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Journal of Radiation Oncology

, Volume 8, Issue 2, pp 163–170 | Cite as

Lymphopenia as a predictor of survival in chemoradiation-treated stage III non-small-cell lung cancer (NSCLC): a multi-center retrospective analysis

  • Vidhya KariveduEmail author
  • Rishi Agarwal
  • Sulsal Ul Haque
  • Bicky Thapa
  • Farhad Fakhrejahani
  • Pingfu Fu
  • Gregory M. M. Videtic
  • Nooshin Hashemi Sadraei
Original Research
  • 16 Downloads

Abstract

Background

Concurrent chemoradiation (CRT) with a platinum-containing regimen is considered standard of care for eligible unresectable stage III non-small-cell lung cancer (NSCLC) patients. Attempts to improve locoregional control, and thereby enhance overall survival (OS), by increasing the dose of radiation failed to do so in a contemporary phase III trial. Better understanding of the effects of radiation on the immune system, particularly absolute lymphocyte counts (ALC), may explain the poorer survival seen with high-dose (HD) radiation compared to low dose (LD). We hypothesized that treatment-induced lymphopenia affects outcomes in stage III NSCLC patients treated with concurrent CRT.

Methods

The study is a retrospective multi-institution study. Stage III NSCLC patients who received CRT between 1994 and 2014 were categorized into LD RT (≤ 66 Gy) and HD RT (> 66 Gy) groups. Overall survival was assessed using Kaplan-Meier method with log-rank test and Cox proportional hazard regression model to estimate the effect of radiation dose (LD vs. HD groups) on OS. Hematologic values including ALC were evaluated at diagnosis and at intervals during treatment. Patients with pre-existing immunodeficiency states and autoimmune disease were excluded from the analysis.

Results

Of the patients, 182 were included in the analysis. Median age was 62 years (range 37–82). Seventy-seven percent were males, 67% Caucasians. Most common types of histology were adenocarcinoma (52%) and squamous cell carcinoma (41%). One-hundred-fifty-four patients received LD RT and 28 received HD RT. Medians (ranges) of pre-treatment ALC were 1730/mm3 (384, 4300) vs. 2065/mm3 (600, 4580) (p = 0.58) between LD and HD groups. Medians (ranges) of nadir ALC were 324/mm3 (20, 2410) vs. 279.5/mm3 (20–930) (p = 0.11) between LD and HD groups. Kaplan-Meier survival curves showed that LD has better OS than the HD group (median survival 31.2 months vs. 13.9 months, p < 0.001). No significant association was detected between RT dose and lymphocytes nadirs or with lymphocyte count prior to RT.

Conclusions

HD RT in stage III NSCLC patients is associated with worse survival. Lower nadir lymphocyte counts, independent of dose of radiation, were not associated with decrease in survival. These findings need further validation in larger studies and in patients treated with immune therapy.

Keywords

Lung cancer NSCLC High dose radiotherapy Lymphopenia 

Notes

Compliance with ethical standards

Funding

No funding was received for this study.

Conflict of interest

During the conduct of this study and manuscript preparation, Nooshin Hashemi Sadraei served on a scientific advisory board was a speaker at Genentech and received research support at Merck. Vidhya Karivedu, Rishi Agarwal, Sulsal Ul Haque, Bicky Thapa, Farhad Fakhrejahani, Pingfu Fu, and Gregory Videtic declare that they have no conflict of interest.

Ethical approval

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. For this type of study formal consent is not required.

Informed consent

Statement of informed consent was not applicable since the manuscript does not contain any patient data. A waiver of informed consent was obtained by the IRB to complete this retrospective study.

