Advertisement

Strahlentherapie und Onkologie

, Volume 194, Issue 2, pp 98–106 | Cite as

Outcome and prognostic factors in single brain metastases from small-cell lung cancer

  • Denise Bernhardt
  • Sebastian Adeberg
  • Farastuk Bozorgmehr
  • Nils Opfermann
  • Juliane Hörner-Rieber
  • Laila König
  • Jutta Kappes
  • Michael Thomas
  • Andreas Unterberg
  • Felix Herth
  • Claus Peter Heußel
  • Arne Warth
  • Jürgen Debus
  • Martin Steins
  • Stefan Rieken
Original Article
  • 343 Downloads

Abstract

Purpose

Whole brain radiation therapy (WBRT) is historically the standard of care for patients with brain metastases (BM) from small-cell lung cancer (SCLC), although locally ablative treatments are the standard of care for patients with 1–4 BM from other solid tumors. The objective of this analysis was to find prognostic factors influencing overall survival (OS) and intracranial progression-free survival (iPFS) in SCLC patients with single BM (SBM) treated with WBRT.

Methods

A total of 52 patients were identified in the authors’ cancer center database with histologically confirmed SCLC and contrast-enhanced magnet resonance imaging (MRI) or computed tomography (CT), which confirmed SBM between 2006 and 2015 and were therefore treated with WBRT. A Kaplan-Meier survival analysis was performed for OS analyses. The log-rank (Mantel-Cox) test was used to compare survival curves. Univariate Cox proportional-hazards ratios (HRs) were used to assess the influence of cofactors on OS and iPFS.

Results

The median OS after WBRT was 5 months and the median iPFS after WBRT 16 months. Patients that received surgery prior to WBRT had a significantly longer median OS of 19 months compared to 5 months in the group receiving only WBRT (p = 0.03; HR 2.24; 95% confidence interval [CI] 1.06–4.73). Patients with synchronous disease had a significantly longer OS compared to patients with metachronous BM (6 months vs. 3 months, p = 0.005; HR 0.27; 95% CI 0.11–0.68). Univariate analysis for OS revealed a statistically significant effect for metachronous disease (HR 2.25; 95% CI 1.14–4.46; p = 0.019), initial response to first-line chemotherapy (HR 0.58; 95% CI 0.35–0.97; p = 0.04), and surgical resection (HR 0.36; 95% CI 0.15–0.88; p = 0.026). OS was significantly affected by metachronous disease in multivariate analysis (HR 2.20; 95% CI 1.09–4.45; p = 0.028).

Conclusions

Univariate analysis revealed that surgery followed by WBRT can improve OS in patients with SBM in SCLC. Furthermore, synchronous disease and response to initial chemotherapy appeared to be major prognostic factors. Multivariate analysis revealed metachronous disease as a significantly negative prognostic factor on OS. The value of WBRT, stereotactic radiosurgery (SRS), or surgery alone or in combination for patients with a limited number of BM in SCLC should be evaluated in further prospective clinical trials.

Keywords

Small cell lung cancer Cranial irradiation Survival WBRT Solitary brain metastasis 

Outcome und Prognosefaktoren bei singulären Hirnmetastasen des kleinzelligen Bronchialkarzinoms

Zusammenfassung

Hintergrund

Die Ganzhirnradiotherapie (WBRT) ist historisch die Standardtherapie zur Behandlung von Hirnmetastasen beim kleinzelligen Bronchialkarzinom (SCLC), auch wenn sich für andere solide Tumoren die lokal-ablativen Verfahren als Therapieoption bei Patienten mit 1–4 Hirnmetastasen etabliert haben. Ziel dieser Analyse war es, Prognosefaktoren zu finden, die das Gesamtüberleben (OS) und das intrakraniell progressionsfreie Überleben (iPFS) von Patienten mit einer singulären Hirnmetastase bei SCLC, die mit einer WBRT behandelt wurden, beeinflussen.

