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High-grade acute organ toxicity and p16INK4A expression as positive prognostic factors in primary radio(chemo)therapy for patients with head and neck squamous cell carcinoma

Höhergradige akute Organtoxizität und p16INK4A Expression als positiver prognostischer Faktor bei der primären Radio(chemo)therapie für Patienten mit Kopf-Hals-Tumoren

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Abstract

Background

Superior treatment response and survival for patients with human papilloma virus (HPV)-positive head and neck cancer (HNSCC) are documented in clinical studies. However, the relevance of high-grade acute organ toxicity (HGAOT), which has also been correlated with improved prognosis, has attracted scant attention in HPV-positive HNSCC patients. Hence we tested the hypothesis that both parameters, HPV and HGAOT, are positive prognostic factors in patients with HNSCC treated with definite radiotherapy (RT) or radiochemotherapy (RCT).

Patients and methods

Pretreatment tumor tissue and clinical records were available from 233 patients receiving definite RT (62 patients) or RCT (171 patients). HPV infection was analysed by means of HPV DNA detection or p16INK4A expression; HGAOT was defined as the occurrence of acute organ toxicity >grade 2 according to the Common Toxicity Criteria. Both variables were correlated with overall survival (OS) using Cox proportional hazards regression.

Results

Positivity for HPV DNA (44 samples, 18.9 %) and p16INK4A expression (102 samples, 43.8 %) were significantly correlated (p < 0.01), and HGAOT occurred in 77 (33 %) patients. Overall, the 5-year OS was 23 %; stratified for p16INK4A expression and HGAOT, OS rates were 47 %, 42 %, 20 % and 10 % for patients with p16INK4A expression and HGAOT, patients with HGAOT only, patients with p16INK4A expression only, and patients without p16INK4A expression or HGAOT, respectively. After multivariate testing p16INK4A expression (p = 0.003) and HGAOT (p < 0.001) were significantly associated with OS.

Conclusion

P16INK4A expression and HGAOT are independent prognostic factors for OS of patients with HNSCC, whereas p16INK4A expression is particularly important for patients without HGAOT.

Zusammenfassung

Hintergrund

Ein besseres Therapieansprechen von humanen Papillomavirus (HPV)-positiven Kopf-Hals-Tumoren (HNSCC) ist durch Studien belegt. Weniger Beachtung hat bisher die Relevanz unerwünschter Therapienebenwirkungen bei diesem Kollektiv gefunden. Für andere Patientenkollektive ist die Korrelation einer höhergradigen akuten Organtoxizität (HGAOT) mit einem längeren Gesamtüberleben (OS) beschrieben. Wir prüften die Hypothese, dass HPV und HGAOT positive prognostische Faktoren bei Patienten mit HNSCC nach primärer Strahlentherapie oder Radiochemotherapie sind.

Patienten und Methodik

Von 233 Patienten, die mit einer primären Radiotherapie (62 Patienten) oder Radiochemotherapie (171 Patienten) behandelt wurden, standen umfassende klinische Daten und Tumormaterial als Paraffinblöcke zur Verfügung. Der HPV-Nachweis wurde immunhistochemisch als p16INK4A-Expression oder mittels PCR/nested PCR für Virus-DNA geführt. HGAOT wurde als das Auftreten einer Mukositis, Hautreaktion, Dysphagie oder Übelkeit > Grad 2 nach Common Toxicity Criteria definiert. Der Zusammenhang beider Variablen mit dem Gesamtüberleben wurde mittels Cox-Regression analysiert.

Ergebnisse

In 102 (43,8 %) Tumorgewebeschnitten wurde p16INK4A nachgewiesen, HPV-DNA wurde in 44 Proben gefunden, wobei sich eine signifikante Korrelation zwischen der p16INK4A- und der HPV-DNA-Expression zeigte (p < 0,001). Insgesamt betrug das 5-Jahres-OS 23 %, bei Stratifizierung nach p16INK4A-Expression und dem Auftreten von HGAOT zeigten sich signifikante Abstufungen bezüglich des OS: HGAOT + p16INK4A 47 % OS, nur HGOAT 42 % OS, nur p16INK4A 20 % OS und kein Merkmal 10 % OS – jeweils nach 5 Jahren. Sowohl die p16INK4A-Expression als auch HGAOT waren signifikant mit dem Gesamtüberleben korreliert.

Schlussfolgerung

Das Auftreten einer HGAOT ist auch für p16INK4A- bzw. HPV-positive Patienten mit HNSCC ein positiver prognostischer Faktor, wobei akute Organtoxizitäten > Grad 2 mit einem signifikant verlängerten OS korreliert sind.

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Acknowledgements

We would like to thank Anke Klages, Judita Wolf-Salgo and Alexandra Bitter for expert technical assistance.

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Authors and Affiliations

  1. Department of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany

    Narges Tehrany, Margret Rave-Fränk PhD, Clemens F. Hess MD, PhD &  Hendrik A. Wolff MD

  2. Department of Pathology, University Medical Center Göttingen, Göttingen, Germany

    Julia Kitz MD, Li Li PhD & Stefan Küffer

  3. Department of Medical Statistics, University Medical Center, Göttingen, Germany

    Stephan Lorenzen PhD & Tim Beißbarth PhD

  4. Institute for Human Genetics, University Medical Center, Göttingen, Germany

    Peter Burfeind PhD

  5. Institute for Cellular and Molecular Immunology, University Medical Center, Göttingen, Germany

    Holger M. Reichardt PhD

  6. Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center Göttingen, Göttingen, Germany

    Martin Canis MD

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  1. Narges Tehrany
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  2. Julia Kitz MD
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  7. Clemens F. Hess MD, PhD
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  12. Hendrik A. Wolff MD
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Corresponding author

Correspondence to Hendrik A. Wolff MD.

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Conflict of interest

N. Tehrany, J. Kitz, M. Rave-Fränk, S. Lorenzen, L. Li, S. Küffer, C.F. Hess, P. Burfeind, H.M. Reichardt, M. Canis, T. Beißbarth, and H.A. Wolff state that there are no conflicts of interest.

We performed a retrospective study on patient probes (formalin-fixed paraffin-embedded (FFPE) pretreatment tumour tissue) and used patient data. The study was approved as mentioned in “Patients and methods”. Animals were not used.

Additional information

H. A. Wolff and T. Beißbarth contributed equally to this work.

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Tehrany, N., Kitz, J., Rave-Fränk, M. et al. High-grade acute organ toxicity and p16INK4A expression as positive prognostic factors in primary radio(chemo)therapy for patients with head and neck squamous cell carcinoma. Strahlenther Onkol 191, 566–572 (2015). https://doi.org/10.1007/s00066-014-0801-3

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