Inaugural bone metastases in non-small cell lung cancer: a specific prognostic entity?

Mélanie Deberne, Stanislas Ropert, Bertrand Billemont, Catherine Daniel, Jeanne Chapron, François Goldwasser, Mélanie Deberne, Stanislas Ropert, Bertrand Billemont, Catherine Daniel, Jeanne Chapron, François Goldwasser

Abstract

Background: In non-small cell lung cancer patients (NSCLC), median survival from the time patients develop bone metastasis is classically described being inferior to 6 months. We investigated the subcategory of patients having an inaugural skeletal-related-event revealing NSCLC. The purpose of this study was to assess the impact of bone involvement on overall survival and to determine biological and tumoral prognosis factors on OS and PFS. An analysis of the subgroup of solitary bone metastasis patients was also performed.

Methods: In a population of 1208 lung cancer patients, 55 consecutive NSCLC patients revealed by inaugural bone metastasis and treated between 2003 and 2010, were retrospectively analysed. Survival was measured with a Kaplan-Meyer curve. Univariate and multivariate analysis were performed using the Stepwise Cox proportional hazard regression model. A p value of less than 0,05 was considered statistically significant.

Results: Estimated incidence of revealing bone metastasis is 4,5% among newly diagnosed lung cancer patients. Median duration of skeletal symptoms before diagnosis was 3 months and revealing bone site was located on axial skeleton in 70% of the cases. Histology was adenocarcinoma (78%), with small primary tumors Tx-T1-2 accounting for 71% of patients. Rate of second SRE is 37%.Median overall survival was 8.15 months, IQR [5-16 months], mean survival 13.4 months, and PFS was 3.5 months. In multivariate analysis, variables significantly associated with shortened survival were advanced T stage (HR=2.8; p=0.004), weight loss>10% (HR=3.1; p=0.02), inaugural spinal epidural metastasis (HR 2.5; p=0.0036), elevated C-reactive protein (HR=4.3; p=0.002) and TTF-1 status (HR=2.42; p=0.004). Inaugural spinal epidural metastasis is a very strong adverse pronostic factor in these cases, with a 3 months median survival. Single bone metastasis patients showed prolonged survival of 14.2 months versus 7.6 months, only in univariate analysis (HR=0.42; p=0.0059).

Conclusion: Prognosis of lung cancer patients with inaugural SRE remains pejorative. Accurately estimating the survival of this population is helpful for bone surgical decision-making at diagnosis. The trend for a higher proportion of adenocarcinoma in NSCLC patients should result with an increasing number of patients with inaugural SRE at diagnosis.

Figures

Figure 1
Figure 1
Overall survival according to Kaplan-Meyer.

