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Pre-chemoradiotherapy low hemoglobin levels indicate increased osteoradionecrosis risk in locally advanced nasopharyngeal cancer patients

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Abstract

Purpose

We aimed to determine whether pretreatment hemoglobin (Hb) levels can predict the risk of osteoradionecrosis (ORN) in patients receiving concurrent chemoradiotherapy (CCRT) for locally advanced nasopharyngeal carcinoma (LA-NPC).

Methods

ORN cases were identified from the records of LA-NPCs who had oral exams before and after CCRT. All Hb measurements were obtained on the first day of treatment. Receiving operating characteristic curve analysis was used to determine the relationship between Hb levels and ORN rates. The relationship between pretreatment Hb levels and ORN rates served as the primary endpoint, and secondary endpoints included the discovery of additional potential ORN risk factors.

Results

Among the 263 eligible LA-NPCs, we identified 8.7% ORN cases. The ideal cutoff Hb before CCRT was 10.6 g/dL. It was revealed that HPR ≤ 10.6 group had a significantly higher ORN rate (32.5% vs. 1.5% for Hb > 10.6; P < 0.001). The mandibular V59.8 ≥ 36% Gy, pre-CCRT ≥ 4 tooth extractions, the presence of post-CCRT tooth extractions, and the time of post-CCRT tooth extractions > 8 months were the other factors associated with significantly increased ORN rates (P < 0.05 for each).

Conclusion

Low pre-CCRT Hb levels appeared to be independently linked to significantly higher ORN rates. Pretreatment Hb levels may be used to establish preventive measures and predict ORN.

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Availability of data and materials

Data cannot be shared publicly because the data is owned and saved by Baskent University Medical Faculty. Data are available from the Baskent University Radiation Oncology Institutional Data Access / Ethics Committee (contact via Baskent University Ethics Committee) for researchers who meet the criteria for access to confidential data: contact address, adanabaskent@baskent.edu.tr.

Abbreviations

ADA:

American Dental Association

AJCC:

American Joint Cancer Committee

AUC:

Area under the curve

CCRT:

Concurrent chemoradiotherapy

CT:

Computed tomography

18-FDG-PET–CT:

18-Fluorodeoxyglucose-positron emission tomography/computed tomography

FDA:

US Food and Drug Administration

Gy:

Gray

Hb:

Hemoglobin

HIF-1:

Hypoxia-induced factor-1

HNC:

Head and neck cancer

IMRT:

Intensity-modulated RT

LA-NPC:

Locally advanced nasopharyngeal carcinoma

MMD:

Mean mandibular dose

MMPD:

Maximum mandibular point dose

N:

Node

NPC:

Nasopharyngeal carcinoma

ORN:

Osteoradionecrosis

PTVs:

Planning target volumes

ROC:

Receiver operating characteristic

RT:

Radiotherapy

SIB-IMRT:

Simultaneous integrated boost intensity-modulated RT

T:

Tumor

TGF-α, TGF-β:

Transforming growth factor

V59.8:

Volume receiving ≥ 59.8 Gy

VEGF:

Vascular endothelial growth factor

References

  1. Baujat B, Audry H, Bourhis J, Chan AT, Onat H, Chua DT et al (2006) Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients. Int J Radiat Oncol Biol Phys 64:47–56

    Article  CAS  PubMed  Google Scholar 

  2. De Felice F, Musio D, Terenzi V, Valentini V, Cassoni A, Tombolini M et al (2014) Treatment improvement and better patient care: which is the most important one in oral cavity cancer? Radiat Oncol 9:263

    Article  PubMed  PubMed Central  Google Scholar 

  3. De Felice F, de Vincentiis M, Luzzi V, Magliulo G, Tombolini M, Ruoppolo G et al (2018) Late radiation-associated dysphagia in head and neck cancer patients: evidence, research and management. Oral Oncol 77:125–130

    Article  PubMed  Google Scholar 

  4. Bras J, de Jonge HK, van Merkesteyn JP (1990) Osteoradionecrosis of the mandible: pathogenesis. Am J Otolaryngol 11:244–250

    Article  CAS  PubMed  Google Scholar 

  5. Ben-David MA, Diamante M, Radawski JD, Vineberg KA, Stroup C, Murdoch-Kinch CA et al (2007) Lack of Osteoradionecrosis of the Mandible after IMRT for head and neck cancer: likely contributions of both dental care and improved dose distribution. Int J Radiat Oncol Biol Phys 68:392–402

    Article  Google Scholar 

  6. Beumer J, Harrison R, Sanders B, Kurrasch M (1983) Postradiation dental extractions: a review of the literature and a report of 72 episodes. Head Neck Surg 6:581–586

