%, necessitat- (15.2% versus 18.3%) [Coleman et al. 2013]. This ing an evaluation of renal function in patients suggests that there may be subpopulations of before administration of zoledronic acid [Gar trell patients in whom bisphosphonates are more effec- et  al. 2014]. Side effects reported with similar tive in preventing the formation of bone metasta- frequency in both denosumab and zoledronic ses, and in these populations they may potentially acid include osteonecrosis of the jaw (ONJ). decrease the formation of extraskeletal metastases. ONJ is a painful exposure of bone in the mandi- How this preventive approach will translate to lung ble and maxilla, commonly occurring after tooth cancer, and how to identify these high-risk patients, extraction and exacerbated by poor dental is yet to be established and will need international hygiene. In trials comparing zoledronic acid with collaborative trials. The SPLENDOUR (Survival denosumab, ONJ rates were similar, with an Improvement in Lung Cancer Induced by incidence of 1–2% over 2–3 years of use [Stopeck Denosumab Therapy) trial will soon be open to et al. 2010; Henry et al. 2011]. Side effects more recruitment. It is a large phase III trial in which commonly associated with denosumab include patients with stage IV NSCLC will be randomized hypocalcaemia, although this is often subclinical to receive standard cytotoxic chemotherapy alone and prevented by adequate vitamin D and cal- or with denosumab, with the primary endpoint cium replacement. In a large randomized trial being overall survival. Patients will be stratified comparing denosumab with zoledronic acid in according to the presence or absence of bone the treatment of bone metastases from solid metastases at trial entry, thus enabling an evalua- tumours (excluding breast and prostate), the tion of the role of denosumab in preventing the incidence of hypocalcaemia was 10% with deno- formation of bone metastases [ClinicalTrials.gov sumab and 5.8% with zoledronic acid [Henry identifier: NCT02129699]. et al. 2011]. Tolerability and toxicity of bone-targeted Other bone-targeted agents agents Several novel bone-targeted agents are currently Zoledronic acid is given as a short intravenous in clinical trials evaluating their efficacy in reduc- infusion, whereas denosumab is given by subcuta- ing skeletal complications, improving quality of neous injection. Both are given with supplements life and improving survival outcomes. of calcium and vitamin D to reduce the risk of hypocalcaemia. Because zoledronic acid is renally excreted and can cause renal toxicity, dose modi- Radiopharmaceuticals fications have to be made in patients with renal Radium-223 is a first-in-class α-particle emitting impairment, an issue not applicable to deno- radioisotope that homes to areas of high bone sumab; hence denosumab is easier to administer turnover, making it ideal in targeting metastatic in an outpatient setting. bone disease [Nilsson et al. 2012]. It has a half life of 11.4 days and achieves its cytotoxic effect by Side effects with both zoledronic acid and deno- causing irreparable double-strand DNA breaks. sumab in metastatic disease are usually mild and Given its extremely short range, 60–100 µm, mar- easily managed, provided the drugs are used at row irradiation is spared, hence limiting its myelo- recommended dosing and schedule [Wilson toxicity [Hobbs et al. 2012]. et  al. 2013]. Side effects reported more com- monly with zoledronic acid than denosumab The results of the phase III ALSYMPCA trial include acute phase reactions and renal toxicity. provided the main evidence for its clinical effec- The acute phase reaction is characterized by tiveness and safety, and led to its approval by the fever, arthralgia and myalgia, and is thought to US Food and Drugs Administration (May 2013) be due to an increase in γ/δ lymphocytes and and the European Medicines Agency (November release of interleukin 6 and tumour necrosis fac- 2013) for use in patients with castration-resistant tor α [Dicuonzo et al. 2003]. It typically occurs prostate cancer (with bone metastases and no 224 http://tam.sagepub.com SC Silva, C Wilson et al. visceral metastases). In this trial, 921 patients cancer cells and surrounding tissues, resulting in with castration-resistant prostate cancer and alterations in the way pain signals are received and symptomatic bone metastases (but no visceral conducted. The main toxicities associated with metastases), were randomized in a 2:1 ratio to these agents are myelotoxicity, which is related to receive radium-223 (six intravenous injections the greater range of these agents (compared with every 4 weeks at a dose of 50 kBq/kg body weight) the α-emitting radium-223), and pain flare. or placebo. An updated analysis showed a median overall survival of 14.9 months in the radium-223 group and 11.3 months in the placebo group (HR Targeted