References

    1. Locher C, Debieuvre D, Coëtmeur D, Goupil F, Molinier O, Collon T, Dayen C, Le Treut J, Asselain B, Martin F, Blanchon F, Grivaux M. Major changes in lung cancer over the last ten years in France: The KBP-CPHG studies. Lung Cancer. 2013;81:32–38. doi: 10.1016/j.lungcan.2013.03.001.
    1. Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006;12:6243s–6249s. doi: 10.1158/1078-0432.CCR-06-0931.
    1. Decroisette C, Monnet I, Berard H, Quere G, Le Caer H, Bota S, Audigier-Valette C, Geriniere L, Vernejoux JM, Chouaid C. Groupe Français de Pneumo-Cancérologie 0601 Team. Epidemiology and treatment costs of bone metastases from lung cancer: a French prospective, observational multicenter study (GFPC 0601) J Thorac Oncol. 2011;6(3):576–82. doi: 10.1097/JTO.0b013e318206a1e3.
    1. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–2550. doi: 10.1056/NEJMoa061884.
    1. Sugiura H, Yamada K, Sugiura T, Hida T, Mitsudomi T. Predictors of survival in patients with bone metastasis of lung cancer. Clin Orthop Relat Res. 2008;466:729–736. doi: 10.1007/s11999-007-0051-0.
    1. Bae YM, Se-Hoon L, Tae Min K, Dong-Wan K, Seok-Chul Y, Hong Gyun W, Young Whan K, Dae Seog H. Prognostic factors for non-small cell lung cancer with bone metastasis at the time of diagnosis. Lung Cancer. 2012;77:572–577. doi: 10.1016/j.lungcan.2012.05.094.
    1. Weiss RJ, Wedin R. Surgery for skeletal metastases in lung cancer. Acta Orthop. 2011;82(1):96–101. doi: 10.3109/17453674.2011.552779.
    1. Nathan S, Healey JH, Mellano D, Hoang B, Lewis I, Morris CD, Athanasian EA, Boland PJ. Survival in patients operated on for pathologic fracture: implications for end-of-life orthopedic care. J Clin Oncol. 2005;23:6072–6081. doi: 10.1200/JCO.2005.08.104.
    1. Kagohashi K, Satoh H, Ishikawa H, Ohtsuka M, Sekizawa K. Bone metastasis as the first manifestation of lung cancer. Int J Clin Pract. 2003;57:184–186.
    1. Charloux A, Quoix E, Wolkove N, Small D, Pauli G, Kreisman H. The increasing incidence of lung adenocarcinoma: reality or artefact? a review of the epidemiology of lung adenocarcinoma. Int J Epidemiol. 1997;26:14–23. doi: 10.1093/ije/26.1.14.
    1. Charloux A, Rossignol M, Purohit A, Small D, Wolkove N, Pauli G, Quoix E, Kreisman H. International differences in epidemiology of lung adenocarcinoma. Lung Cancer. 1997;16(2-3):133–143. doi: 10.1016/S0169-5002(96)00623-X.
    1. Jasmin C, Coleman RE, Coia LR, Capanna R, Saillant G. Daniel E.Roos, Lung Cancer, in “the Textbook of Bone Metastases”. John Wiley and Sons; 2005.
    1. Kosteva JLC. Incidence and distribution of skeletal metastases in NSCLC in the era of PET. Lung Cancer. 2004. p. 86.
    1. Tsuya A, Kurata T, Tamura K, Fukuoka M. Skeletal metastases in non-small cell lung cancer: a retrospective study. Lung Cancer. 2007;57:229–232. doi: 10.1016/j.lungcan.2007.03.013.
    1. Delea T, Langer C, McKiernan J, Liss M, Edelsberg J, Brandman J, Sung J, Raut M, Oster G. The cost of treatment of skeletal-related events in patients with bone metastases from lung cancer. Oncology. 2004;67:390–396. doi: 10.1159/000082923.
    1. Katagiri H, Takahashi M, Wakai K, Sugiura H, Kataoka T, Nakanishi K. Prognostic factors and a scoring system for patients with skeletal metastasis. J Bone Joint Surg. 2005;87-B:698–703. doi: 10.1302/0301-620X.87B5.15185.
    1. Forsberg JA, Wedin R, Bauer HC, Hansen BH, Laitinen M, Trovik CS, Keller JO, Bol PJ, Healey JH. External validation of the Bayesian estimated tools for survival ( BETS) models in patients with surgically treated skeletal metastases. BMC Cancer. 2012;12:493. doi: 10.1186/1471-2407-12-493.
    1. Schiff D, O’Neill BP, Suman VJ. Spinal epidural metastasis as the initial manifestation of malignancy: clinical features and diagnostic approach. Neurology. 1997;49:452–456. doi: 10.1212/WNL.49.2.452.
    1. Paesmans M, Sculier JP, Libert P, Bureau G, Dabouis G, Thiriaux J, Michel J, Van Cutsem O, Sergysels R, Mommen P. Prognostic factors for survival in advanced non-small-cell lung cancer: univariate and multivariate analyses including recursive partitioning and amalgamation algorithms in 1,052 patients: the European lung cancer working party. J Clin Oncol. 1995;13:1221–1230.
