Neutrophilia in locally advanced cervical cancer: A novel biomarker for image-guided adaptive brachytherapy?

Alexandre Escande, Christine Haie-Meder, Pierre Maroun, Sébastien Gouy, Renaud Mazeron, Thomas Leroy, Enrica Bentivegna, Philippe Morice, Eric Deutsch, Cyrus Chargari, Alexandre Escande, Christine Haie-Meder, Pierre Maroun, Sébastien Gouy, Renaud Mazeron, Thomas Leroy, Enrica Bentivegna, Philippe Morice, Eric Deutsch, Cyrus Chargari

Abstract

Objective: To study the prognostic value of leucocyte disorders in a prospective cohort of cervical cancer patients receiving definitive chemoradiation plus image-guided adaptive brachytherapy (IGABT).

Results: 113 patients were identified. All patients received a pelvic irradiation concomitant with chemotherapy, extended to the para-aortic area in 13 patients with IVB disease. Neutrophilia and leukocytosis were significant univariate prognostic factors for poorer local failure-free survival (p = 0.000 and p = 0.002, respectively), associated with tumor size, high-risk clinical target volume (HR-CTV) and anemia. No effect was shown for distant metastases but leukocytosis and neutrophila were both poor prognostic factors for in-field relapses (p = 0.003 and p < 0.001). In multivariate analysis, HR-CTV volume (p = 0.026) and neutrophils count > 7,500/μl (p = 0.018) were independent factors for poorer survival without local failure, with hazard ratio (HR) of 3.1.

Materials and methods: We examined patients treated in our Institution between April 2009 and July 2015 by concurrent chemoradiation (45 Gy in 25 fractions +/- lymph node boosts) followed by a magnetic resonance imaging (MRI)-guided adaptive pulse-dose rate brachytherapy (15 Gy to the intermediate-risk clinical target volume). The prognostic value of pretreatment leucocyte disorders was examined. Leukocytosis and neutrophilia were defined as a leukocyte count or a neutrophils count exceeding 10,000 and 7,500/μl, respectively.

Conclusions: Neutrophilia is a significant prognostic factor for local relapse in locally advanced cervical cancer treated with MRI-based IGABT. This biomarker could help identifying patients with higher risk of local relapse and requiring dose escalation.

Keywords: biomarkers; image-guided adaptive brachytherapy; locally advanced cervical cancer; neutrophilia; prognostic factor.

Conflict of interest statement

CONFLICTS OF INTEREST

None.

Figures

Figure 1. Estimated survival without local failure…
Figure 1. Estimated survival without local failure in patients with or without neutrophilia

