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01-04-2017 | Research Article

Predictive value of hypoxia in advanced head and neck cancer after treatment with hyperfractionated radio-chemotherapy and hypoxia modification

Authors: B. Clavo, F. Robaina, D. Fiuza, A. Ruiz, M. Lloret, D. Rey-Baltar, P. Llontop, A. Riveros, J. Rivero, F. Castañeda, S. Quintero, N. Santana-Rodríguez

Published in: Clinical and Translational Oncology | Issue 4/2017

Abstract

Purpose

Hypoxia has predictive value in head and neck cancer (HNC). It has been well described, albeit in a small number of clinical Centres. The aim of this study was to describe our experience using the polarographic probe technique to assess the predictive value of tumour oxygenation in patients with advanced HNC treated with hyperfractionated radio-chemotherapy. Hypoxia modification was induced using percutaneous spinal cord stimulation (SCS).

Methods/patients

Male patients (n = 12; stage IVb n = 8; IVa n = 4; mean age 58: range 46–70 years) with advanced HNC were evaluated. Planned therapy was hyperfractionated-radiotherapy, oral tegafur (precursor of 5-fluorouracil) and hypoxia modification using SCS. Pre-treatment analyses included: haemoglobin levels and tumour oxygenation (using the Eppendorf polarographic probe device). Oxygenation was expressed as median-pO₂ (in mmHg) and hypoxia as the percentage of pO₂ values ≤5 mmHg (HP5) and ≤2.5 mmHg (HP2.5).

Results

Lower haemoglobin levels were directly correlated with median pO₂ (p = 0.017) and inversely correlated with HP5 (p = 0.020) and more advanced stages (IVb vs. IVa; p = 0.028). Patients who subsequently developed systemic metastasis had tumours that were more hypoxic, with lower median pO₂ (p = 0.036) and higher HP5 (p = 0.036). The subgroup of patients with HP2.5 above the median (the most hypoxic tumours) had lower loco-regional control (p = 0.027), cause-specific survival (p = 0.008), and overall survival (p = 0.008).

Conclusions

Higher tumour hypoxia showed predictive value in HNC in our study, and was significantly associated with lower overall survival, cause-specific survival, and loco-regional control. Tumour hypoxia determination could be used to select patients who would most benefit by hypoxia modification during chemo-radiotherapy of HNC.

Vaupel P. Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol. 2004;14(3):198–206.CrossRefPubMed

Gray LH, Conger AD, Ebert M, Hornsey S, Scott OCA. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol. 1953;26:638–48.CrossRefPubMed

Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature. 1996;379(6560):88–91.CrossRefPubMed

Nordsmark M, Bentzen SM, Rudat V, Brizel D, Lartigau E, Stadler P, et al. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol. 2005;77(1):18–24.CrossRefPubMed

Rajendran JG, Schwartz DL, O’Sullivan J, Peterson LM, Ng P, Scharnhorst J, et al. Tumor hypoxia imaging with [F-18] fluoromisonidazole positron emission tomography in head and neck cancer. Clin Cancer Res. 2006;12(18):5435–41.CrossRefPubMedPubMedCentral

Rischin D, Hicks RJ, Fisher R, Binns D, Corry J, Porceddu S, et al. Prognostic significance of [18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: a substudy of Trans-Tasman Radiation Oncology Group Study 98.02. J Clin Oncol. 2006;24(13):2098–104. doi:10.1200/JCO.2005.05.2878.CrossRefPubMed

Mortensen LS, Johansen J, Kallehauge J, Primdahl H, Busk M, Lassen P, et al. FAZA PET/CT hypoxia imaging in patients with squamous cell carcinoma of the head and neck treated with radiotherapy: results from the DAHANCA 24 trial. Radiother Oncol. 2012;105(1):14–20. doi:10.1016/j.radonc.2012.09.015.CrossRefPubMed

Janssens GO, Rademakers SE, Terhaard CH, Doornaert PA, Bijl HP, van den Ende P, et al. Accelerated radiotherapy with carbogen and nicotinamide for laryngeal cancer: results of a phase III randomized trial. J Clin Oncol. 2012;30(15):1777–83. doi:10.1200/JCO.2011.35.9315.CrossRefPubMed

Toustrup K, Sorensen BS, Lassen P, Wiuf C, Alsner J, Overgaard J. Gene expression classifier predicts for hypoxic modification of radiotherapy with nimorazole in squamous cell carcinomas of the head and neck. Radiother Oncol. 2012;102(1):122–9. doi:10.1016/j.radonc.2011.09.010.CrossRefPubMed

10.

Eustace A, Mani N, Span PN, Irlam JJ, Taylor J, Betts GN, et al. A 26-gene hypoxia signature predicts benefit from hypoxia-modifying therapy in laryngeal cancer but not bladder cancer. Clin Cancer Res. 2013;19(17):4879–88. doi:10.1158/1078-0432.CCR-13-0542.CrossRefPubMedPubMedCentral

11.

Overgaard J. Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck–a systematic review and meta-analysis. Radiother Oncol. 2011;100(1):22–32. doi:10.1016/j.radonc.2011.03.004.CrossRefPubMed

12.