    1. Takigawa N, Segawa Y, Okahara M, Maeda Y, Takata I, Kataoka M, Fujii M. Prognostic factors for patients with advanced non-small cell lung cancer: univariate and multivariate analyses including recursive partitioning and amalgamation. Lung Cancer. 1996;15:67. doi: 10.1016/0169-5002(96)00571-5.
    1. Wilop S, Crysandt M, Bendel M, Mahnken AH, Osieka R, Jost E. Correlation of C-reactive protein with survival and radiographic response to first-line platinum-based chemotherapy in advanced non-small cell lung cancer. Onkologie. 2008;31:665–670.
    1. Berghmans T, Paesmans M, Mascaux C, Martin B, Meert AP, Haller A, Lafitte JJ, Sculier JP. Thyroid transcription factor 1- a new prognostic factor in lung cancer: a meta-analysis. Ann Oncol. 2006;17:1673–1676. doi: 10.1093/annonc/mdl287.
    1. Muggia FM. Overview of cancer-related hypercalcemia: epidemiology and etiology. Semin Oncol. 1990;17:3–9.
    1. Rosen LS, Gordon D, Tchekmedyian S, Yanagihara R, Hirsh V, Krzakowski M, Pawlicki M, de Souza P, Zheng M, Urbanowitz G, Reitsma D, Seaman JJ. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial–the zoledronic acid lung cancer and other solid tumors study group. J Clin Oncol. 2003;21:3150–3157. doi: 10.1200/JCO.2003.04.105.
    1. Hirsh V, Tchekmedyian NS, Rosen LS, Zheng M, Hei YJ. Clinical benefit of zoledronic acid in patients with lung cancer and other solid tumors: analysis based on history of skeletal complications. Clin Lung Cancer. 2004;6:170–174. doi: 10.3816/CLC.2004.n.030.
    1. Hirsh V, Major PP, Lipton A, Cook RJ, Langer CJ, Smith MR, Brown JE, Coleman RE. Zoledronic acid and survival in patients with metastatic bone disease from lung cancer and elevated markers of osteoclast activity. J Thorac Oncol. 2008;3:228–236. doi: 10.1097/JTO.0b013e3181651c0e.
    1. Zarogoulidis K, Boutsikou E, Zarogoulidis P, Eleftheriadou E, Kontakiotis T, Lithoxopoulou H, Tzanakakis G, Kanakis I, Karamanos NK. The impact of zoledronic acid therapy in survival of lung cancer patients with bone metastasis. Int J Cancer. 2009;125:1705–1709. doi: 10.1002/ijc.24470.
    1. Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, Scagliotti GV, Sleeboom H, Spencer A, Vadhan-Raj S, von Moos R, Willenbacher W, Woll PJ, Wang J, Jiang Q, Jun S, Dansey R, Yeh H. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011;29:1125–1132. doi: 10.1200/JCO.2010.31.3304.
    1. Scagliotti GV, Hirsh V, Siena S, Henry DH, Woll PG, Manegold C, Solal-Celigny P, Rodriguez G, Krzakowski M, Mehta MD, Lipton L, Garcia-Saenz JA, Pereira JR, Prabhash K, Ciuleanu TE, Kanarev V, Wang H, Balakumaran A, Jacobs I. Overall survival improvement in patients with lung cancer and bone metastases treated by denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study. J Thorac Oncol. 2012;7(12):1823–1829. doi: 10.1097/JTO.0b013e31826aec2b.
    1. Hirano Y, Oda M, Tsunezuka Y, Ishikawa N, Watanabe G. Long-term survival cases of lung cancer presented as solitary bone metastasis. Ann Thorac Cardiovasc Surg. 2005;11:401–404.
    1. Okamoto T, Maruyama R, Shoji F, Asoh H, Ikeda J, Miyamoto T, Nakamura T, Miyake T, Ichinose Y. Long-term survivors in stage IV non-small-cell-lung cancer. Lung Cancer. 2005;47:85–91. doi: 10.1016/j.lungcan.2004.06.006.
    1. Collaud S, Stahel R, Inci I, Hillinger S, Schneiter D, Kestenholz P, Weder W. Survival of patients treated surgically for synchronous single-organ metastatic NSCLC and advanced pathologic TN stage. Lung Cancer. 2012;3:234–8.
    1. Wang XS, Rhines LD, Shiu AS, Yang JN, Selek U, Gning I, Liu P, Allen PK, Azeem SS, Brown PD, Sharp HJ, Weksberg DC, Cleeland CS, Chang EL. Stereotactic body radiation therapy for management of spinal metastases in patients without spinal cord compression: a phase 1–2 trial. Lancet Oncol. 2012;13:395–402. doi: 10.1016/S1470-2045(11)70384-9.
    1. Milano MT, Katz AW, Zhang H, Okunieff P. Oligometastases treated with stereotactic body radiotherapy: long-term follow-up of prospective study. Int J Radiat Oncol Biol Phys. 2012;83:878–886. doi: 10.1016/j.ijrobp.2011.08.036.

Source: PubMed

3
Abonner