    Article  PubMed  Google Scholar 

  7. Jawad H, Hodson NA, Nixon PJ (2015) A review of dental treatment of head and neck cancer patients, before, during and after radiotherapy: part 1. Br Dent J 218:65–68

    Article  CAS  PubMed  Google Scholar 

  8. Jawad H, Hodson NA, Nixon PJ (2015) A review of dental treatment of head and neck cancer patients, before, during and after radiotherapy: part 2. Br Dent J 218:69–74

    Article  CAS  PubMed  Google Scholar 

  9. Pignon JP, le Maître A, Maillard E, Bourhis J, MACH-NC Collaborative Group (2009) Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 92:4–14

    Article  PubMed  Google Scholar 

  10. Meleca JB, Zhang E, Fritz MA, Ciolek PJ (2021) Overview and emerging trends in the treatment of osteoradionecrosis. Curr Treat Options Oncol 22:115

    Article  Google Scholar 

  11. Chrcanovic BR, Albrektsson T, Wennerberg A (2016) Dental implants in irradiated versus nonirradiated patients: a meta-analysis. Head Neck 38:448–441

    Article  PubMed  Google Scholar 

  12. Buglione M, Cavagnini R, Di Rosario F, Sottocornola L, Maddalo M, Vassalli L et al (2016) Oral toxicity management in head and neck cancer patients treated with chemotherapy and radiation: Dental pathologies and osteoradionecrosis (Part 1) literature review and consensus statement. Crit Rev Oncol Hematol 97:131–142

    Article  PubMed  Google Scholar 

  13. Caparrotti F, Huang SH, Lu L, Bratman SV, Ringash J, Bayley A et al (2017) Osteoradionecrosis of the mandible in patients with oropharyngeal carcinoma treated with intensity-modulated radiotherapy. Cancer 123:3691–3700

    Article  PubMed  Google Scholar 

  14. Oh HK, Chambers MS, Garden AS, Wong PF, Martin JW (2004) Risk of osteoradionecrosis after extraction of impacted third molars in irradiated head and neck cancer patients. J Oral Maxillofac Surg 62:139–144

    Article  PubMed  Google Scholar 

  15. Costantino PD, Friedman CD, Steinberg MJ (1995) Irradiated bone and its management. Otolaryngol Clin North Am 28:1021–1038

    Article  CAS  PubMed  Google Scholar 

  16. Thorn JJ, Hansen HS, Specht L, Bastholt L (2000) Osteoradionecrosis of the jaws: clinical characteristics and relation to the field of irradiation. J Oral Maxillofac Surg 58:1088–1095

    Article  CAS  PubMed  Google Scholar 

  17. Horiot JC, Bone MC, Ibrahim E, Castro JR (1981) Systematic dental management in head and neck irradiation. Int J Radiat Oncol Biol Phys 7:1025–1029

    Article  CAS  PubMed  Google Scholar 

  18. Marx RE (1983) Osteoradionecrosis: a new concept of its pathophysiology. J Oral Maxillofac Surg 41:283–288

    Article  CAS  PubMed  Google Scholar 

  19. Xu J, Zheng Z, Fang D, Gao R, Liu Y, Fan ZP et al (2012) Early-stage pathogenic sequence of jaw osteoradionecrosis in vivo. J Dent Res 91:702–708

    Article  CAS  PubMed  Google Scholar 

  20. Helvaci MR, Aydogan A, Akkucuk S, Oruc C, Ugur M (2014) Sickle cell diseases and ileus. Int J Clin Exp Med 7:2871–2876

    PubMed  PubMed Central  Google Scholar 

  21. Darby IA, Hewitson TD (2016) Hypoxia in tissue repair and fibrosis. Cell Tissue Res 365:553–562

    Article  CAS  PubMed  Google Scholar 

  22. Chrcanovic BR, Reher P, Sousa AA, Harris M (2010) Osteoradionecrosis of the jaws–a current overview–part 1: physiopathology and risk and predisposing factors. Oral Maxillofac Surg 14:3–16

    Article  PubMed  Google Scholar 

  23. Dhanda J, Pasquier D, Newman L, Shaw R (2016) Current concepts in osteoradionecrosis after head and neck radiotherapy. Clin Oncol (R Coll Radiol) 28:459–466

    Article  CAS  PubMed  Google Scholar 

  24. Castillo-Rodríguez RA, Trejo-Solís C, Cabrera-Cano A, Gómez-Manzo S, Dávila-Borja VM (2022) Hypoxia as a modulator of inflammation and immune response in cancer. Cancers (Basel) 14:2291

    Article  PubMed  Google Scholar 

  25. Beresford MJ, Burcombe R, Ah-See ML, Stott D, Makris A (2006) Pre-treatment haemoglobin levels and the prediction of response to neoadjuvant chemotherapy in breast cancer. Clin Oncol (R Coll Radiol) 18:453–458