References

  1. 1.
    Asmar R, Rizvi NA (2015) Immunotherapy for advanced lung cancer. Cancer J 21(5):383–391.  https://doi.org/10.1097/ppo.0000000000000151 CrossRefGoogle Scholar
  2. 2.
    Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeno J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Ozguroglu M (2017) Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 377:1919–1929.  https://doi.org/10.1056/NEJMoa1709937 CrossRefGoogle Scholar
  3. 3.
    Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim Y-C, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeño J, Faivre-Finn C, Reck M, Vansteenkiste J, Spigel DR, Wadsworth C, Melillo G, Taboada M, Dennis PA, Özgüroğlu M Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. New England Journal of Medicine 0 (0):null. doi: https://doi.org/10.1056/NEJMoa1809697
  4. 4.
    Grossman SA, Ellsworth S, Campian J, Wild AT, Herman JM, Laheru D, Brock M, Balmanoukian A, Ye X (2015) Survival in patients with severe lymphopenia following treatment with radiation and chemotherapy for newly diagnosed solid tumors. J Natl Compr Cancer Netw 13(10):1225–1231.  https://doi.org/10.6004/jnccn.2015.0151 CrossRefGoogle Scholar
  5. 5.
    McMichael A (1992) Cytotoxic T lymphocytes and immune surveillance. Cancer Surv 13:5–21Google Scholar
  6. 6.
    Feng J-F, Liu J-S, Huang Y (2014) Lymphopenia predicts poor prognosis in patients with esophageal squamous cell carcinoma. Medicine 93(27):e257.  https://doi.org/10.1097/md.0000000000000257 CrossRefGoogle Scholar
  7. 7.
    Lissoni P, Brivio F, Fumagalli L, Messina G, Ghezzi V, Frontini L, Giani L, Vaghi M, Ardizzoia A, Gardani GS (2004) Efficacy of cancer chemotherapy in relation to the pretreatment number of lymphocytes in patients with metastatic solid tumors. Int J Biol Markers 19(2):135–140CrossRefGoogle Scholar
  8. 8.
    Ray-Coquard I, Cropet C, Van Glabbeke M, Sebban C, Le Cesne A, Judson I, Tredan O, Verweij J, Biron P, Labidi I, Guastalla JP, Bachelot T, Perol D, Chabaud S, Hogendoorn PC, Cassier P, Dufresne A, Blay JY (2009) Lymphopenia as a prognostic factor for overall survival in advanced carcinomas, sarcomas, and lymphomas. Cancer Res 69(13):5383–5391.  https://doi.org/10.1158/0008-5472.can-08-3845 CrossRefGoogle Scholar
  9. 9.
    Campian JL, Sarai G, Ye X, Marur S, Grossman SA (2014) Association between severe treatment-related lymphopenia and progression-free survival in patients with newly diagnosed squamous cell head and neck cancer. Head Neck 36(12):1747–1753.  https://doi.org/10.1002/hed.23535 CrossRefGoogle Scholar
  10. 10.
    Campian JL, Ye X, Brock M, Grossman SA (2013) Treatment-related lymphopenia in patients with stage III non-small-cell lung cancer. Cancer Investig 31(3):183–188.  https://doi.org/10.3109/07357907.2013.767342 CrossRefGoogle Scholar
  11. 11.
    Tang C, Liao Z, Gomez D, Levy L, Zhuang Y, Gebremichael RA, Hong DS, Komaki R, Welsh JW (2014) Lymphopenia association with gross tumor volume and lung V5 and its effects on non-small cell lung cancer patient outcomes. Int. J. Radiat. Oncol. Biol. Phys. 89(5):1084–1091.  https://doi.org/10.1016/j.ijrobp.2014.04.025 CrossRefGoogle Scholar
  12. 12.
    Balmanoukian A, Ye X, Herman J, Laheru D, Grossman SA (2012) The association between treatment-related lymphopenia and survival in newly diagnosed patients with resected adenocarcinoma of the pancreas. Cancer Investig 30(8):571–576.  https://doi.org/10.3109/07357907.2012.700987 CrossRefGoogle Scholar
  13. 13.
    Pirker R (2016) Improving survival of patients with locally advanced non-small-cell cancer remains a challenge: comment to PROCLAIM. J Thorac Dis 8(7):E607–E610.  https://doi.org/10.21037/jtd.2016.05.54 CrossRefGoogle Scholar
  14. 14.
    Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53(282):457–481.  https://doi.org/10.1080/01621459.1958.10501452 CrossRefGoogle Scholar
  15. 15.
    Cox DR (1972) Regression models and life-tables. J R Stat Soc Ser B Methodol 34(2):187–220Google Scholar
  16. 16.
    Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD (2011) Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 103(19):1452–1460.  https://doi.org/10.1093/jnci/djr325 CrossRefGoogle Scholar
  17. 17.
    Albain KS, Crowley JJ, III ATT, Gandara DR, Farrar WB, Clark JI, Beasley KR, Livingston RB (2002) Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest Oncology Group phase II study, SWOG 9019. J Clin Oncol 20(16):3454–3460.  https://doi.org/10.1200/jco.2002.03.055 CrossRefGoogle Scholar
  18. 18.
    Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, Bogart J, Hu C, Forster K, Magliocco A, Kavadi V, Garces YI, Narayan S, Iyengar P, Robinson C, Wynn RB, Koprowski C, Meng J, Beitler J, Gaur R, Curran W Jr, Choy H (2015) Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 16(2):187–199.  https://doi.org/10.1016/s1470-2045(14)71207-0 CrossRefGoogle Scholar
  19. 19.
    Hanna N, Neubauer M, Yiannoutsos C, McGarry R, Arseneau J, Ansari R, Reynolds C, Govindan R, Melnyk A, Fisher W, Richards D, Bruetman D, Anderson T, Chowhan N, Nattam S, Mantravadi P, Johnson C, Breen T, White A, Einhorn L (2008) Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol 26(35):5755–5760.  https://doi.org/10.1200/jco.2008.17.7840 CrossRefGoogle Scholar
  20. 20.
    van Meerbeeck JP, Kramer GW, Van Schil PE, Legrand C, Smit EF, Schramel F, Tjan-Heijnen VC, Biesma B, Debruyne C, van Zandwijk N, Splinter TA, Giaccone G (2007) Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 99(6):442–450.  https://doi.org/10.1093/jnci/djk093 CrossRefGoogle Scholar
  21. 21.
    Grossman SA, Ye X, Lesser G, Sloan A, Carraway H, Desideri S, Piantadosi S (2011) Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. doi: https://doi.org/10.1158/1078-0432.CCR-11-0774

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Hematology/OncologyUniversity of CincinnatiCincinnatiUSA
  2. 2.Division of Internal MedicineFairview Hospital-Cleveland ClinicClevelandUSA
  3. 3.Division of Hematology/OncologyLargoUSA
  4. 4.Department of Population and Quantitative Health Sciences, School of MedicineCase Western UniversityClevelandUSA
  5. 5.Department of Radiation OncologyCleveland ClinicClevelandUSA

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