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Editorial ARTICLE

Front. Oncol., 06 November 2018 | https://doi.org/10.3389/fonc.2018.00511

Editorial: Central Nervous System Metastases in Lung Cancer Patients: From Prevention to Diagnosis and Treatment

  • 1Department of Pulmonary Diseases, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
  • 2Division of Hematology-Oncology, Georgetown University, Washington, DC, United States

Introduction

Approximately 40% of lung cancer patients will develop central nervous system (CNS) metastases during the course of their disease (1). Most of these are brain metastases (BM), but 3–9% will develop leptomeningeal metastases (2, 3). The proportion of lung cancer patients diagnosed with CNS metastases has increased over the years due to increased use of brain imaging as part of initial cancer staging, advances in imaging techniques and better systemic disease control (46). CNS metastases can have a negative impact on quality of life (QoL) and overall survival (OS) (79). As such, prevention of CNS metastases development, as well as optimal treatment of already established CNS metastases is important.

Contributors in this Research Topic of Frontiers in Oncology, section Thoracic Oncology describe the advances in CNS metastases management in lung cancer patients, from prediction and prevention, to diagnosis and treatment.

Prediction and Prevention of CNS Metastases Development and Diagnostic Pitfalls

Known risk factors for CNS metastases development are small cell lung cancer, adenocarcinoma histology, advanced nodal status, tumor stage and younger age (1013). Patients with a driver mutation have a high risk of CNS metastases (14). This seems mainly due to their long survival, combined with the poor blood-brain-barrier penetration of the older generation tyrosine kinase inhibitors (TKIs) (Pedrosa et al.). However, these factors alone cannot predict accurately enough which patients will develop CNS metastases and better prediction models are needed. In the review of Pedrosa et al. the process of BM development and the evidence for the clinical and molecular factors associated with increased risk of BM diagnosis in lung cancer is summarized. In addition, they provide an excellent overview of new promising strategies to identify patients at high risk for BM development, including signatures derived from circulating tumor DNA measurements, single-nucleotide polymorphisms, copy number alterations, microRNAs and long non-coding RNAs (Pedrosa et al.). As it is known that among the non-small cell lung cancer (NSCLC) patients treated with curative intent, stage III patients have the highest risk of brain metastases development [30% (9, 15, 16)], preventive treatments such as prophylactic cranial irradiation (PCI) have been studied especially in this patient population (15, 16). Most studies have been published before the year 2000, but afterwards three new trials incorporating adequate baseline brain imaging, have reported their results. All studies showed a reduction of BM incidence after PCI compared to no PCI (Witlox et al.). Other important factors to consider before administering PCI are toxicity (acute as well as long-term), QoL and OS. Witlox et al. provide an up-to-date systematic review and meta-analysis of all published studies in this field. They provide detailed data on the effects of PCI on BM reduction, toxicity, QoL and OS and discuss areas for future research.

Although brain imaging techniques have improved over the years facilitating the diagnosis of BM, differential diagnosis can be challenging, especially in a patient with a medical history of cancer, as is discussed in the case report by Vanfleteren et al. It is stressed that even in an immunocompetent patient, a diagnosis of cerebral aspergillosis cannot be excluded. A short review of existing literature on this topic is also provided.

Local Treatment of Brain Metastases

When BM are diagnosed, local treatment options consist of radiotherapy [stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT)] and surgery (17, 18). SRS is more and more often used in the treatment of BM. In the past, SRS was mainly used for up to four BM, but a recent trial showed that SRS is feasible for a higher number of BM (19). More than fifty percent of BM patients treated with SRS will experience an intracranial relapse (19, 20), and especially in this palliative setting patient participation in the decision making around available treatment options [e.g., SRS, WBRT, systemic treatment (with/without concurrent cranial irradiation), best supportive care] is important. Hartgerink et al. discuss the current evidence of SRS for NSCLC BM, and the incorporation of decision aid tools in the future directions for NSCLC BM treatment. Furthermore, local treatment can be complicated by symptomatic radiation necrosis for which no high-level evidence-based treatment exists, although bevacizumab is a promising treatment option (2123). Differential diagnosis of radiation necrosis and BM progression can be difficult (21, 22). Loganadane et al. provide a very nice overview of the pathobiology, epidemiology, predictive factors, diagnosis and emerging treatment of radiation necrosis, with a specific focus on NSCLC.

Systemic Treatment of CNS Metastases

Systemic treatment options for BM have expanded over the last years (24, 25). Until recently, chemotherapy was the only treatment option with a poor penetration in the CNS (26). Angiogenesis inhibitors are promising in the treatment of NSCLC BM (23, 27, 28), but clinical trials of anti-angiogenic agents in NSCLC have largely excluded BM patients (29). Furthermore, TKIs have improved prognosis significantly in those with a druggable driver mutation (25, 30, 31). Newer TKIs are often designed to have better CNS penetration compared to first-generation TKIs (24, 30, 31). In the review of Kelly et al. the management of CNS metastases in EGFR mutated NSCLC patients is discussed, including the role of newer generation EGFR-TKIs, immunotherapy, and EGFR-TKIs combined with cranial irradiation or angiogenesis inhibition. Remon and Besse provide a broader overview of incidence and treatment of BM in oncogene addicted NSCLC patients, including rare driver mutations such as ALK, ROS1, RET, BRAF, and NTRK. Relevant research questions such as optimal sequence of treatment (upfront cranial irradiation or upfront TKI, sequence of TKI) are also discussed. In the case report of Meedendorp et al. treatment of a BM patient with acquired resistance to EGFR-TKI is discussed, stressing the importance of a molecular tumor board for decision making. Last, leptomeningeal metastases remain challenging to treat, especially in non-oncogene addicted NSCLC patients. Turkaj et al. provide an up-to-date review of possible treatment options for these patients, including systemic as well as intrathecal chemotherapy as well as radiotherapy options.

Conclusion

With the articles in this Research Topic, we hope to provide a review of present and future treatment options for lung cancer CNS metastases, including evidence for predictive markers, preventive treatments, and local as well as systemic treatment options for already diagnosed CNS metastases.

Author Contributions

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

Conflict of Interest Statement

LH: none related to current manuscript, outside of current manuscript: research funding Roche, Boehringer Ingelheim (both institution), advisory board: Boehringer, BMS, (both institution), travel reimbursement: Roche, BMS (self). DS: speaker's bureau Astra Zeneca, Takeda; advisory board Astra Zeneca, Takeda, BMS; institutional research funding as PI: BMS, Genentech, Incyte, Lilly Oncology, Astra Zeneca, Novocure. A-MD: none related to current manuscript, outside of current manuscript: advisory board BMS, MSD, Roche, Eli Lilly, Takeda, Pfizer, Boehringer Ingelheim (all institution).

References

1. Yawn BP, Wollan PC, Schroeder C, Gazzuola L, Mehta M. Temporal and gender-related trends in brain metastases from lung and breast cancer. Minn Med. (2003) 86:32–7.

PubMed Abstract | Google Scholar

2. Remon J, Le Rhun E, Besse B. Leptomeningeal carcinomatosis in non-small cell lung cancer patients: a continuing challenge in the personalized treatment era. Cancer Treat Rev. (2017) 53:128–37. doi: 10.1016/j.ctrv.2016.12.006

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Kuiper JL, Hendriks LE, van der Wekken AJ, de Langen AJ, Bahce I, Thunnissen E, et al. Treatment and survival of patients with EGFR-mutated non-small cell lung cancer and leptomeningeal metastasis: a retrospective cohort analysis. Lung Cancer (2015) 89:255–61. doi: 10.1016/j.lungcan.2015.05.023

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Costa DB, Shaw AT, Ou SH, Solomon BJ, Riely GJ, Ahn MJ, et al. Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases. J Clin Oncol. (2015) 33:1881–8. doi: 10.1200/JCO.2014.59.0539

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Terae S, Yoshida D, Kudo K, Tha KK, Fujino M, Miyasaka K. Contrast-enhanced FLAIR imaging in combination with pre- and postcontrast magnetization transfer T1-weighted imaging: usefulness in the evaluation of brain metastases. J Magn Reson Imag. (2007) 25:479–87. doi: 10.1002/jmri.20847

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Levy A, Faivre-Finn C, Hasan B, De Maio E, Berghoff AS, Girard N, et al. Diversity of brain metastases screening and management in non-small cell lung cancer in Europe: results of the European Organisation for Research and Treatment of Cancer Lung Cancer Group survey. Eur J Cancer (2018) 93:37–46. doi: 10.1016/j.ejca.2018.01.067

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Roughley A, Damonte E, Taylor-Stokes G, Rider A, Munk V. Impact of brain metastases on quality of life and estimated life expectancy in patients with advanced non-small cell lung cancer. Value Health (2014) 17:A650. doi: 10.1016/j.jval.2014.08.2364

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Sperduto PW, Chao ST, Sneed PK, Luo X, Suh J, Roberge D, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Rad Oncol Biol Phy. (2010) 77:655–61. doi: 10.1016/j.ijrobp.2009.08.025

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Peters S, Bexelius C, Munk V, Leighl N. The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small-cell lung cancer. Cancer Treat Rev. (2016) 45:139–62. doi: 10.1016/j.ctrv.2016.03.009

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Hochstenbag MM, Twijnstra A, Hofman P, Wouters EF, ten Velde GP. MR-imaging of the brain of neurologic asymptomatic patients with large cell or adenocarcinoma of the lung. Does it influence prognosis and treatment? Lung Cancer (2003) 42:189–93. doi: 10.1016/S0169-5002(03)00291-5

CrossRef Full Text | Google Scholar

11. Hendriks LE, Brouns AJ, Amini M, Uyterlinde W, Wijsman R, Bussink J, et al. Development of symptomatic brain metastases after chemoradiotherapy for stage III non-small cell lung cancer: does the type of chemotherapy regimen matter? Lung Cancer. (2016) 101:68–75. doi: 10.1016/j.lungcan.2016.09.008

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Gaspar LE, Chansky K, Albain KS, Vallieres E, Rusch V, Crowley JJ, et al. Time from treatment to subsequent diagnosis of brain metastases in stage III non-small-cell lung cancer: a retrospective review by the Southwest Oncology Group. J Clin Oncol. (2005) 23:2955–61. doi: 10.1200/JCO.2005.08.026

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Slotman B, Faivre-Finn C, Kramer G, Rankin E, Snee M, Hatton M, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. (2007) 357:664–72. doi: 10.1056/NEJMoa071780

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Rangachari D, Yamaguchi N, VanderLaan PA, Folch E, Mahadevan A, Floyd SR, et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer (2015) 88:108–11. doi: 10.1016/j.lungcan.2015.01.020

CrossRef Full Text | Google Scholar

15. Sun DS, Hu LK, Cai Y, Li XM, Ye L, Hou HY, et al. A systematic review of risk factors for brain metastases and value of prophylactic cranial irradiation in non-small cell lung cancer. Asian Pac J Cancer Prev. (2014) 15:1233–9. doi: 10.7314/APJCP.2014.15.3.1233

PubMed Abstract | CrossRef Full Text | Google Scholar

16. De Ruysscher D, Dingemans AC, Praag J, Belderbos J, Tissing-Tan C, Herder J, et al. Prophylactic cranial irradiation versus observation in radically treated stage III non-small-cell lung cancer: a randomized phase III NVALT-11/DLCRG-02 Study. J Clin Oncol. (2018) 36:2366–77. doi: 10.1200/JCO.2017.77.5817

PubMed Abstract | CrossRef Full Text | Google Scholar

17. NCCN Guidelines Central Nervous System Cancers Version 1.2018 (2018).

18. Novello S, Barlesi F, Califano R, Cufer T, Ekman S, Levra MG, et al. Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. (2016) 27 (Suppl. 5):v1–27. doi: 10.1093/annonc/mdw326