Methodik

In unserer internen Datenbank wurden 52 Patienten identifiziert, die an einem histologisch gesicherten SCLC erkrankt waren, eine in der kontrastmittelgestützten Computertomographie (CT) oder Magnetresonanztomographie (MRT) diagnostizierte singuläre Hirnmetastase aufwiesen und diesbezüglich zwischen 2006 und 2015 mit einer WBRT behandelt worden waren. Für das OS wurde eine Kaplan-Meier-Überlebensanalyse durchgeführt. Die Überlebenskurven wurden unter Anwendung des Log-Rang-Tests (Mantel-Cox) verglichen. Mithilfe univariater „proportional-hazards ratios“ (HR) wurde der Einfluss von Kofaktoren auf OS und iPFS untersucht.

Resultate

Das mediane OS nach einer WBRT betrug 5 Monate, das mediane iPFS 16 Monate. Patienten, die eine operative Behandlung der Hirnmetastase vor der WBRT erhielten, zeigten ein signifikant verlängertes medianes OS von 19 Monaten im Vergleich zu 5 Monaten bei Patienten, die lediglich eine WBRT erhielten (p = 0,03; HR 2,24; 95 %-Konfidenzintervall [KI] 1,06–4,73). Patienten mit synchronen Hirnmetastasen zeigten ein signifikant längeres OS im Vergleich zu Patienten mit metachron aufgetretenen Hirnmetastasen (6 Monate vs. 3 Monate; p = 0,005; HR 0,27; 95 %-KI 0,11–0,68). In der univariaten Analyse wurde das OS signifikant beeinflusst von einer metachronen Hirnmetastasierung (HR 2,25; 95 %-KI 1,14–4,46; p = 0,019), dem Ansprechen auf die initiale Chemotherapie (HR 0,58; 95 %-KI 0,35–0,97; p = 0,04) und der operativen Resektion der Hirnmetastase (HR 0,36; 95 %-KI 0,15–0,88; p = 0,026). Das OS wurde in der multivariaten Analyse durch eine metachrone Erkrankungssituation signifikant negativ beeinflusst (HR 2,20; 95 %-KI 1,09–4,45; p = 0,028).

Schlussfolgerung

Die Ergebnisse der univariaten Analyse zeigen, dass die Operation gefolgt von einer adjuvanten WBRT ggf. das Überleben von Patienten mit SCLC und singulärer Hirnmetastase verlängern kann. Außerdem erwiesen sich eine synchrone Hirnmetastasierung und das Ansprechen auf die initiale Chemotherapie in der univariaten Analyse als wichtige positive Prognosefaktoren für das OS. Aus der multivariaten Analyse ergibt sich, dass eine metachrone Erkrankungssituation einen signifikanten negativen Einfluss auf das Überleben hat. In zukünftigen prospektiven Studien sollte die Bedeutung der WBRT, Stereotaxie, Operation oder Kombination dieser Therapien für SCLC-Patienten mit limitierter Anzahl von Hirnmetastasen überprüft werden.

Schlüsselwörter

Kleinzelliges Bronchialkarzinom Kraniale Bestrahlung Überleben Ganzhirnradiotherapie Solitäre Hirnmetastasen 

Notes

Acknowledgements

This work was supported by a Heidelberg University young investigator grant to DB.

Conflict of interest

D. Bernhardt, S. Adeberg, F. Bozorgmehr, N. Opfermann, J. Hörner-Rieber, L. König, J. Kappes, M. Thomas, A. Unterberg, F. Herth, C.P. Heußel, A. Warth, J. Debus, M. Steins and S. Rieken declare that they have no competing interests.