agents 0.70; 95% CI 0.58–0.83; p < 0.001) [Parker et al. Cabozantinib is an oral tyrosine kinase inhibitor 2013]. In addition, time to first symptomatic skel- which blocks tyrosine kinase (MET), vascular etal event was 15.6 months in the radium-223 endothelial growth factor receptor 2 and proto- group and 9.8 months in the placebo group (HR oncogene (RET). MET is known to be overex- 0.66; 95% CI 0.52–0.83; p < 0.001) [Sartor et al. pressed in bone metastases from solid tumours, 2014]. No significant difference was seen in fre- that is, prostate cancer [Knudsen et al. 2002] and quency of grade 3 or 4 toxicities, while there was is involved in the proliferation, differentiation and a significant improvement in quality of life in the migration of osteoblasts and osteoclasts [Grano radium-223 group. et al. 1996]. A phase II randomized trial of cabo- zantinib 100 mg daily in prostate cancer showed An open-label phase II study of radium-223 in 68% of patients had improvement of bone disease patients with breast cancer (n = 23) with bone- on bone scan, including a complete response in dominant disease and previous bisphosphonate 12%. BALP and serum CTX also decreased by at treatment used four treatments of 50 kBq/kg least 50% in 57% of patients, with improvements every 4 weeks and evaluated the effect on urine in bone pain in 67% of patients [Smith et  al. NTX and serum BALP. NTX fell with treatment 2013]. The most common adverse events were [median change from baseline –4.1; interquartile fatigue, gastrointestinal toxicities and plantar pal- range (IQR) –17 to 1.7], with the greatest decline mar erythrodysesthesia. It is not known whether in NTX seen in patients with a high baseline lev- similar effects will be seen in patients with bone els. BALP also fell (median change from baseline metastases from other tumour types. –3.4; IQR −16 to 1.2). A secondary endpoint analysis was the effect of radiun-223 on bone pain The Src family of nonreceptor tyrosine kinases showing a consistent reduction in Brief Pain regulate a number of cell-signalling pathways and Inventory scores during treatment. These data inhibition of the Src family has been shown in show that radium-223 can further decrease bone preclinical studies to interrupt the development turnover in a breast cancer population already of osteoclasts from precursors, hence inhibiting treated with bisphosphonates [Coleman et  al. the progression of bone metastases [Zhang et  al. 2014]. The role of radium-223 in patients with 2009]. Lung cancers express Src and a phase II lung cancer is yet to be tested. study of saracatinib in patients with NSCLC who had attained at least stable disease with platinum Strontium-89 and Samarium-153 are β-emitting chemotherapy (n = 37) showed a soft tissue radionuclides which have been shown to have a response rate of 5.5% (95% CI 2–13%) and sta- role in the palliation of pain associated with bone bilization of disease in a further 17% (95% CI metastases [Lewington et  al. 1991; Serafini et  al. 4–29%), indicating some single-agent activity in 1998; Sartor et al. 2004; Tian et al. 1999]. Neither second-line therapy [Laurie et al. 2014]. Adverse agent has been shown to have a survival benefit. events included fatigue, gastrointestinal toxicity Strontium-89 has a half life of 50.5 days, a mean and skin rashes. Specific effects on bone metasta- range of 6.7 mm and is approved for use in painful ses from NSCLC were not reported. Ongoing bone metastases in prostate cancer with bone studies evaluating the effects of saracatinib in metastases; while samarium-153, with a half life of bone metastases from solid tumours will provide 1.95 days, and mean range of 3.4 mm, can be used more evidence for their role in NSCLC, including for osteoblastic metastases of other cancer types. the phase II SarCaBon study evaluating the effect The mechanism behind their palliative effect is of saracatinib in reducing pain associated with not fully understood, but is likely related to cell bone metastases [ClinicalTrials.gov identifier: signalling changes induced by radiation damage to NCT01605227]. http://tam.sagepub.com 225 Therapeutic Advances in Medical Oncology 7(4) Coleman, R. (1997) Skeletal complications of Conclusion malignancy. Cancer 80(8 Suppl.): 1588–1594. Zoledronic acid and denosumab have improved outcomes for patients with lung cancer with bone Coleman, R. 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Bone-targeted agents in the treatment of lung cancer:

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582178 TAM0010.1177/1758834015582178Therapeutic Advances in Medical OncologySilva research-article2015 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Bone-targeted agents in the treatment 2015, Vol. 7(4) 219 –228 DOI: 10.1177/ of lung cancer © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ Shobha C. Silva, Caroline Wilson and Penella J. Woll journalsPermissions.nav Abstract: Over a third of patients with lung cancer will develop bone metastases during the course of their disease, resulting in symptoms of pain and immobility, and skeletal- related events (SREs) such as fracture, hypercalcaemia, surgery or radiotherapy to bones, and malignant spinal cord compression. These reduce quality of life and increase mortality. Preclinical research has identified the interactions between tumour cells and bone that are key to tumour cell survival and associated osteolysis. These data have led to the development of drugs to prevent osteoclast-mediated bone breakdown, such as zoledronic acid and denosumab, which are now licensed for use in patients with bone metastases from solid tumours. Both zoledronic acid and denosumab reduce the risk of SREs and increase time to first SRE, with minimal side effects. In addition, denosumab improved survival in patients with lung cancer compared with zoledronic acid. Ongoing trials are testing whether these drugs can prevent the development of bone metastases from lung cancer. New bone-targeted agents showing promise in breast and prostate cancer include radium-223, cabozantinib and Src inhibitors. These agents require further evaluation in patients with lung cancer. Keywords: denosumab, skeletal-related events, survival outcomes, vicious cycle, zoledronic acid Correspondence to: Introduction mediators including parathyroid-like related hor- Penella J. Woll, BMedSci, Lung cancer is the commonest cause of death mone, interleukin 1 and tumour necrosis factor, MBBS, PhD, MRCP Academic Unit of Clinical from cancer worldwide. Over a third of patients which promote the maturation of osteoclasts result- Oncology, Weston Park with advanced lung cancer develop bone metasta- ing in increased bone resorption. Hypercalcaemia Hospital, Whitham Road, Sheffield S10 2SJ, UK ses during the course of their illness [Coleman, leads to debilitating symptoms, including fatigue, p.j.woll@sheffield.ac.uk 1997], presenting a significant morbidity burden. nausea and constipation. It is a poor prognostic fac- Shobha C. Silva, MBBS, These morbidities include bone pain, hypercal- tor, with a life expectancy of a few months [Ralston MRCP Caroline Wilson, PhD, caemia, pathological fractures, spinal cord com- et al. 1990; Clines and Guise, 2005]. MRCP pression and bone marrow infiltration. Weston Park Hospital, Sheffield, UK Pathological fractures occur most commonly in Bone pain is the most common type of cancer- weight-bearing bones (long bones, vertebrae), related pain [Mercadante, 1997] with both and are more likely if the bone metastases are mechanical and neurogenic components, requir- large, lytic and involve the cortex [Coleman, ing a combination of pharmacological (nonsteroi- 2006]. The sequelae of fractures include pain, dal anti-inflammatory drugs, opioid analgesics, reduced mobility, hospitalization, deterioration in gamma-aminobutyric acid (GABA) analogues, quality of life, and requirement for interventions corticosteroids) and nonpharmacological therapies including surgery and radiotherapy. (surgical stabilization, palliative radiotherapy, nerve blocks, transcutaneous electric nerve stimulation), Malignant spinal cord/cauda equina compression is a in addition to systemic anticancer treatments. medical emergency, typically characterized by back pain, followed by weakness and, less com- Hypercalcaemia is related to direct induction of local monly, sensory loss, with bladder and bowel dys- osteolysis by tumour cells, as well as to chemical function being late findings. Early diagnosis and http://tam.sagepub.com 219 Therapeutic Advances in Medical Oncology 7(4) Table 1. Frequency of SREs in 250 patients with prompt intervention with surgery, vertebroplasty NSCLC and other solid tumours (Rosen et al. 2004). or radiotherapy are crucial to avoiding irreversi- ble neurological sequelae [Martenson et al. 1985; Skeletal complication Number of events (%) Kim et al. 1990]. Radiation to bone 86 (34) Pathological fracture 55 (22) Bone marrow infiltration can lead to pancytopenia, Surgery to bone 13 (5) putting patients at risk of infection and bleeding. Spinal cord 10 (4) It can also compromise other anticancer treat- compression ments, such as cytotoxic chemotherapy. Hypercalcaemia 9 (4) Any SRE 120 (48) The morbidities associated with bone metastases (often referred to as skeletal-related events, SREs) NSCLC, non-small cell lung cancer; SRE, skeletal- have major impacts on patients’ quality of life and related event. present a significant economic burden. For patients with lung cancer and bone metastases, a retrospec- tive analysis in the USA showed the lifetime SRE cost per patient to be US$12,000 [Delea et  al. interacting with RANK. The ratio between 2004]. Placebo treatment arms of clinical trials of RANKL and OPG produced by osteoblasts antiresorptive agents in