Elsevier

Lung Cancer

Volume 65, Issue 2, August 2009, Pages 219-222
Lung Cancer

Risk factors for skeletal-related events in patients with non-small cell lung cancer treated by chemotherapy

https://doi.org/10.1016/j.lungcan.2008.10.026Get rights and content

Abstract

The purpose of this study was to identify the risk factors for skeletal-related events (SREs) in patients with advanced non-small cell lung cancer (NSCLC). SREs were defined as pathologic fractures, spinal cord compression, requirement for radiation therapy, other radiological intervention, or surgery to the bone, and hypercalcemia of malignancy. Time-to-the first SRE and SRE-free survival, and their associations with the patient characteristics were evaluated retrospectively in 642 patients with metastatic NSCLC who received systemic chemotherapy. A total of 118 (18.4%) patients developed SREs during or after the initial chemotherapy. Of these, 107 required radiotherapy to the bone, 5 developed hypercalcemia of malignancy, 3 developed compression fracture of the vertebrae, 2 required surgical treatment of the bone, and 1 underwent radiofrequency ablation therapy to the bone. The first SRE occurred within 12 months in 80 (67.8%) of the 107 patients. The results of multivariate analysis revealed that male sex, performance status (PS) of 2–3 and multiple bone metastases were risk factors for the first SRE, with hazard ratios (HRs) (95% confidence interval [CI]) to the reference of 1.44 (0.98–2.11), 2.21 (0.97–5.03) and 4.43 (2.91–6.76), respectively. SRE-free survival showed a similar trend. The HRs (CI) of male sex, PS of 2 and multiple bone metastases were 1.64 (1.30–2.06), 3.72 (2.31–5.98) and 1.80 (1.40–2.31), respectively. In conclusion, the presence of multiple bone metastases was significantly associated with the development of SRE in patients with advanced NSCLC treated by systemic chemotherapy. Male sex and poor performance status may be additional risk factors for the development of SREs in these patients.

Introduction

The bone is a preferred site of metastasis in patients with advanced cancer, which is attributable to the abundant blood flow to the red marrow, high expression levels of adhesion molecules on the tumor cells that bind them to marrow stromal cells and the bone matrix, and a large amount of growth factors in the bone that provide fertile ground for tumor cell growth [1]. Bone metastases are encountered in 30–40% of patients with metastatic lung cancer and 30–55% of patients with lung cancer at autopsy [2], [3]. Bone metastases are a serious complication leading to skeletal-related events (SREs), including bone pain requiring radiotherapy, pathologic fractures, and spinal cord compression [2], [3]. There have been few reports on the frequency and risk factors of SREs in patients with advanced non-small cell lung cancer (NSCLC), probably because these patients with bone metastases also show systemic disease progression along with progression of the bone metastases, and had a poor prognosis with an estimated median survival time of less than 6 months [2]. With the recent advances in the systemic treatment of NSCLC, however, the median survival of advanced NSCLC patients has increased to approximately 1 year, increasing the period for which the patients are at risk for SREs. A recent phase III trial of zoledronic acid versus placebo in NSCLC patients with bone metastases showed that the frequency of SREs did not differ between the patients receiving zoledronic acid (42%) and those receiving placebo (45%), however, there was a trend toward a longer median time-to-the first SRE in patients receiving zoledronic acid (5.6 months versus 5.0 months, p = 0.188) [4]. These results suggest that zoledronic acid may delay the appearance of SREs in NSCLC patients with bone metastases, but that this effect may be limited to the subgroup of patients at a high risk for SREs. Thus, we tried to identify the risk factors for SREs in patients with advanced NSCLC who were treated with systemic chemotherapy.

Section snippets

Patient selection

Patients were retrospectively selected for this study according to the following criteria: (1) a histological or cytological diagnosis of NSCLC; (2) stage IV disease or postoperative recurrence with distant metastases; (3) no prior chemotherapy; (4) chemotherapy prescribed by the National Cancer Center Hospital between December 2000 and June 2006. Patients with postoperative local recurrence without distant metastases were excluded.

Data collection and statistical analyses

The patients’ baseline characteristics before the initial

Results

A total of 642 patients fulfilled the eligibility criteria for this study. The first-line chemotherapy was platinum-based chemotherapy in 469 (73.1%) patients, gefitinib in 117 (18.2%) patients, third-generation monotherapy in 47 (7.3%) patients, and non-platinum doublets in 9 (1.4%) patients. Responses to these chemotherapies were complete response in 6 patients and partial response in 177 patients, yielding a response rate of 28.5%. Disease progression was observed in 580 (90.3%) patients.

Discussion

This study showed that the male sex, a poor performance status and presence of multiple bone metastases were associated with a short time-to-the first SRE and poor SRE-free survival. To the best of our knowledge, this is the first study identifying risk factors for the development of SREs in patients with advanced NSCLC treated by administered systemic chemotherapy.

Hypercalcemia of malignancy has been included in the definition of SRE, and we adopted the traditional definition for this study.

Conflict of interest statement

The authors indicated no potential conflicts of interest.

Acknowledgement

The authors would like to thank Mika Nagai for her invaluable assistance in the preparation of this manuscript.

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