References

  1. 1.
    Alvarado-Luna G, Morales-Espinosa D (2016) Treatment for small cell lung cancer, where are we now?—a review. Transl Lung Cancer Res 5:26–38 (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4758961&tool=pmcentrez&rendertype=abstract. Accessed 21 December 2016)PubMedPubMedCentralGoogle Scholar
  2. 2.
    Ammirati M, Cobbs CS, Linskey ME, Paleologos NA, Ryken TC, Burri SH et al (2010) The role of retreatment in the management of recurrent/progressive brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 96:85–96 (http://www.ncbi.nlm.nih.gov/pubmed/19957016. Accessed 30 June 2017)CrossRefPubMedGoogle Scholar
  3. 3.
    Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC et al (2004) Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 363:1665–1672 (http://www.sciencedirect.com/science/article/pii/S0140673604162508. Accessed 1 September 2015)CrossRefPubMedGoogle Scholar
  4. 4.
    Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K et al (2006) Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 295:2483–2491 (http://www.ncbi.nlm.nih.gov/pubmed/16757720. Accessed 8 October 2015)CrossRefPubMedGoogle Scholar
  5. 5.
    Aupérin A, Arriagada R, Pignon JP, Le Péchoux C, Gregor A, Stephens RJ et al (1999) Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341:476–484 (http://www.ncbi.nlm.nih.gov/pubmed/10441603. Accessed 16 December 2015)CrossRefPubMedGoogle Scholar
  6. 6.
    Bernhardt D, Bozorgmehr F, Adeberg S, Opfermann N, von Eiff D, Rieber J et al (2016) Outcome in patients with small cell lung cancer re-irradiated for brain metastases after prior prophylactic cranial irradiation. Lung Cancer 101:76.  https://doi.org/10.1016/j.lungcan.2016.09.010 CrossRefPubMedGoogle Scholar
  7. 7.
    Bernhardt D, Adeberg S, Bozorgmehr F, Opfermann N, Hoerner-Rieber J, König L et al (2017) Outcome and prognostic factors in patients with brain metastases from small-cell lung cancer treated with whole brain radiotherapy. J Neurooncol 134(1):205 (http://www.ncbi.nlm.nih.gov/pubmed/28560661. Accessed 19 June 2017)CrossRefPubMedGoogle Scholar
  8. 8.
    Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG et al (2009) Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 10:1037–1044 (http://www.sciencedirect.com/science/article/pii/S1470204509702633. Accessed 9 October 2015)CrossRefPubMedGoogle Scholar
  9. 9.
    Chen Y, Li J, Hu Y, Zhang Y, Lin Z, Zhao Z et al (2016) Prophylactic cranial irradiation could improve overall survival in patients with extensive small cell lung cancer. Strahlenther Onkol 192:905–912 (http://link.springer.com/10.1007/s00066-016-1038-0. Accessed 29 May 2017)CrossRefPubMedGoogle Scholar
  10. 10.
    Flannery TW, Suntharalingam M, Regine WF, Chin LS, Krasna MJ, Shehata MK et al (2008) Long-term survival in patients with synchronous, solitary brain metastasis from non-small-cell lung cancer treated with radiosurgery. Int J Radiat Oncol Biol Phys 72:19–23 (http://www.sciencedirect.com/science/article/pii/S0360301607047712. Accessed 13 September 2016)CrossRefPubMedGoogle Scholar
  11. 11.
    Huber K, Dunst J (2015) Auch Patienten im Stadium “extensive disease” eines kleinzelligen Bonchialkarzinoms profitieren von einer konsolidierenden Mediastinalbestrahlung, analog dem Vorgehen bei “limited disease”. Strahlenther Onkol 191:78–80 (http://link.springer.com/10.1007/s00066-014-0795-x. Accessed 29 May 2017)CrossRefPubMedGoogle Scholar
  12. 12.
    Kalemkerian GP, Akerley W, Bogner P, Borghaei H, Chow LQ, Downey RJ et al (2013) Small cell lung cancer. J Natl Compr Canc Netw 11:78–98 (http://www.ncbi.nlm.nih.gov/pubmed/23307984. Accessed 19 June 2017)CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Louie AV, Rodrigues G, Yaremko B, Yu E, Dar AR, Dingle B et al (2009) Management and prognosis in synchronous solitary resected brain metastasis from non-small-cell lung cancer. Clin Lung Cancer 10:174–179 (http://www.sciencedirect.com/science/article/pii/S1525730411704818. Accessed 13 September 2016)CrossRefPubMedGoogle Scholar
  14. 14.
    Mascaux C, Paesmans M, Berghmans T, Branle F, Lafitte JJ, Lemaitre F et al (2000) A systematic review of the role of etoposide and cisplatin in the chemotherapy of small cell lung cancer with methodology assessment and meta-analysis. Lung Cancer 30:23–36 (http://www.ncbi.nlm.nih.gov/pubmed/11008007. Accessed 17 December 2015)CrossRefPubMedGoogle Scholar
  15. 15.
    Mehta MP, Tsao MN, Whelan TJ, Morris DE, Hayman JA, Flickinger JC et al (2005) The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys 63:37–46 (http://www.ncbi.nlm.nih.gov/pubmed/16111570. Accessed 15 September 2016)CrossRefPubMedGoogle Scholar
  16. 16.
    Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ et al (1990) A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:494–500 (http://www.nejm.org/doi/abs/10.1056/NEJM199002223220802. Accessed 3 July 2017)CrossRefPubMedGoogle Scholar
  17. 17.
