Survival in Patients With Severe Lymphopenia Following Treatment With Radiation and Chemotherapy for Newly Diagnosed Solid Tumors

Restricted access

Background: The immune system plays an important role in cancer surveillance and therapy. Chemoradiation can cause severe treatment-related lymphopenia (TRL) (<500 cells/mm3) that is associated with reduced survival. Materials and Methods: Data from 4 independent solid tumor studies on serial lymphocyte counts, prognostic factors, treatment, and survival were collected and analyzed. The data set included 297 patients with newly diagnosed malignant glioma (N=96), resected pancreatic cancer (N=53), unresectable pancreatic cancer (N=101), and non–small cell lung cancer (N=47). Results: Pretreatment lymphocyte counts were normal in 83% of the patient population, and no patient had severe baseline lymphopenia. Two months after initiating chemoradiation, 43% developed severe and persistent lymphopenia (P=.001). An increased risk for death was attributable to TRL in each cancer cohort (gliomas: hazard rate [HR], 1.8; 95% CI, 1.13–2.87; resected pancreas: HR, 2.2; 95% CI, 1.17–4.12; unresected pancreas: HR, 2.9; 95% CI, 1.53–5.42; and lung: HR, 1.7; 95% CI, 0.8–3.61) and in the entire study population regardless of pathologic findings (HR, 2.1; 95% CI, 1.54–2.78; P<.0001). Severe TRL was observed in more than 40% of patients 2 months after initiating chemoradiation, regardless of histology or chemotherapy regimen, and was independently associated with shorter survival from tumor progression. Conclusions: Increased attention and research should be focused on the cause, prevention, and reversal of this unintended consequence of cancer treatment that seems to be related to survival in patients with solid tumors.

Correspondence: Stuart A. Grossman, MD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Cancer Research Building #2, Suite 1M-16, 1550 Orleans Street, Baltimore, MD 21231. E-mail: grossman@jhmi.edu
  • 1.

    BremnesRMAl-ShibliKDonnemT. The role of tumor-infiltrating immune cells and chronic inflammation at the tumor site on cancer development, progression, and prognosis: emphasis on non-small cell lung cancer. J Thorac Oncol2011;6:824833.

    • Search Google Scholar
    • Export Citation
  • 2.

    GoodenMJde BockGHLeffersN. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer2011;105:93103.

    • Search Google Scholar
    • Export Citation
  • 3.

    LoiSSirtaineNPietteF. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol2013;31:860867.

    • Search Google Scholar
    • Export Citation
  • 4.

    MeiZLiuYLiuC. Tumour-infiltrating inflammation and prognosis in colorectal cancer: systematic review and meta-analysis. Br J Cancer2014;110:15951605.

    • Search Google Scholar
    • Export Citation
  • 5.

    OelkrugCRamageJM. Enhancement of T cell recruitment and infiltration into tumours. Clin Exp Immunol2014;178:18.

  • 6.

    MonforteAAbramsDPradierC. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. AIDS2008;22:21432153.

    • Search Google Scholar
    • Export Citation
  • 7.

    GrulichAE. Cancer: the effects of HIV and antiretroviral therapy, and implications for early antiretroviral therapy initiation. Curr Opin HIV AIDS2009;4:183187.

    • Search Google Scholar
    • Export Citation
  • 8.

    Le ScodanRMassardCMouret-FourmeE. Brain metastases from breast carcinoma: validation of the radiation therapy oncology group recursive partitioning analysis classification and proposition of a new prognostic score. Int J Radiat Oncol Biol Phys2007;69:839845.

    • Search Google Scholar
    • Export Citation
  • 9.

    Ray-CoquardICropetCVan GlabbekeM. Lymphopenia as a prognostic factor for overall survival in advanced carcinomas, sarcomas, and lymphomas. Cancer Res2009;69:53835391.

    • Search Google Scholar
    • Export Citation
  • 10.

    VinayDSRyanEPPawelecG. Immune evasion in cancer: mechanistic basis and therapeutic strategies[published online ahead of print March 25 2015]. Semin Cancer Bioldoi: 10.1016/j.semcancer.2015.03.004.

    • Search Google Scholar
    • Export Citation
  • 11.

    ZitvogelLApetohLGhiringhelliF. The anticancer immune response: indispensable for therapeutic success?J Clin Invest2008;118:19912001.

    • Search Google Scholar
    • Export Citation
  • 12.

    MellmanICoukosGDranoffG. Cancer immunotherapy comes of age. Nature2011;480:480489.

  • 13.

    MeyerKK. Radiation-induced lymphocyte-immune deficiency. A factor in the increased visceral metastases and decreased hormonal responsiveness of breast cancer. Arch Surg1970;101:114121.

    • Search Google Scholar
    • Export Citation
  • 14.

    RabenMWalachNGaliliUSchlesingerM. The effect of radiation therapy on lymphocyte subpopulations in cancer patients. Cancer1976;37:14171421.

    • Search Google Scholar
    • Export Citation
  • 15.