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Yamamoto M, Serizawa T, Shuto T, Akabane A, Higuchi Y, Kawagishi J, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol. (2014) 15:387–95. doi: 10.1016/S1470-2045(14)70061-0

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Zindler JD, Slotman BJ, Lagerwaard FJ. Patterns of distant brain recurrences after radiosurgery alone for newly diagnosed brain metastases: implications for salvage therapy. Radiother Oncol. (2014) 112:212–6. doi: 10.1016/j.radonc.2014.07.007

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Tomura N, Kokubun M, Saginoya T, Mizuno Y, Kikuchi Y. Differentiation between treatment-induced necrosis and recurrent tumors in patients with metastatic brain tumors: comparison among (11)C-Methionine-PET, FDG-PET, MR permeability imaging, and MRI-ADC-preliminary results. Am J Neuroradiol. (2017) 38:1520–7. doi: 10.3174/ajnr.A5252

CrossRef Full Text | Google Scholar

22. Soussain C, Ricard D, Fike JR, Mazeron JJ, Psimaras D, Delattre JY. CNS complications of radiotherapy and chemotherapy. Lancet (2009) 374:1639–51. doi: 10.1016/S0140-6736(09)61299-X

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Boothe D, Young R, Yamada Y, Prager A, Chan T, Beal K. Bevacizumab as a treatment for radiation necrosis of brain metastases post stereotactic radiosurgery. Neuro Oncol (2013) 15:1257–63. doi: 10.1093/neuonc/not085

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Frega S, Bonanno L, Guarneri V, Conte P, Pasello G. Therapeutic perspectives for brain metastases in non-oncogene addicted non-small cell lung cancer (NSCLC): towards a less dismal future? Crit Rev Oncol Hematol. (2018) 128:19–29. doi: 10.1016/j.critrevonc.2018.05.013

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Ferrara R, Mezquita L, Besse B. Progress in the management of advanced thoracic malignancies in 2017. J Thor Oncol. (2018) 13:301–22. doi: 10.1016/j.jtho.2018.01.002

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Postmus PE, Smit EF. Chemotherapy for brain metastases of lung cancer: a review. Ann Oncol. (1999) 10:753–9. doi: 10.1023/A:1008318515795

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Besse B, Lasserre SF, Compton P, Huang J, Augustus S, Rohr UP. Bevacizumab safety in patients with central nervous system metastases. Clin Cancer Res. (2010) 16:269–78. doi: 10.1158/1078-0432.CCR-09-2439

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Besse B, Le Moulec S, Mazieres J, Senellart H, Barlesi F, Chouaid C, et al. Bevacizumab in patients with nonsquamous non-small cell lung cancer and asymptomatic, untreated brain metastases (BRAIN): a nonrandomized, phase II Study. Clin Cancer Res. (2015) 21:1896–903. doi: 10.1158/1078-0432.CCR-14-2082

PubMed Abstract | CrossRef Full Text

29. Russo AE, Priolo D, Antonelli G, Libra M, McCubrey JA, Ferrau F. Bevacizumab in the treatment of NSCLC: patient selection and perspectives. Lung Cancer (2017) 8:259–69. doi: 10.2147/LCTT.S110306

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. (2017). 377:829–38 doi: 10.1056/NEJMoa1704795

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. (2018) 378:113–25. doi: 10.1056/NEJMoa1713137

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: brain metastases from lung cancer, leptomeningeal metastases, treatment—contemporary views, diagnosis, driver mutations, cranial irradiation

Citation: Hendriks LEL, Subramaniam DS and Dingemans A-MC (2018) Editorial: Central Nervous System Metastases in Lung Cancer Patients: From Prevention to Diagnosis and Treatment. Front. Oncol. 8:511. doi: 10.3389/fonc.2018.00511

Received: 30 September 2018; Accepted: 19 October 2018;
Published: 06 November 2018.

Edited and reviewed by: Stephen V. Liu, Georgetown University, United States

Copyright © 2018 Hendriks, Subramaniam and Dingemans. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Lizza E. L. Hendriks, lizza.hendriks@mumc.nl