References

    1. Pötter R, Georg P, Dimopoulos JC, Grimm M, Berger D, Nesvacil N, Georg D, Schmid MP, Reinthaller A, Sturdza A, Kirisits C. Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer. Radiother Oncol. 2011;100:116–23.
    1. Mazeron R, Gilmore J, Dumas I, Champoudry J, Goulart J, Vanneste B, Tailleur A, Morice P, Haie-Meder C. Adaptive 3D image guided brachytherapy: a strong argument in the debate on systematic radical hysterectomy for locally advanced cervical cancer. Oncologist. 2013;18:415–22.
    1. Pötter R, Dimopoulos J, Georg P, Waldhäusl C, Wachter-Gerstner N, Weitmann H, Reinthaller A, Knocke TH, Wachter S, Kirisits C. Clinical impact of MRI assisted dose volume adaptation and dose escalation in brachytherapy of locally advanced cervix cancer. Radiother Oncol. 2007;83:148–155.
    1. Lindegaard JC, Fokdal LU, Nielsen SK, Juul-Christensen J, Tanderup K. MRI-guided adaptive radiotherapy in locally advanced cervical cancer from a Nordic perspective. Acta Oncol. 2013;52:1510–9.
    1. Mazeron R, Castelnau-Marchand P, Dumas I, del Campo ER, Kom LK, Martinetti F, Farha G, Tailleur A, Morice P, Chargari C, Lefkopoulos D, Haie-Meder C. Impact of treatment time and dose escalation on local control in locally advanced cervical cancer treated by chemoradiation and image-guided pulsed-dose rate adaptive brachytherapy. Radiother Oncol. 2015;114:257–63.
    1. Chargari C, Magné N, Dumas I, Messai T, Vicenzi L, Gillion N, Morice P, Haie-Meder C. Physics and clinical contribution with MRI-based Pulsed dose rate brachytherapy in patients with cervix carcinoma. Int J Radiat Oncol Biol Phys. 2009;74:133–139.
    1. Schmid MP, Franckena M, Kirchheiner K, Sturdza A, Georg P, Dörr W, Pötter R. Distant metastasis in patients with cervical cancer after primary radiotherapy with or without chemotherapy and image guided adaptive brachytherapy. Gynecol Oncol. 2014;133:256–62.
    1. Kim SM, Choi HS, Byun JS. Overall 5-year survival rate and prognostic factors in patients with stage IB and IIA cervical cancer treated by radical hysterectomy and pelvic lymph node dissection. Int J Gynecol Cancer. 2000;10:305–312.
    1. Mabuchi S, Matsumoto Y, Isohashi F, Yoshioka Y, Ohashi H, Morii E, Hamasaki T, Aozasa K, Mutch DG, Kimura T. Pretreatment leukocytosis is an indicator of poor prognosis in patients with cervical cancer. Gynecol Oncol. 2011;122:25–32.
    1. Mabuchi S, Matsumoto Y, Hamasaki T, Kawano M, Hisamatsu T, Mutch DG, Kimura T. Elevated white blood cell count at the time of recurrence diagnosis is an indicator of short survival in patients with recurrent cervical cancer. Int J Gynecol Cancer. 2012;22:1545–51.
    1. Zamarron BF, Chen W. Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci. 2011;7:651–658.
    1. Nagaraj S, Gabrilovich DI. Myeloid-derived suppressor cells in human cancer. Cancer J. 2010;16:348–353.
    1. Mayr NA, Huang Z, Wang JZ, Lo SS, Fan JM, Grecula JC, Sammet S, Sammet CL, Jia G, Zhang J, Knopp MV, Yuh WT. Characterizing tumor heterogeneity with functional imaging and quantifying high-risk tumor volume for early prediction of treatment outcome: cervical cancer as a model. Int J Radiat Oncol Biol Phys. 2012;83:972–9.
    1. Dunst J, Kuhnt T, Strauss HG, Krause U, Pelz T, Koelbl H, Haensgen G. Anemia in cervical cancers: impact on survival, patterns of relapse, and association with hypoxia and angiogenesis. Int J Radiat Oncol Biol Phys. 2003;56:778–87.
    1. Granger JM, Kontoyiannis DP. Etiology and outcome of extreme leukocytosis in 758 nonhematologic cancer patients: a retrospective, single-institution study. Cancer. 2009;115:3919–3923.
    1. Wilcox RA. Cancer-associated myeloproliferation: old association, new therapeutic target. Mayo Clin Proc. 2010;85:656–663.
    1. Matsumoto Y, Mabuchi S, Muraji M, Morii E, Kimura T. Squamous cell carcinoma of the uterine cervix producing granulocyte colony-stimulating factor: a report of 4 cases and a review of the literature. Int J Gynecol Cancer. 2010;20:417–421.
    1. Mabuchi S, Matsumoto Y, Kawano M, Minami K, Seo Y, Sasano T, Takahashi R, Kuroda H, Hisamatsu T, Kakigano A, Hayashi M, Sawada K, Hamasaki T. Uterine cervical cancer displaying tumor-related leukocytosis: a distinct clinical entity with radioresistant feature. J Natl Cancer Inst. 2014;19:106.
    1. Connor JP. Aggressive carcinosarcoma of the uterine cervix associated with high levels of granulocyte colony stimulating factor: case report and laboratory correlates. Gynecol Oncol. 2006;103:349–53.
    1. Jeffery S, Russell J, Brown Martin. The irradiated tumor microenvironment: role of tumor-associated macrophages in vascular recovery. Front Physiol. 2013;4:157.
    1. Chargari C, Mazeron R, Escande A, Maroun P, Dumas I, Martinetti F, Tafo-Guemnie A, Deutsch E, Morice P, Haie-Meder C. Image-guided adaptive brachytherapy in cervical cancer: Patterns of relapse by brachytherapy planning parameters. Brachytherapy in press
    1. Chargari C, Magne N, Guy JB, Rancoule C, Levy A, Goodman KA, Deutsch E. Optimize and refine therapeutic index in radiation therapy: Overview of a century. Cancer Treat Rev. 2016;45:58–67.
    1. Levy A, Chargari C, Marabelle A, Perfettini JL, Magné N, Deutsch E. Can immunostimulatory agents enhance the abscopal effect of radiotherapy? Eur J Cancer. 2016;62:36–45.
    1. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics. REporting recommendations for tumour MARKer prognostic studies (REMARK) Br J Cancer. 2005;93:387–91.
    1. Magné N, Chargari C, SanFilippo N, Messai T, Gerbaulet A, Haie-Meder C. Technical aspects and perspectives of the vaginal mold applicator for brachytherapy of gynecological malignancies. Brachytherapy. 2009;9:274–7.
    1. Pötter R, Haie-Meder C, Van Limbergen E, Barillot I, De Brabandere M, Dimopoulos J, Dumas I, Erickson B, Lang S, Nulens A, Petrow P, Rownd J, Kirisits C. Recommendations from gynaecological (GYN) GEC ESTRO working group (II): concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology. Radiother Oncol. 2006;78:67–77.
    1. Haie-Meder C, Pötter R, Van Limbergen E, Briot E, De Brabandere M, Dimopoulos J, Dumas I, Hellebust TP, Kirisits C, Lang S, Muschitz S, Nevinson J, Nulens A. Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (I): concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV. Radiother Oncol. 2005;74:235–45.

Source: PubMed

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