Lung cancer frequently spreads to bone, with metastases evident at post-mortem in up to 36% of patients [20
] and bone marrow micrometastases found in 22%–60% of individuals [21
]. The bone microenvironment is exposed to many growth factors and cytokines that provide a fertile ‘soil’ for cancer cells, making bone a preferred site of metastasis in advanced cancer. Individuals with lung cancer and bone metastases have poor prognoses with median survival times from detection of metastases typically measured in months [20
]. Most patients who develop bone metastases experience complications such as hypercalcaemia, severe bone pain requiring palliative radiotherapy or analgesics, pathological fractures, spinal cord compression and bone instability requiring orthopaedic surgery. The last four of these complications are collectively known as skeletal-related events (SREs), although some historical studies also included hypercalcaemia in this grouping.
SREs are a complication of the unrestricted resorption of mineralised bone by osteoclasts and result in significant morbidity, requiring frequent hospitalisation, outpatient visits and reduced QoL [22
]. Unfortunately, screening and treatment of asymptomatic bone metastases are not considered necessary in clinical practice. Consequently, bone metastases are often not diagnosed in individuals with NSCLC until they cause substantial pain or an SRE [24
]. It is therefore important to raise both patient and physician awareness of bone metastases in lung cancer. Furthermore, therapy should be considered at the time of bone metastasis detection, before debilitating pain develops and SREs are experienced. Positron-emission tomography scans may be useful for early detection of asymptomatic bone metastases [25
]; however, recent European Society for Medical Oncology (ESMO) guidelines recommend a bone scan only if there is bone pain, hypercalcaemia or elevated alkaline phosphatase levels [3
Owing to the historically short survival time in patients with NSCLC, reports of SRE frequency in this population are limited to data from the placebo arm of a large clinical trial [28
], retrospective studies from Asia [30
] (Figure ) and a Serbian bone scintigraphy study [33
Figure 2 Overview of the occurrence of SREs in patients with NSCLC. (A) Data from the placebo arm of a large clinical trial including patients with NSCLC (Rosen et al. 2004 ) and two retrospective audits of patients with NSCLC in Japan (Tsuya et al. 2007 [ (more ...)
In a large multinational, randomised, double-blind phase III trial of zoledronic acid versus placebo in patients with bone metastases secondary to lung cancer and other solid tumours (except carcinomas of the breast and prostate) [28
], 46% of individuals treated with placebo experienced at least one SRE during the 21-month study, with an overall average of 2.71 SREs per year in the placebo arm [28
]. A breakdown of the types of SREs experienced is shown in Figure A. A retrospective exploratory analysis revealed that before study entry, 69% of all randomised patients had experienced at least one SRE, and that these individuals had a higher risk of a subsequent SRE than those with no previous SREs (odds ratio: 1.41). During the study, the median time to first SRE among the subgroup of patients who had previously experienced an SRE and were subsequently randomised to placebo was ~3.5 months [34
The Serbian study retrospectively analysed 100 patients with lung cancer who underwent bone scintigraphy during a 3-year period (2003–2005) [33
]. Bone metastases were confirmed in 57% of patients, with suspicious findings recorded in 11% of individuals [33
Results from retrospective studies from Japan [30
] and Korea [31
] confirmed these findings. In one Japanese study, the charts of all patients with NSCLC treated from February 2002 to January 2005 at a single hospital were analysed for disease stage [using the tumour–node–metastasis (TNM) staging system], presence of bone metastases, frequency of SREs and survival [32
]. Of 230 assessable individuals, 70 (30.4%) had bone metastases during their treatment, consistent with the frequency reported from autopsy studies [20
]. Bone metastases were evident at the time of initial diagnosis in 46 of these 70 patients (65.7%) [32
]. Moreover, of patients with bone metastases, 50.0% experienced SREs, the most common of which were radiotherapy to bone (34.3%) and hypercalcaemia (20.0%; Figure A). Among 135 individuals with stage IV NSCLC, 41.5% had bone metastases; 44.6% of those with bone metastases experienced SREs (Table ). Median survival time was shorter (187 days) for patients with SREs than for those without (366 days; Table ), although this difference was not statistically significant.
Comparison of median survival times of patients with stage III or stage IV NSCLC, with or without bone metastases and SREs
The second Japanese study retrospectively analysed 642 patients with metastatic NSCLC treated from December 2000 to June 2006 and showed that median survival was 15.4 months [30
]. First-line platinum-based chemotherapy was given to 73.1% of patients, and 18.2% of patients were treated with gefitinib. Only 6.6% of patients received the bisphosphonate zoledronic acid. In total, 118 (18.4%) patients experienced SREs (Figure A), 40.7% of which were within 6 months of starting first-line antitumour therapy. A further 27.1% of individuals experienced an SRE 6–12 months after commencing treatment. Multivariate analysis revealed that men, patients with a performance status of 2–3 and those with multiple bone metastases were at greatest risk of a first SRE.
Finally, a more recent Korean retrospective study of 273 patients with bone metastases secondary to NSCLC treated from January 2006 to March 2009 showed that 62.6% had at least one SRE and 16.8% experienced multiple SREs [31
]. Radiotherapy to bone was by far the most common SRE reported (Figure B). Analysis of risk factors for SREs suggested that long-term smoking, non-adenocarcinoma tumours, poor performance status and no history of treatment with EGFR TKIs were predictors for SREs [31
]. Surprisingly, only 20.9% of patients with bone metastases were receiving bisphosphonates and only 6.6% received a bone-targeted agent before experiencing an SRE.