Tumor volume as a prognostic marker in p16-positive and p16-negative oropharyngeal cancer patients treated with definitive intensity-modulated radiotherapy

  • Timo Carpén
  • Kauko Saarilahti
  • Caj Haglund
  • Antti Markkola
  • Jussi Tarkkanen
  • Jaana Hagström
  • Petri Mattila
  • Antti Mäkitie
Original Article

Abstract

Purpose

To investigate the impact of primary gross tumor volume (pGTV) and nodal gross tumor volume (nGTV) in oropharyngeal squamous cell carcinoma (OPSCC) and the difference in their role between human papillomavirus (HPV)-positive and HPV-negative patients.

Methods

The patient cohort consists of 91 OPSCC patients treated with definitive radiochemotherapy or radiotherapy using intensity-modulated radiotherapy (IMRT). All patients had a minimum follow-up of 31 months. Volume measurements were made from computer tomography (CT) scans and HPV status was assessed by p16 immunohistochemistry. The end points were as follows: overall survival (OS), disease-free survival (DFS) and locoregional control (LRC).

Results

pGTV was a significant independent prognostic factor for overall survival (OS; p = 0.020) in p16-negative patients. nGTV of p16-negative tumors had significant prognostic value in all end points in multivariate analyses. High-stage (III–IVc) p16-negative tumors were only associated with significantly poorer OS (p = 0.046) but not with poorer LRC or DFS when compared with the low-stage (I–II) tumors. nGTV of p16-positive tumors was an independent prognostic factor for DFS (p = 0.005) and LRC (p = 0.007) in multivariate analyses.

Conclusion

pGTV may serve as an independent prognostic factor in p16-negative patients and nGTV may serve as an independent prognostic factor both in p16-positive and p16-negative patients treated with radiochemotherapy or radiotherapy using IMRT. Tumor volume may have an impact on selecting patients for de-escalation protocols in the future, both in p16-positive and p16-negative patients.

Keywords

Human papillomavirus Survival Oncology Radiochemotherapy Marker 

Tumorvolumen als prognostischer Marker bei p16-positiven und p16-negativen Patienten mit Oropharyngealkarzinom unter Therapie mit definitiver intensitätsmodulierter Strahlentherapie

Zusammenfassung

Zielstellung

Ziel war es, die Bedeutung des makroskopischen Tumorvolumens des Primärtumors („primary gross tumor volume“, pGTV) und des makroskopischen Tumorvolumens der Lymphknoten („nodal gross tumor volume“, nGTV) bei Plattenepithelkarzinomen des Oropharynx („oropharyngeal squamous cell carcinoma“, OPSCC) und deren Unterschiede zwischen für humanes Papillomavirus (HPV) positiven und HPV-negativen Patienten zu untersuchten.

Methoden

In die Studie eingeschlossen wurden 91 OPSCC-Patienten, die mit definitiver intensitätsmodulierter Strahlentherapie („intensity-modulated radiotherapy“, IMRT) mit oder ohne gleichzeitige Chemotherapie behandelt wurden. Bei allen Patienten betrug der Nachbeobachtungszeitraum mindestens 31 Monate. Die Volumenmessungen erfolgten anhand von Computertomographie(CT)-Aufnahmen. Der HPV-Status wurde durch die p16-Immunhistochemie ermittelt. Die Endpunkte waren Gesamtüberleben („overall survival“, OS), krankheitsfreies Überleben („disease-free survival“, DFS) und lokoregionale Kontrolle („locoregional control“, LRC).

Ergebnisse

Das pGTV war ein signifikanter unabhängiger prognostischer Faktor für das OS (p = 0,20) bei p16-negativen Patienten. Das nGTV von p16-negativen Tumoren wies einen signifikanten prognostischen Wert für alle Endpunkte in multivariaten Analysen auf. p16-negative Tumoren in hohen Stadien (III-IVc) waren im Vergleich zu den Tumoren in niedrigeren Stadien (I‑II) nur mit einem signifikant schlechteren OS (p = 0,046), nicht aber mit schlechteren Werten für LRC oder DFS assoziiert. Das nGTV von p16-negativen Tumoren erwies sich in multivariaten Analysen als unabhängiger prognostischer Faktor für DFS (p = 0,005) und LRC (p = 0,007).

Schlussfolgerung

Das pGTV kann als unabhängiger prognostischer Faktor bei p16-negativen Patienten und das nGTV als unabhängiger prognostischer Faktor sowohl bei p16-positiven als auch bei p16-negativen Patienten dienen, bei denen eine Radiochemotherapie oder Strahlentherapie unter Verwendung der IMRT erfolgt. Das Tumorvolumen kann bei der Auswahl der Patienten für ein Deeskalationsprotokoll sowohl bei p16-positiven als auch bei p16-negativen Patienten eine Rolle spielen.

Schlüsselwörter

Humanes Papillomavirus Überleben Onkologie Radiochemotherapie Marker 

Notes

Acknowledgements

This study was supported by grants from the Helsinki University Hospital Research Fund and the Finska Läkaresällskapet.

Compliance with ethical guidelines

Conflict of interest

T. Carpén, K. Saarilahti, C. Haglund, A. Markkola, J. Tarkkanen, J. Hagström, P. Mattila, and A. Mäkitie declare that they have no competing interests.

Ethical standards

This article does not contain any studies with human participants or animals performed by any of the authors. Consent was obtained from all patients identifiable from images or other information within the manuscript. In the case of underage patients, consent was obtained from a parent or legal guardian.

References

  1. 1.
    Chao KS, Ozyigit G, Blanco AI, Thorstad WL, Deasy JO, Haughey BH, Spector GJ, Sessions DG (2004) Intensity-modulated radiation therapy for oropharyngeal carcinoma: impact of tumor volume. Int J Radiat Oncol Biol Phys 59(1):43–50.  https://doi.org/10.1016/j.ijrobp.2003.08.004 CrossRefPubMedGoogle Scholar
  2. 2.
    Chen SW, Yang SN, Liang JA, Lin FJ, Tsai MH (2009) Prognostic impact of tumor volume in patients with stage III–IVA hypopharyngeal cancer without bulky lymph nodes treated with definitive concurrent chemoradiotherapy. Head Neck 31(6):709–716.  https://doi.org/10.1002/hed.21011 CrossRefPubMedGoogle Scholar
  3. 3.
    Lok BH, Setton J, Caria N, Romanyshyn J, Wolden SL, Zelefsky MJ, Park J, Rowan N, Sherman EJ, Fury MG, Ho A, