Strahlentherapie und Onkologie

, Volume 194, Issue 12, pp 1152–1162 | Cite as

Risk factors for brain metastasis in patients with small cell lung cancer without prophylactic cranial irradiation

  • Yawen Zheng
  • Linlin Wang
  • Weichong Zhao
  • Yan Dou
  • Wei Lv
  • Hongyan Yang
  • Yuping Sun
  • Ligang XingEmail author
Original Article



This study aimed to determine the risk factors for brain metastasis (BM) and the prognostic factors for overall survival (OS) in patients with small cell lung cancer without prophylactic cranial irradiation (PCI).

Patients and methods

Limited stage small cell lung cancer (LS-SCLC) patients achieving a complete response (CR) or partial response (PR) were enrolled into this study between January 2010 and December 2016. We retrospectively evaluated the influencing factors for time to BM and overall survival (OS).


A total of 153 patients were enrolled into this study. Sixty-eight developed BM during the follow-up period. For the whole cohort, the 1‑ and 2‑year BM rates were 29.4 and 41.2%, respectively. Multivariate analysis showed that T stage (hazard ratio [HR] = 2.27, P = 0.024), neutrophil-to-lymphocyte ratio (NLR; HR = 2.07, P = 0.029), time to thoracic radiotherapy (HR = 0.34, P = 0.002) and chemotherapy cycles (HR = 0.49, P = 0.036) were the independent influencing factors of time to BM. Only NLR (HR = 2.11, P = 0.005) and time to thoracic radiotherapy (HR = 1.95, P = 0.011) were independent prognostic factors of OS. Of the 68 patients developing BM, those with BM occurring as the first relapse (42/68) had better OS than the others (39.5 months vs 23.0 months, P = 0.016).


LS-SCLC patients without PCI had a high risk of BM. High T stage, high NLR, early thoracic radiotherapy and fewer chemotherapy cycles were the risk factors of BM. Further research is needed to confirm the results.


Small cell lung cancer Brain metastasis Prophylactic cranial irradiation Risk factor Neutrophil-to-lymphocyte ratio 



Three-dimensional conformal radiotherapy


Area under the curve


Brain metastasis


Body mass index


Carcinoembryonic antigen


Conventional fractionated radiotherapy


Complete response


Gross tumor volume


Hyperfractionated radiotherapy


Intensity-modulated radiotherapy


Limited stage small cell lung cancer


Neutrophil-to-lymphocyte ratio


Neuron-specific enolase


Overall survival


Prophylactic cranial irradiation


Progression-free survival


Platelet-to-lymphocyte ratio


Partial response


Receiver operating characteristic

Risikofaktoren für Hirnmetastasen bei Patienten mit kleinzelligem Lungenkarzinom ohne prophylaktische Schädelbestrahlung



Ziel dieser Studie war es, Risikofaktoren für eine Hirnmetastasierung („brain metastasis“, BM) und prognostische Faktoren des Gesamtüberlebens („overall survival“, OS) bei Patienten mit kleinzelligem Lungenkarzinom („small cell lung cancer“, SCLC) ohne prophylaktische Schädelbestrahlung („prophylactic cranial irradiation“, PCI) zu ermitteln.

Patienten und Methoden

Von Januar 2010 bis Dezember 2016 wurden Patienten mit SCLC im limitierten Stadium („limited-stage“, LS-SCLC) mit kompletter („complete response“, CR) oder partieller Remission („partial response“, PR) in die Studie aufgenommen. Einflussfaktoren auf die Zeit bis zur BM und das OS wurden retrospektiv ausgewertet.


Von 153 Patienten entwickelten 68 während der Nachbeobachtungszeit eine BM. Bei 29,4 bzw. 41,2 % aller Patienten kam es binnen eines bzw. 2 Jahren zur BM. Gemäß der multivariaten Analyse waren T‑Stadium (Hazard Ratio, HR = 2,27; p = 0,024), Neutrophilen-Lymphozyten-Quotient („neutrophil-to-lymphocyte ratio“, NLR; HR = 2,07; p = 0,029), Zeit bis zur Strahlentherapie des Thorax (HR = 0,34; p = 0,002) und Anzahl der Chemotherapiezyklen (HR = 0,49; p = 0,036) unabhängige Einflussfaktoren auf die Zeit bis zur BM. Nur NLR (HR = 2,11; p = 0,005) und Zeit bis zur Strahlentherapie des Thorax (HR = 1,95; p = 0,011) stellten unabhängige prognostische Faktoren des OS dar. Unter den 68 Patienten mit BM wiesen diejenigen, bei denen die BM als Erstrezidiv auftrat (42/68), ein längeres OS auf die übrigen (39,5 vs. 23,0 Monate; p = 0,016).


Bei Patienten mit LS-SCLC ohne PCI bestand ein hohes Risiko für BM. Hohes T‑Stadium, hoher NLR, frühe Strahlentherapie des Thorax und weniger Chemotherapiezyklen waren Risikofaktoren für BM. Weitere Untersuchungen sind erforderlich, um die Ergebnisse zu verifizieren.


Kleinzelliges Lungenkarzinom Hirnmetastasierung Prophylaktische Schädelbestrahlung Risikofaktor Neutrophilen-Lymphozyten-Quotient 



The authors are thankful to all the patients included and their clinicians in charge.

Compliance with ethical guidelines

Conflict of interest

Y. Zheng, L. Wang, W. Zhao, Y. Dou, W. Lv, H. Yang, Y. Sun and L. Xing declare that they have no competing interests.

Ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Supplementary material

66_2018_1362_MOESM1_ESM.docx (212 kb)
Supplementary 1 The cutoff value of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) is 2.55 and 125.7, respectively
66_2018_1362_MOESM2_ESM.docx (25 kb)
Supplementary 2 Univariate and multivariate analysis of the prognostic factors of OS


  1. 1.
    Aupérin A, Arriagada R, Pignon J, Le Péchoux C, Gregor A, Stephens R, Kristjansen P, Johnson B, Ueoka H, Wagner H, Aisner J (1999) Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic cranial irradiation overview collaborative group. N Engl J Med 341:476–484CrossRefGoogle Scholar
  2. 2.
    Giuliani M, Sun A, Bezjak A, Ma C, Le LW, Brade A, Cho J, Leighl NB, Shepherd FA, Hope AJ (2010) Utilization of prophylactic cranial irradiation in patients with limited stage small cell lung carcinoma. Cancer 116:5694–5699CrossRefGoogle Scholar
  3. 3.
    Sakaguchi M, Maebayashi T, Aizawa T, Ishibashi N, Saito T (2016) Treatment outcomes of patients with small cell lung cancer without prophylactic cranial irradiation. J Thorac Dis 8:2571–2579CrossRefGoogle Scholar
  4. 4.
    Gregory PK, Billy WL, Wallace A, Albert A (2016) NCCN guidelines: small cell lung cancer, version 1.2016. National Comprehensive Cancer Network (NCCN).
  5. 5.
    Péchoux C, Sun A, Slotman B, De Ruysscher D, Belderbos J, Gore E (2016) Prophylactic cranial irradiation for patients with lung cancer. Lancet Oncol 17:e277–e293CrossRefGoogle Scholar
  6. 6.
    Patel S, Macdonald OK, Suntharalingam M (2009) Evaluation of the use of prophylactic cranial irradiation in small cell lung cancer. Cancer 115:842–850CrossRefGoogle Scholar
  7. 7.
    Le Pechoux C, Dunant A, Senan S, Wolfson A, Quoix E, Faivre-Finn C, Ciuleanu T, Arriagada R, Jones R, Wanders R, Lerouge D, Laplanche A (2009) Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01). Lancet Oncol 10:467–474 (a randomised clinical trial)CrossRefGoogle Scholar
  8. 8.
    Wolfson AH, Bae K, Komaki R, Meyers C, Movsas B, Le Pechoux C, Werner-Wasik M, Videtic GM, Garces YI, Choy H (2011) Primary analysis of a phase II randomized trial Radiation Therapy Oncology Group (RTOG) 0212. Int J Radiat Oncol Biol Phys 81:77–84 (impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with limited-disease small-cell lung cancer)CrossRefGoogle Scholar
  9. 9.
    Lok BH, Ma J, Foster A, Perez CA, Shi W, Zhang Z, Li BT, Rudin CM, Rimner A, Wu AJ (2017) Factors influencing the utilization of prophylactic cranial irradiation in patients with limited-stage small cell lung cancer. Adv Radiat Oncol 2:548–554CrossRefGoogle Scholar
  10. 10.
    Damhuis R, Senan S, Belderbos JS (2017) Usage of prophylactic cranial irradiation in elderly patients with small-cell lung cancer. Clin Lung Cancer 19(2):e263–e267. CrossRefPubMedGoogle Scholar
  11. 11.