    Article  CAS  PubMed  Google Scholar 

  26. Zheng YY, Wu TT, Chen Y, Hou XG, Yang Y, Zhang JY et al (2020) Platelet-to-hemoglobin ratio as a novel predictor of long-term adverse outcomes in patients after percutaneous coronary intervention: a retrospective cohort study. Eur J Prev Cardiol 27:2216–2219

    Article  PubMed  Google Scholar 

  27. Mori K, Janisch F, Mostafaei H, Lysenko I, Karakiewicz PI, Enikeev DV et al (2020) Prognostic value of hemoglobin in metastatic hormone-sensitive prostate cancer: a systematic review and meta-analysis. Clin Genitourin Cancer 18(4):e402–e409

    Article  PubMed  Google Scholar 

  28. Eichbaum MH, Weiss LM, Bruckner T, Schneeweiss A, Sinn HP, Gebauer G et al (2009) Prognostic impact of hemoglobin levels before and during carboplatin/taxane-based chemotherapy in patients with primary invasive epithelial ovarian cancer. Med Sci Monit 15(4):C156-163

    Google Scholar 

  29. Zeng Q, Shen LJ, Li S, Chen L, Guo X, Qian CN, Wu PH (2016) The effects of hemoglobin levels and their interactions with cigarette smoking on survival in nasopharyngeal carcinoma patients. Cancer Med 5(5):816–826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Montgomery J, Syed MI, Rana I, Singh J, Clark LJ (2010) Hemoglobin monitoring in head and neck cancer patients undergoing radiotherapy. Ann Otol Rhinol Laryngol 119(7):472–475

    Article  PubMed  Google Scholar 

  31. Hoff CM (2012) Importance of hemoglobin concentration and its modification for the outcome of head and neck cancer patients treated with radiotherapy. Acta Oncol 51(4):419–432

    Article  CAS  PubMed  Google Scholar 

  32. Lee G, Choi S, Kim K, Yun JM, Son JS, Jeong SM et al (2018) Association of hemoglobin concentration and its change with cardiovascular and all-cause mortality. J Am Heart Assoc 7(3):e007723

    Article  PubMed  PubMed Central  Google Scholar 

  33. Ataga KI, Gordeuk VR, Agodoa I, Colby JA, Gittings K, Allen IE (2020) Low hemoglobin increases risk for cerebrovascular disease, kidney disease, pulmonary vasculopathy, and mortality in sickle cell disease: a systematic literature review and meta-analysis. PLoS ONE 15(4):e0229959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. White SC, Pharoah MJ (2018) Oral radiology-E-book: principles and interpretation. Elsevier, St. Louis, pp 808–832

    Google Scholar 

  35. World Health Organization (1968) Nutritional anemias. Report of a WHO scientific group. World Health Tech Organ Report Series 405

  36. Yilmaz B, Somay E, Selek U, Topkan E (2021) Pretreatment systemic immune-inflammation index predict needs for teeth extractions for locally advanced head and neck cancer patients undergoing concurrent chemoradiotherapy. Ther Clin Risk Manag 17:1113–1121

    Article  PubMed  PubMed Central  Google Scholar 

  37. Notani K, Yamazaki Y, Kitada H, Sakakibara N, Fukuda H, Omori K et al (2003) Management of mandibular osteoradionecrosis corresponding to the severity of osteoradionecrosis and the method of radiotherapy. Head Neck 25:181–186

    Article  PubMed  Google Scholar 

  38. Moon DH, Moon SH, Wang K, Weissler MC, Hackman TG, Zanation AM et al (2017) Incidence of, and risk factors for, mandibular osteoradionecrosis in patients with oral cavity and oropharynx cancers. Oral Oncol 72:98–103

    Article  PubMed  Google Scholar 

  39. Reuther T, Schuster T, Mende U, Kübler A (2003) Osteoradionecrosis of the jaws as a side effect of radiotherapy of head and neck tumour patients–a report of a thirty year retrospective review. Int J Oral Maxillofac Surg 32:289–295

    Article  CAS  PubMed  Google Scholar 

  40. Owosho AA, Tsai CJ, Lee RS, Freymiller H, Kadempour A, Varthis S et al (2017) The prevalence and risk factors associated with osteoradionecrosis of the jaw in oral and oropharyngeal cancer patients treated with intensity-modulated radiation therapy (IMRT): the Memorial Sloan Kettering Cancer Center experience. Oral Oncol 64:44–51

    Article  PubMed  Google Scholar 

  41. Aarup-Kristensen S, Hansen CR, Forner L, Brink C, Eriksen JG, Johansen J (2019) Osteoradionecrosis of the mandible after radiotherapy for head and neck cancer: risk factors and dose-volume correlations. Acta Oncol 58:1373–1377