Clavo B, Robaina F, Catala L, Perez JL, Lloret M, Carames MA, et al. Effect of cervical spinal cord stimulation on regional blood flow and oxygenation in advanced head and neck tumours. Ann Oncol. 2004;15(5):802–7.CrossRefPubMed

13.

Clavo B, Robaina F, Valcarcel B, Catala L, Perez JL, Cabezon A, et al. Modification of loco-regional microenvironment in brain tumors by spinal cord stimulation. Implications for radio-chemotherapy. J Neurooncol. 2012;106(1):177–84. doi:10.1007/s11060-011-0660-z.CrossRefPubMed

14.

Lara PC, Lloret M, Clavo B, Apolinario RM, Bordon E, Rey A, et al. Hypoxia downregulates Ku70/80 expression in cervical carcinoma tumors. Radiother Oncol. 2008;89(2):222–6. doi:10.1016/j.radonc.2008.07.018.CrossRefPubMed

15.

Lara PC, Lloret M, Clavo B, Apolinario RM, Henriquez-Hernandez LA, Bordon E, et al. Severe hypoxia induces chemo-resistance in clinical cervical tumors through MVP over-expression. Radiat Oncol. 2009;4:29. doi:10.1186/1748-717X-4-29.CrossRefPubMedPubMedCentral

16.

Stone HB, Brown JM, Phillips TL, Sutherland RM. Oxygen in human tumors: correlations between methods of measurement and response to therapy. Summary of a workshop held November 19-20, 1992, at the National Cancer Institute, Bethesda, Maryland. Radiat Res. 1993;136(3):422–34.CrossRefPubMed

17.

Sundfor K, Lyng H, Trope CG, Rofstad EK. Treatment outcome in advanced squamous cell carcinoma of the uterine cervix: relationships to pretreatment tumor oxygenation and vascularization. Radiother Oncol. 2000;54(2):101–7.CrossRefPubMed

18.

Nordsmark M, Alsner J, Keller J, Nielsen OS, Jensen OM, Horsman MR, et al. Hypoxia in human soft tissue sarcomas: adverse impact on survival and no association with p53 mutations. Br J Cancer. 2001;84(8):1070–5.CrossRefPubMedPubMedCentral

19.

Tatum JL, Kelloff GJ, Gillies RJ, Arbeit JM, Brown JM, Chao KS, et al. Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. Int J Radiat Biol. 2006;82(10):699–757.CrossRefPubMed

20.

Brizel DM, Scully SP, Harrelson JM, Layfield LJ, Bean JM, Prosnitz LR, et al. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res. 1996;56(5):941–3.PubMed

21.

Pitson G, Fyles A, Milosevic M, Wylie J, Pintilie M, Hill R. Tumor size and oxygenation are independent predictors of nodal diseases in patients with cervix cancer. Int J Radiat Oncol Biol Phys. 2001;51(3):699–703.CrossRefPubMed

22.

Becker A, Stadler P, Lavey RS, Hansgen G, Kuhnt T, Lautenschlager C, et al. Severe anemia is associated with poor tumor oxygenation in head and neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys. 2000;46(2):459–66.CrossRefPubMed

23.

Clavo B, Perez JL, Lopez L, Suarez G, Lloret M, Morera J, et al. Influence of haemoglobin concentration and peripheral muscle pO2 on tumour oxygenation in advanced head and neck tumours. Radiother Oncol. 2003;66(1):71–4.CrossRefPubMed

24.

Biete Sola A, Calvo Manuel FA, Clavo Varas B, Fernandez Perez C, Porto Vazquez C, de la Torre Tomas A et al. Erythropoietin in cancer treatment: considerations about Henke’s article. Clin Transl Oncol. 2005;7(8):332–5.

25.

Fyles AW, Milosevic M, Pintilie M, Syed A, Hill RP. Anemia, hypoxia and transfusion in patients with cervix cancer: a review. Radiother Oncol. 2000;57(1):13–9.CrossRefPubMed

26.

Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet. 2009;373(9674):1532–42. doi:10.1016/S0140-6736(09)60502-X.CrossRefPubMed

27.

Clavo B, Santana N, Biete A. Epoetins and mortality in patients with cancer. Lancet. 2009;374(9686):287; author reply-8. doi:10.1016/S0140-6736(09)61355-6.

28.

Vaupel P. Hypoxia and aggressive tumor phenotype: implications for therapy and prognosis. Oncologist. 2008;13(Suppl 3):21–6. doi:10.1634/theoncologist.13-S3-21.CrossRefPubMed

29.

Pignon JP, le Maitre A, Maillard E, Bourhis J. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009;92(1):4–14. doi:10.1016/j.radonc.2009.04.014.CrossRefPubMed

30.

Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567–78.CrossRefPubMed

Title: Predictive value of hypoxia in advanced head and neck cancer after treatment with hyperfractionated radio-chemotherapy and hypoxia modification
Authors: B. Clavo
F. Robaina
D. Fiuza
A. Ruiz
M. Lloret
D. Rey-Baltar
P. Llontop
A. Riveros
J. Rivero
F. Castañeda
S. Quintero
N. Santana-Rodríguez
Publication date: 01-04-2017
Publisher: Springer International Publishing
Published in: Clinical and Translational Oncology / Issue 4/2017
Print ISSN: 1699-048X
Electronic ISSN: 1699-3055
DOI: https://doi.org/10.1007/s12094-016-1541-x

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