bone metastases have pro- controls RANKL-stimulated osteoclast activity vided evidence of the frequency of SREs in non- [Dougall et al. 1999; Kong et al. 1999]. small cell lung cancer (NSCLC) and other solid tumours, demonstrating that 48% of patients with When metastatic tumour cells arrive in bone, they bone metastases experience SREs and highlighting localize to areas that are highly vascular, particu- the need for preventive treatments (Table 1) larly trabecular bone [Holen, 2012], where they [Rosen et  al. 2004b; Coleman 2004]. Moreover, interact with osteoblasts and osteoclasts. The the development of bone metastases and SREs presence of tumour cells in bone disrupts the increases the risk of death and reduces median sur- RANKL:OPG coupling mechanism, as osteo- vival time (Table 2). clasts are stimulated by tumour-secreted parathy- roid-related protein (PTHrP), which increases The impact of bone metastases on morbidity and local production of RANKL [Kingsley et  al. mortality has been increasingly recognized over 2007]. The increase in osteoclast bone resorption the past 20 years and has led to interest in under- releases growth factors such as transforming standing the pathophysiology and pharmacologi- growth factor β, which are stored in bone matrix cal treatment of bone metastases from solid and further increase tumour secretion of PTHrP tumours. The remainder of this review will focus [Mourskaia et  al. 2009]. Other tumour-secreted primarily on the two drugs that are licensed for factors such as bone morphogenetic proteins acti- use in America, the UK and Europe for patients vate osteoblasts directly, which subsequently with bone metastases from solid tumours: zole- release more RANKL and less OPG to initiate dronic acid and denosumab. osteoclast differentiation [Dai et al. 2005]. These interactions create what is termed ‘the vicious cycle’ of bone metastasis [Mundy, 1997], a Bone-targeted agents in preclinical models tumour-induced self-propagating breakdown of Bone is a dynamic organ that is constantly remod- bone (Figure 1). elled. The balance between bone formation by osteoblasts and resorption by osteoclasts is criti- Both zoledronic acid and denosumab have been cal to prevent pathological excess of either pro- shown in vitro and in vivo to disrupt this vicious cess that could alter bone volume and architecture. cycle, primarily by their effect on osteoclast- One such coupling mechanism involves the recep- mediated bone resorption. Zoledronic acid is tor activator of nuclear factor κβ (RANK) and an intravenous-administered nitrogen-containing osteoprotegerin (OPG) (Figure 1). RANK ligand bisphosphonate and is the most potent of the (RANKL) is secreted by osteoblasts and binds to bisphosphonates [Russell et  al. 2008], binding RANK on the surface of preosteoclasts to pro- avidly to the bone surface, with a half life in mote differentiation into osteoclasts. This is pre- serum of about 2 hours [Lin, 1996]. The drug is vented by osteoblast secretion of OPG, which incorporated into the hydroxyapatite matrix binds and inactivates RANKL preventing it from and is taken up by osteoclasts during the 220 http://tam.sagepub.com SC Silva, C Wilson et al. Table 2. Effects of bone metastases and SREs on survival in lung cancer. Author Type of study Population (n) and Outcome tumour type Bauml et al. Single 376 NSCLC Bone metastases were an [2013] centre retrospective independent adverse prognostic analysis factor for survival. Saad [2007] Retrospective analysis of >3000 solid tumours Pathological fracture increased pooled data from RCTs including lung cancer death by 20% in all tumours of zoledronic acid except lung cancer* Tsuya [2007] Retrospective analysis 259 NSCLC ⩾1 SRE reduced median survival by half (366 days to 187 days) Hirsh et al. Retrospective analysis of 507 solid tumours Development of SREs reduced [2008] a phase III study including lung cancer median survival by half *The reason for this exception was thought to be due to the short median survival of lung cancer patient. In addition, nearly 70% lung cancer patients already had an SRE at study entry. NSCLC, non-small cell lung cancer; RCT, randomized controlled trial; SRE, skeletal-related event. Figure 1. The vicious cycle of bone metastases. Once tumour cells arrive in bone they interact with the bone forming osteoblasts (Ob) and bone-resorbing osteoclasts (Oc). Tumour cells secrete factors that stimulate Oc, that is, parathyroid-related protein (PTHrP). The increase in osteoclast bone resorption releases growth factors such as transforming growth factor β (TGFβ) which are stored in bone matrix which further increase tumour secretion of PTHrP. Other tumour-secreted factors such as bone morphogenetic proteins (BMPs) activate osteoblasts directly which subsequently release more receptor activator of nuclear factor κβ ligand (RANKL) and less osteoprotegerin (OPG), a RANKL decoy, to initiate osteoclast differentiation and hence further bone resorption. resorption process. Zoledronic acid inhibits bone, zoledronic acid has been shown to reduce farnesyl pyrophosphate synthase [van Beek et al. tumour-induced osteolysis, and to reduce 1999] preventing prenylation of small guano- tumour burden outside bone in subcutaneous sine-5-triphosphatease (GTPases), which are tumours from breast, lung and prostate [Holen responsible for many cellular functions in osteo- and Coleman, 2010]. Denosumab is a subcuta- clasts, thus inducing apoptosis and loss of cell neously administered human immunoglobulin membrane integrity [Coxon and Rogers, 2003]. G antibody that binds to and neutralizes RANKL In animal models of breast cancer metastases to in a similar way to OPG, with a serum half life of http://tam.sagepub.com 221 Therapeutic Advances in Medical Oncology 7(4) 46 days [Brown and Coleman, 2012]. In animal follow up, these benefits were sustained [Rosen models denosumab reduces tumour-induced et al. 2004b]. osteolysis and tumour progression in bone from breast, lung and prostate cancer, and it has been In phase II and III trials in patients with breast shown to decrease metastasis outside of bone cancer and bone metastases, denosumab was [Dougall et al. 2014]. shown to have similar efficacy to intravenous bis- phosphonates in reducing SREs but led to a greater reduction in bone turnover markers and Clinical evidence for prevention of SREs with significantly delayed the time to first on-study bone-targeted agents in lung cancer SRE [hazard ratio (HR) 0.77; 95% confidence The encouraging preclinical data demonstrating interval (CI) 0.66–0.89; p = 0.001] [Stopeck that both zoledronic acid and denosumab can et  al. 2010]. In a phase III trial in patients with modify the bone microenvironment and affect bone metastases from solid tumours (apart from skeletal and extraskeletal tumour growth led to breast and prostate) and multiple myeloma, eligi- clinical trials that have provided the evidence ble patients were randomized to receive deno- for licensing in the USA, the UK and Europe sumab or zoledronic acid. Of the 1776 patients for patients with bone metastases from solid recruited, 811 had lung cancer (702, 47% had tumours. The endpoints in clinical trials of NSCLC). Denosumab was found to be noninfe- bone-targeted agents vary and have included rior (trending to superiority) to zoledronic acid in survival outcomes [Rosen et  al. 2004b; Hirsh terms of delaying time to first on-study SRE (HR et  al. 2008; Henry et  al. 2011], SRE incidence, 0.84; 95% CI 0.71–0.98; p = 0.0007), with a 4.3 time to first SRE [Henry et al. 2011], changes in month improvement in time to first SRE (20.6 bone biomarkers [Lipton et  al. 2008] or symp- months in the denosumab group versus 16.3 tom outcomes including changes in reported months in the zoledronic acid group) [Henry pain or opioid use [Van Moos, 2010; Henry et al. 2011]. The authors also noted that the sub- et  al. 2011; Rosen et  al. 2004b]. Bone bio- cutaneous formulation was more convenient than markers that have been studied include markers the intravenous infusion required for zoledronic of bone formation such as bone alkaline acid. phosphatase (BALP), type I procollagen and markers of bone resorption such as serum and urine N-terminal telopeptide (NTX), which Clinical evidence for a survival benefit for have been shown to correlate with SREs and bone-targeted agents in lung cancer survival. Survival outcomes with bone-targeted agents in lung cancer have been evaluated in clinical trials Zoledronic acid is the only bisphosphonate that has assessing the role of these agents in patients with demonstrated long-term efficacy and safety in and without bone metastases. patients with lung cancer with bone metastases. Zoledronic acid has been shown to effectively reduce the risk of SREs in patients with meta- Bone metastases at trial entry static prostate cancer [Lipton et al. 2002], multi- Zoledronic acid, when used as a single agent, has ple myeloma and breast cancer [Berenson et  al. not been found to improve survival outcomes in 2001; Rosen et  al. 2001]. Rosen and colleagues patients with lung cancer and bone metastases. In analysed 773 patients with bone metastases from a phase III study of zoledronic acid (4 mg) or pla- solid tumours (of whom nearly half had NSCLC) cebo given 3 weekly for 9 months in 773 patients randomized to receive 4 mg or 8 mg of zoledronic with solid tumour (n = 378 NSCLC), neither acid or placebo. Due to concerns over renal toxic- time to progression of bone lesions (145 days ver- ity, the 8 mg arm was later discontinued. sus 109 days, p = 0.415) nor survival (202.5 days Zoledronic acid significantly reduced the risk of versus 183 days, p = 0.929) was significantly bet- all skeletal events (including hypercalcaemia) in ter in the zoledronic acid arm [Rosen et al. 2004b]. the 4 mg group compared with placebo (38% ver- A subgroup analysis, restricted to patients with sus 47%, p = 0.039) [Rosen et  al. 2003]. This NSCLC patients, suggested that high levels of the dose of zoledronic acid was also shown to increase biomarker urinary NTX at baseline predicted the median time to first SRE by more than 2 benefit from zoledronic acid and significantly months compared with placebo (p = 0.023). In decreased the relative risk of death 35% (relative an updated analysis after 21 months of treatment/ risk 0.650, p = 0.024) [Hirsh et al. 2008]. These 222 http://tam.sagepub.com SC Silva, C Wilson et al. Table 3. Ongoing trials of bone-targeted agents in lung cancer. Clinical Trial. Phase N Population Design Primary endpoint gov identifier NCT01951586 II 216 NSCLC 4-6 cycles of standard doublet Overall survival stage IV platinum-based chemotherapy +/- denosumab 120 mg every 3–4 weeks NCT02129699 III 1000 NSCLC 4-6 cycles of standard doublet Overall survival (Splendour) stage IV platinum-based chemotherapy +/- denosumab 120 mg every 3–4 weeks NCT01737216 II 100 4-6 cycles of standard doublet Progression-free Aged >70 platinum-based survival years, lung chemotherapy +/- zoledronicacid cancer 4 mg every 4 weeks/every 12 weeks until progression NSCLC, non-small cell lung cancer. data suggest that NTX is a useful biomarker and Absence of bone metastases at trial entry the survival benefits of zoledronic acid are great- A randomized trial in 437 patients with stage est in patients with a baseline high bone turnover, IIIA/B NSCLC without metastases evaluated the likely due to the increased risk of SREs in this use of zoledronic acid administered every 3–4 group and subsequent prevention by antiresorp- weeks for 24 months after completion of primary tive therapy. However, predicting which individ- therapy (including surgery, radiotherapy and ual patients will benefit from zoledronic acid is chemotherapy) without progression [Scagliotti not currently possible. et al. 2012b]. No significant differences were seen between zoledronic acid treated patients and con- More recently, denosumab has been shown to trols in progression-free survival (PFS) (9 months significantly improve survival in patients with versus 11.3 months respectively, p = 0.096), risk lung cancer and bone metastases in a subgroup of death (HR 1.17; 95% CI 0.86–1.59), or the analysis (n = 811) [Scagliotti et  al. 2012a] of a number of patients who developed bone metasta- large international phase III study comparing ses (6.6% versus 9%). Similar results were seen in denosumab (120 mg every 4 weeks) with zole- a smaller (n = 150) phase II study of zoledronic dronic acid (4 mg every 4 weeks) in solid tumours acid versus control in patients with stage IIIB/IV (excluding breast and prostate) [Henry et  al. NSCLC after primary therapy with docetaxel and 2011]. Denosumab increased overall survival carboplatin, with no difference between treatment compared with zoledronic acid (8.9 months ver- groups in time to progression or overall survival sus 7.7 months, p = 0.01). In NSCLC, the great- [Pandya et al. 2010]. These data suggest that zole- est benefit from denosumab appeared to be in dronic acid may decrease the formation of bone those patients with squamous cell carcinoma metastases, but as disease progression in patients with an increased survival of 2.2 months com- with lung cancer is primarily in extraskeletal sites, pared with zoledronic acid (HR 0.68, p = 0.035); there is no impact of the drug on survival out- however, the trend to increased survival was seen comes. No data are currently available on the use in all histological subtypes, including small-cell of denosumab to prevent the formation of bone lung cancer. Although a subgroup analysis, this metastases specifically from lung cancer. represents a large prospective randomized trial in NSCLC. Following on from these data, deno- The ability of osteoclast inhibitors to prevent the sumab was licensed for use in patients with estab- formation of bone metastases and improve survival lished bone metastases from solid tumours in in patients with solid tumours has been demon- America (2010) and Europe (2011). Ongoing strated in a large meta-analysis (23,000 patients) of trials of both zoledronic acid and denosumab on adjuvant trials of bisphosphonates in early breast survival outcomes in lung cancer will add to cancer. There was a significant decrease in bone existing data (Table 3). recurrence in the treated population compared http://tam.sagepub.com 223 Therapeutic Advances in Medical Oncology 7(4) with controls (6.9% versus 8.4%). In addition, with the first cycle with an incidence in meta- there was a nonsignificant trend to a reduction in static breast cancer and myeloma trials of 16– nonbone recurrence in postmenopausal women 38% [Rosen et  al. 2004a; Body et  al. 