    Article  CAS  PubMed  Google Scholar 

  42. Khoo SC, Nabil S, Fauzi AA, Yunus SSM, Ngeow WC, Ramli R (2021) Predictors of osteoradionecrosis following irradiated tooth extraction. Radiat Oncol 16:130

    Article  PubMed  PubMed Central  Google Scholar 

  43. Wang TH, Liu CJ, Chao TF, Chen TJ, Hu YW (2017) Risk factors for and the role of dental extractions in osteoradionecrosis of the jaws: a national-based cohort study. Head Neck 39:1313–1321

    Article  PubMed  Google Scholar 

  44. Jiang Y, Zhu X, Qu S (2014) Incidence of osteoradionecrosis in patients who have undergone dental extraction prior to radiotherapy: a systematic review and meta-analysis. J Oral Maxillofac Surg Med Pathol 26:269–275

    Article  Google Scholar 

  45. Nabil S, Samman N (2011) Incidence and prevention of osteoradionecrosis after dental extraction in irradiated patients: a systematic review. Int J Oral Maxillofac Surg 40:229–243

    Article  CAS  PubMed  Google Scholar 

  46. Dumoulin S, van Maanen A, Magremanne M (2021) Dental prevention of maxillo-mandibular osteoradionecrosis: a ten-year retrospective study. J Stomatol Oral Maxillofac Surg 122(2):127–134

    Article  CAS  PubMed  Google Scholar 

  47. Kuo TJ, Leung CM, Chang HS, Wu CN, Chen WL, Chen GJ et al (2016) Jaw osteoradionecrosis and dental extraction after head and neck radiotherapy: a nationwide population-based retrospective study in Taiwan. Oral Oncol 56:71–77

    Article  PubMed  Google Scholar 

  48. Dutheil F, Guillemin F, Biau J, Pham-Dang N, Saroul N, Clavère P, Lapeyre M (2021) Facteurs prédictifs de l’ostéoradionécrose mandibulaire après irradiation des cancers des voies aérodigestives supérieures [Predictive factors for mandibular osteoradionecrosis after irradiation of head and neck cancers]. Cancer Radiother 25(5):484–493

    Article  CAS  PubMed  Google Scholar 

  49. Topkan E, Ekici NY, Ozdemir Y, Besen AA, Yildirim BA, Mertsoylu H et al (2019) Baseline hemoglobin < 110 g/dL has stronger prognostic value than anemia status in nasopharynx cancers treated with chemoradiotherapy. Int J Biol Markers 34(2):139–147

    Article  CAS  PubMed  Google Scholar 

  50. Chapchay K, Weinberger J, Eliashar R, Adler N (2019) Anterior skull base reconstruction following ablative surgery for osteoradionecrosis: case report and review of literature. Ann Otol Rhinol Laryngol 128:1134–1140

    Article  PubMed  Google Scholar 

  51. Albisinni S, Pretot D, Al Hajj Obeid W, Aoun F, Quackels T, Peltier A et al (2019) The impact of neutrophil-to-lymphocyte, platelet-to-lymphocyte and haemoglobin-to-platelet ratio on localised renal cell carcinoma oncologic outcomes. Prog Urol 29:423–431

    Article  CAS  PubMed  Google Scholar 

  52. Ji C, Su Y, Zhang C, Huang W (2015) Reference intervals for hemoglobin and age- and gender-related trends in the population of southwest China. Clin Lab 61(12):1831–1836

    CAS  PubMed  Google Scholar 

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Acknowledgements

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Funding

This research did not receive any specific Grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Oral and Maxillofacial Radiology, Faculty of Dentistry, Baskent University, Ankara, Turkey

    Busra Yilmaz

  2. Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Baskent University, Adana, Turkey

    Efsun Somay

  3. Department of Radiation Oncology, Faculty of Medicine, Baskent University, Adana, Turkey

    Erkan Topkan

  4. Department of Radiation Oncology, Bahcesehir University, Istanbul, Turkey

    Berrin Pehlivan

  5. Department of Radiation Oncology, School of Medicine, Koc University, Istanbul, Turkey

    Ugur Selek

  6. Department of Radiation Oncology, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA

    Ugur Selek

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  1. Busra Yilmaz
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All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

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Yilmaz, B., Somay, E., Topkan, E. et al. Pre-chemoradiotherapy low hemoglobin levels indicate increased osteoradionecrosis risk in locally advanced nasopharyngeal cancer patients. Eur Arch Otorhinolaryngol 280, 2575–2584 (2023). https://doi.org/10.1007/s00405-023-07864-7

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