    MacLennanICKayHE. Analysis of treatment in childhood leukemia. IV. The critical association between dose fractionation and immunosuppression induced by cranial irradiation. Cancer1978;41:108111.

    • Search Google Scholar
    • Export Citation
  • 16.

    De RuysscherDWaerMVandeputteM. Changes of lymphocyte subsets after local irradiation for early stage breast cancer and seminoma testis: long-term increase of activated (HLA-DR+) T cells and decrease of “naive” (CD4-CD45R) T lymphocytes. Eur J Cancer1992;28A:17291734.

    • Search Google Scholar
    • Export Citation
  • 17.

    OnsrudMGrahmIGaudernackG. Early stage carcinoma of the uterine cervix. Effects of intracavitary radium treatment on lymphoid cells in blood and pelvic lymph nodes. Acta Radiol Oncol1986;25:127130.

    • Search Google Scholar
    • Export Citation
  • 18.

    FuksZStroberSBobroveAM. Long term effects of radiation of T and B lymphocytes in peripheral blood of patients with Hodgkin's disease. J Clin Invest1976;58:803814.

    • Search Google Scholar
    • Export Citation
  • 19.

    YovinoSGrossmanSA. Severity, etiology and possible consequences of treatment-related lymphopenia in patients with newly diagnosed high-grade gliomas. CNS Oncol2012;1:149154.

    • Search Google Scholar
    • Export Citation
  • 20.

    GrossmanSAYeXLesserG. Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin Cancer Res2011;17:54735480.

    • Search Google Scholar
    • Export Citation
  • 21.

    CampianJLYeXBrockMGrossmanSA. Treatment-related lymphopenia in patients with stage III non-small-cell lung cancer. Cancer Invest2013;31:183188.

    • Search Google Scholar
    • Export Citation
  • 22.

    WildATYeXEllsworthSG. The association between chemoradiation-related lymphopenia and clinical outcomes in patients with locally advanced pancreatic adenocarcinoma. Am J Clin Oncol2015;38:259265.

    • Search Google Scholar
    • Export Citation
  • 23.

    BalmanoukianAYeXHermanJ. The association between treatment-related lymphopenia and survival in newly diagnosed patients with resected adenocarcinoma of the pancreas. Cancer Invest2012;30:571576.

    • Search Google Scholar
    • Export Citation
  • 24.

    GrossmanSAYeXPiantadosiS. Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clin Cancer Res2010;16:24432449.

    • Search Google Scholar
    • Export Citation
  • 25.

    KaplanELMeierP. Non parametric estimation from incomplete observations. Journal of the American Statistical Association1958;53:457481.

    • Search Google Scholar
    • Export Citation
  • 26.

    BrookmeyerRCrowleyJ. A confidence interval for the median survival time. Biometrics1982;38:2941.

  • 27.

    CoxDROatesD. Analysis of survival data. New York, NY: Chapman & Hall; 1984.

  • 28.

    DerSimonianRLairdN. Meta-analysis in clinical trials. Control Clin Trials1986;7:177188.

  • 29.

    HigginsJPThompsonSG. Quantifying heterogeneity in a meta-analysis. Stat Med2002;21:15391558.

  • 30.

    NeyeloffJLFuchsSCMoreiraLB. Meta-analyses and Forest plots using a Microsoft Excel spreadsheet: step-by-step guide focusing on descriptive data analysis. BMC Res Notes2012;5:52.

    • Search Google Scholar
    • Export Citation
  • 31.

    NakamuraNKusunokiYAkiyamaM. Radiosensitivity of CD4 or CD8 positive human T-lymphocytes by an in vitro colony formation assay. Radiat Res1990;123:224227.

    • Search Google Scholar
    • Export Citation
  • 32.

    MacLennanICKayHE. Analysis of treatment in childhood leukemia. IV. The critical association between dose fractionation and immunosuppression induced by cranial irradiation. Cancer1978;41:108111.

    • Search Google Scholar
    • Export Citation
  • 33.

    WeekeE. The development of lymphopenia in uremic patients undergoing extracorporeal irradiation of the blood with portable beta units. Radiat Res1973;56:554559.

    • Search Google Scholar
    • Export Citation
  • 34.

    MatsubaraSHoriuchiJOkuyamaT. Chromosome aberrations in the peripheral lymphocytes induced by brachytherapy and external cobalt teletherapy. Int J Radiat Oncol Biol Phys1985;11:10851094.

    • Search Google Scholar
    • Export Citation
  • 35.

    YovinoSKleinbergLRGrossmanSA. The etiology of treatment-related lymphopenia in patients with malignant gliomas: modeling radiation dose to circulating lymphocytes explains clinical observations and suggests methods of modifying the impact of radiation on immune cells. Cancer Invest2013;31:140144.

    • Search Google Scholar
    • Export Citation
  • 36.

    EllsworthSBalmanoukianAKosF. Sustained CD4+ cell driven lymphopenia without a compensatory IL7/Il15 response among high-grade glioma patients treated with radiation and temozolomide. Oncoimmunology2014;3:e27357.

    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 279 279 22
PDF Downloads 83 82 11
EPUB Downloads 0 0 0