    Postmus PE, Haaxma-Reiche H, Smit EF, Groen HJM, Karnicka H, Lewinski T et al (2000) Treatment of brain metastases of small-cell lung cancer: comparing teniposide and teniposide with whole-brain radiotherapy—a phase III study of the European organization for the research and treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 18:3400–3408 (http://jco.ascopubs.org/content/18/19/3400.long. Accessed 23 August 2016)CrossRefPubMedGoogle Scholar
  18. 18.
    Pujol JL, Carestia L, Daurès JP (2000) Is there a case for cisplatin in the treatment of small-cell lung cancer? A meta-analysis of randomized trials of a cisplatin-containing regimen versus a regimen without this alkylating agent. Br J Cancer 83:8–15 (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2374541&tool=pmcentrez&rendertype=abstract. Accessed 15 September 2016)CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Quan AL, Videtic GMM, Suh JH (2004) Brain metastases in small cell lung cancer. Oncology 18:961–972 (discussion 974, 979–80, 987 Available: http://www.ncbi.nlm.nih.gov/pubmed/15328892. Accessed 23 August 2016)PubMedGoogle Scholar
  20. 20.
    Scharp M, Hauswald H, Bischof M, Debus J, Combs SE (2014) Re-irradiation in the treatment of patients with cerebral metastases of solid tumors: retrospective analysis. Radiat Oncol 9:4 (Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3904456&tool=pmcentrez&rendertype=abstract. Accessed 19 April 2016)CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Schröder C, Engenhart-Cabillic R, Vorwerk H, Schmidt M, Huhnt W, Blank E et al (2017) Changes in pulmonary function and influencing factors after high-dose intrathoracic radio(chemo)therapy. Strahlenther Onkol 193:125–131 (http://link.springer.com/10.1007/s00066-016-1067-8. Accessed 29 May 2017)CrossRefPubMedGoogle Scholar
  22. 22.
    Schröder C, Engenhart-Cabillic R, Vorwerk H, Schmidt M, Huhnt W, Blank E et al (2017) Patient’s quality of life after high-dose radiation therapy for thoracic carcinomas. Strahlenther Onkol 193:132–140 (http://link.springer.com/10.1007/s00066-016-1068-7. Accessed 29 May 2017)CrossRefPubMedGoogle Scholar
  23. 23.
    Seute T, Leffers P, ten Velde GPM, Twijnstra A (2004) Neurologic disorders in 432 consecutive patients with small cell lung carcinoma. Cancer 100:801–806 (http://www.ncbi.nlm.nih.gov/pubmed/14770437. Accessed 19 April 2016)CrossRefPubMedGoogle Scholar
  24. 24.
    Shibamoto Y, Baba F, Oda K, Hayashi S, Kokubo M, Ishihara S‑I et al (2008) Incidence of brain atrophy and decline in mini-mental state examination score after whole-brain radiotherapy in patients with brain metastases: a prospective study. Int J Radiat Oncol Biol Phys 72:1168–1173 (http://www.ncbi.nlm.nih.gov/pubmed/18495375. Accessed 15 September 2016)CrossRefPubMedGoogle Scholar
  25. 25.
    Slotman B, Faivre-Finn C, Kramer G, Rankin E, Snee M, Hatton M et al (2007) Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357:664–672 (http://www.ncbi.nlm.nih.gov/pubmed/17699816. Accessed 16 December 2015)CrossRefPubMedGoogle Scholar
  26. 26.
    Soffietti R, Kocher M, Abacioglu UM, Villa S, Fauchon F, Baumert BG et al (2013) A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life. J Clin Oncol 31:65–72 (Available: http://www.ncbi.nlm.nih.gov/pubmed/23213105. Accessed 15 September 2016)CrossRefPubMedGoogle Scholar
  27. 27.
    Takahashi T, Yamanaka T, Seto T, Harada H, Nokihara H, Saka H et al (2017) Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 18:663–671 (Available: http://www.ncbi.nlm.nih.gov/pubmed/28343976. Accessed 12 May 2017)CrossRefPubMedGoogle Scholar
  28. 28.
    Tsao MN, Rades D, Wirth A, Lo SS, Danielson BL, Gaspar LE et al (2012) Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): an American Society for Radiation Oncology evidence-based guideline. Pract Radiat Oncol 2:210–225 (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3808749&tool=pmcentrez&rendertype=abstract. Accessed 15 September 2016)CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Videtic GMM, Adelstein DJ, Mekhail TM, Rice TW, Stevens GHJ, Lee S‑Y et al (2007) Validation of the RTOG recursive partitioning analysis (RPA) classification for small-cell lung cancer-only brain metastases. Int J Radiat Oncol Biol Phys 67:240–243 (Available: http://www.sciencedirect.com/science/article/pii/S0360301606027659. Accessed 22 August 2016)CrossRefPubMedGoogle Scholar
  30. 30.
    Welzel G, Fleckenstein K, Schaefer J, Hermann B, Kraus-Tiefenbacher U, Mai SK et al (2008) Memory function before and after whole brain radiotherapy in patients with and without brain metastases. Int J Radiat Oncol Biol Phys 72:1311–1318 (Available: http://www.ncbi.nlm.nih.gov/pubmed/18448270. Accessed 1 October 2015)CrossRefPubMedGoogle Scholar
  31. 31.
    Zelen M (1973) Keynote address on biostatistics and data retrieval. Cancer Chemother Rep 4:31–42 (Available: http://www.ncbi.nlm.nih.gov/pubmed/4580860. Accessed 27 June 2016)Google Scholar