2007]. treated with zoledronic acid compared with con- Renal toxicity is dose and schedule dependent, trols (9%; 95% CI 5–19%), resulting in a signifi- but with the standard 4 mg dose infused over 15 cantly improved 10-year breast cancer mortality min the incidence is about 10–15%, necessitat- (15.2% versus 18.3%) [Coleman et al. 2013]. This ing an evaluation of renal function in patients suggests that there may be subpopulations of before administration of zoledronic acid [Gar trell patients in whom bisphosphonates are more effec- et  al. 2014]. Side effects reported with similar tive in preventing the formation of bone metasta- frequency in both denosumab and zoledronic ses, and in these populations they may potentially acid include osteonecrosis of the jaw (ONJ). decrease the formation of extraskeletal metastases. ONJ is a painful exposure of bone in the mandi- How this preventive approach will translate to lung ble and maxilla, commonly occurring after tooth cancer, and how to identify these high-risk patients, extraction and exacerbated by poor dental is yet to be established and will need international hygiene. In trials comparing zoledronic acid with collaborative trials. The SPLENDOUR (Survival denosumab, ONJ rates were similar, with an Improvement in Lung Cancer Induced by incidence of 1–2% over 2–3 years of use [Stopeck Denosumab Therapy) trial will soon be open to et al. 2010; Henry et al. 2011]. Side effects more recruitment. It is a large phase III trial in which commonly associated with denosumab include patients with stage IV NSCLC will be randomized hypocalcaemia, although this is often subclinical to receive standard cytotoxic chemotherapy alone and prevented by adequate vitamin D and cal- or with denosumab, with the primary endpoint cium replacement. In a large randomized trial being overall survival. Patients will be stratified comparing denosumab with zoledronic acid in according to the presence or absence of bone the treatment of bone metastases from solid metastases at trial entry, thus enabling an evalua- tumours (excluding breast and prostate), the tion of the role of denosumab in preventing the incidence of hypocalcaemia was 10% with deno- formation of bone metastases [ClinicalTrials.gov sumab and 5.8% with zoledronic acid [Henry identifier: NCT02129699]. et al. 2011]. Tolerability and toxicity of bone-targeted Other bone-targeted agents agents Several novel bone-targeted agents are currently Zoledronic acid is given as a short intravenous in clinical trials evaluating their efficacy in reduc- infusion, whereas denosumab is given by subcuta- ing skeletal complications, improving quality of neous injection. Both are given with supplements life and improving survival outcomes. of calcium and vitamin D to reduce the risk of hypocalcaemia. Because zoledronic acid is renally excreted and can cause renal toxicity, dose modi- Radiopharmaceuticals fications have to be made in patients with renal Radium-223 is a first-in-class α-particle emitting impairment, an issue not applicable to deno- radioisotope that homes to areas of high bone sumab; hence denosumab is easier to administer turnover, making it ideal in targeting metastatic in an outpatient setting. bone disease [Nilsson et al. 2012]. It has a half life of 11.4 days and achieves its cytotoxic effect by Side effects with both zoledronic acid and deno- causing irreparable double-strand DNA breaks. sumab in metastatic disease are usually mild and Given its extremely short range, 60–100 µm, mar- easily managed, provided the drugs are used at row irradiation is spared, hence limiting its myelo- recommended dosing and schedule [Wilson toxicity [Hobbs et al. 2012]. et  al. 2013]. Side effects reported more com- monly with zoledronic acid than denosumab The results of the phase III ALSYMPCA trial include acute phase reactions and renal toxicity. provided the main evidence for its clinical effec- The acute phase reaction is characterized by tiveness and safety, and led to its approval by the fever, arthralgia and myalgia, and is thought to US Food and Drugs Administration (May 2013) be due to an increase in γ/δ lymphocytes and and the European Medicines Agency (November release of interleukin 6 and tumour necrosis fac- 2013) for use in patients with castration-resistant tor α [Dicuonzo et al. 2003]. It typically occurs prostate cancer (with bone metastases and no 224 http://tam.sagepub.com SC Silva, C Wilson et al. visceral metastases). In this trial, 921 patients cancer cells and surrounding tissues, resulting in with castration-resistant prostate cancer and alterations in the way pain signals are received and symptomatic bone metastases (but no visceral conducted. The main toxicities associated with metastases), were randomized in a 2:1 ratio to these agents are myelotoxicity, which is related to receive radium-223 (six intravenous injections the greater range of