    Arriagada R, Le Chevalier T, Borie F, Riviere A, Chomy P, Monnet I, Tardivon A, Viader F, Tarayre M, Benhamou S (1995) Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. J Natl Cancer Inst 87:183–190CrossRefGoogle Scholar
  12. 12.
    Gong L, Wang QI, Zhao L, Yuan Z, Li R, Wang P (2013) Factors affecting the risk of brain metastasis in small cell lung cancer with surgery: is prophylactic cranial irradiation necessary for stage I–III disease? Int J Radiat Oncol Biol Phys 85:196–200CrossRefGoogle Scholar
  13. 13.
    Chen Y, Li J, Zhang Y, Hu Y, Zhang G, Yan X, Lin Z, Zhao Z, Jiao S (2018) Early versus late prophylactic cranial irradiation in patients with extensive small cell lung cancer. Strahlenther Onkol. CrossRefPubMedGoogle Scholar
  14. 14.
    Deng M, Ma X, Liang X, Zhu C, Wang M (2017) Are pretreatment neutrophil-lymphocyte ratio and platelet-lymphocyte ratio useful in predicting the outcomes of patients with small-cell lung cancer? Oncotarget 8:37200–37207PubMedPubMedCentralGoogle Scholar
  15. 15.
    Wen Q, Meng X, Xie P, Wang S, Sun X, Yu J (2017) Evaluation of factors associated with platinum-sensitivity status and survival in limited-stage small cell lung cancer patients treated with chemoradiotherapy. Oncotarget 8:81405–81418PubMedPubMedCentralGoogle Scholar
  16. 16.
    Mutschelknaus L, Azimzadeh O, Heider T, Winkler K, Vetter M, Kell R, Tapio S, Merl-Pham J, Huber SM, Edalat L, Radulovic V, Anastasov N, Atkinson MJ, Moertl S (2017) Radiation alters the cargo of exosomes released from squamous head and neck cancer cells to promote migration of recipient cells. Sci Rep 7:12423CrossRefGoogle Scholar
  17. 17.
    Steeg PS (2006) Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12:895–904CrossRefGoogle Scholar
  18. 18.
    Chen G, Huynh M, Chen A, Fehrenbacher L, Gandara D, Lau D (2008) Chemotherapy for brain metastases in small-cell lung cancer. Clin Lung Cancer 9:35–38CrossRefGoogle Scholar
  19. 19.
    Cao X, Wen ZS, Wang XD, Li Y, Liu KY, Wang X (2017) The clinical effect of metformin on the survival of lung cancer patients with diabetes: a comprehensive systematic review and Meta-analysis of retrospective studies. J Cancer 8:2532–2541CrossRefGoogle Scholar
  20. 20.
    Wang HM, Liao ZX, Komaki R, Welsh JW, O’Reilly MS, Chang JY, Zhuang Y, Levy LB, Lu C, Gomez DR (2013) Improved survival outcomes with the incidental use of beta-blockers among patients with non-small-cell lung cancer treated with definitive radiation therapy. Ann Oncol 24:1312–1319CrossRefGoogle Scholar
  21. 21.
    De Ruysscher D, Lueza B, Le Pechoux C, Johnson DH, O’Brien M, Murray N, Spiro S, Wang X, Takada M, Lebeau B, Blackstock W, Skarlos D, Baas P, Choy H, Price A, Seymour L, Arriagada R, Pignon JP (2016) Impact of thoracic radiotherapy timing in limited-stage small-cell lung cancer: usefulness of the individual patient data meta-analysis. Ann Oncol 27:1818–1828CrossRefGoogle Scholar
  22. 22.
    Rusthoven CG, Kavanagh BD (2017) Prophylactic Cranial Irradiation (PCI) versus active MRI surveillance for small cell lung cancer: the case for equipoise. J Thorac Oncol 12:1746–1754CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Oncology, Jinan Central HospitalShandong UniversityJinanChina
  2. 2.Department of Radiation Oncology, Shandong Key Laboratory of Radiation OncologyShandong Cancer Hospital Affiliated to Shandong UniversityJinanChina
  3. 3.Shandong Academy of Medical SciencesJinanChina

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