Copyright information

© Springer-Verlag GmbH Deutschland 2017

Authors and Affiliations

  • Denise Bernhardt
    • 1
    • 2
    • 6
  • Sebastian Adeberg
    • 1
    • 2
    • 5
    • 6
  • Farastuk Bozorgmehr
    • 3
    • 7
  • Nils Opfermann
    • 1
    • 2
  • Juliane Hörner-Rieber
    • 1
    • 2
  • Laila König
    • 1
    • 2
    • 6
  • Jutta Kappes
    • 4
  • Michael Thomas
    • 3
    • 7
  • Andreas Unterberg
    • 10
  • Felix Herth
    • 4
    • 7
  • Claus Peter Heußel
    • 7
    • 8
    • 9
  • Arne Warth
    • 7
    • 11
  • Jürgen Debus
    • 1
    • 2
    • 5
    • 6
  • Martin Steins
    • 3
    • 7
  • Stefan Rieken
    • 1
    • 2
  1. 1.Department of Radiation Oncology, INF 400University Hospital HeidelbergHeidelbergGermany
  2. 2.Heidelberg Institute of Radiation Oncology (HIRO)HeidelbergGermany
  3. 3.Department of Thoracic Oncology, Thoraxklinik, Translational Lung Research Centre Heidelberg (TLRC-H)Heidelberg UniversityHeidelbergGermany
  4. 4.Department of Pneumology, ThoraxklinikHeidelberg UniversityHeidelbergGermany
  5. 5.Clinical Cooperation Unit Radiation OncologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  6. 6.Heidelberg Ion-Beam Therapy Center (HIT)HeidelbergGermany
  7. 7.Translational Lung Research Centre Heidelberg (TLRC-H)German Centre for Lung Research (DZL)HeidelbergGermany
  8. 8.Diagnostic and Interventional Radiology with Nuclear Medicine, ThoraxklinikUniversity of HeidelbergHeidelbergGermany
  9. 9.Diagnostic and Interventional RadiologyUniversity of HeidelbergHeidelbergGermany
  10. 10.Department of Neurosurgery, INF 400University Hospital HeidelbergHeidelbergGermany
  11. 11.Institute of PathologyHeidelberg UniversityHeidelbergGermany

Personalised recommendations