these agents (compared with every 4 weeks at a dose of 50 kBq/kg body weight) the α-emitting radium-223), and pain flare. or placebo. An updated analysis showed a median overall survival of 14.9 months in the radium-223 group and 11.3 months in the placebo group (HR Targeted agents 0.70; 95% CI 0.58–0.83; p < 0.001) [Parker et al. Cabozantinib is an oral tyrosine kinase inhibitor 2013]. In addition, time to first symptomatic skel- which blocks tyrosine kinase (MET), vascular etal event was 15.6 months in the radium-223 endothelial growth factor receptor 2 and proto- group and 9.8 months in the placebo group (HR oncogene (RET). MET is known to be overex- 0.66; 95% CI 0.52–0.83; p < 0.001) [Sartor et al. pressed in bone metastases from solid tumours, 2014]. No significant difference was seen in fre- that is, prostate cancer [Knudsen et al. 2002] and quency of grade 3 or 4 toxicities, while there was is involved in the proliferation, differentiation and a significant improvement in quality of life in the migration of osteoblasts and osteoclasts [Grano radium-223 group. et al. 1996]. A phase II randomized trial of cabo- zantinib 100 mg daily in prostate cancer showed An open-label phase II study of radium-223 in 68% of patients had improvement of bone disease patients with breast cancer (n = 23) with bone- on bone scan, including a complete response in dominant disease and previous bisphosphonate 12%. BALP and serum CTX also decreased by at treatment used four treatments of 50 kBq/kg least 50% in 57% of patients, with improvements every 4 weeks and evaluated the effect on urine in bone pain in 67% of patients [Smith et  al. NTX and serum BALP. NTX fell with treatment 2013]. The most common adverse events were [median change from baseline –4.1; interquartile fatigue, gastrointestinal toxicities and plantar pal- range (IQR) –17 to 1.7], with the greatest decline mar erythrodysesthesia. It is not known whether in NTX seen in patients with a high baseline lev- similar effects will be seen in patients with bone els. BALP also fell (median change from baseline metastases from other tumour types. –3.4; IQR −16 to 1.2). A secondary endpoint analysis was the effect of radiun-223 on bone pain The Src family of nonreceptor tyrosine kinases showing a consistent reduction in Brief Pain regulate a number of cell-signalling pathways and Inventory scores during treatment. These data inhibition of the Src family has been shown in show that radium-223 can further decrease bone preclinical studies to interrupt the development turnover in a breast cancer population already of osteoclasts from precursors, hence inhibiting treated with bisphosphonates [Coleman et  al. the progression of bone metastases [Zhang et  al. 2014]. The role of radium-223 in patients with 2009]. Lung cancers express Src and a phase II lung cancer is yet to be tested. study of saracatinib in patients with NSCLC who had attained at least stable disease with platinum Strontium-89 and Samarium-153 are β-emitting chemotherapy (n = 37) showed a soft tissue radionuclides which have been shown to have a response rate of 5.5% (95% CI 2–13%) and sta- role in the palliation of pain associated with bone bilization of disease in a further 17% (95% CI metastases [Lewington et  al. 1991; Serafini et  al. 4–29%), indicating some single-agent activity in 1998; Sartor et al. 2004; Tian et al. 1999]. Neither second-line therapy [Laurie et al. 2014]. Adverse agent has been shown to have a survival benefit. events included fatigue, gastrointestinal toxicity Strontium-89 has a half life of 50.5 days, a mean and skin rashes. Specific effects on bone metasta- range of 6.7 mm and is approved for use in painful ses from NSCLC were not reported. Ongoing bone metastases in prostate cancer with bone studies evaluating the effects of saracatinib in metastases; while samarium-153, with a half life of bone metastases from solid tumours will provide 1.95 days, and mean range of 3.4 mm, can be used more evidence for their role in NSCLC, including for osteoblastic metastases of other cancer types. the phase II SarCaBon study evaluating the effect The mechanism behind their palliative effect is of saracatinib in reducing pain associated with not fully understood, but is likely related to cell bone metastases [ClinicalTrials.gov identifier: signalling changes induced by radiation damage to NCT01605227]. http://tam.sagepub.com 225 Therapeutic Advances in Medical Oncology 7(4) Coleman, R. (1997) Skeletal complications of Conclusion malignancy. Cancer 80(8 Suppl.): 1588–1594. Zoledronic acid and denosumab have improved outcomes for patients with lung cancer with bone Coleman, R. 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Journal

Therapeutic Advances in Medical OncologySAGE

Published: Apr 22, 2015

Keywords: denosumab; skeletal-related events; survival outcomes; vicious cycle; zoledronic acid

References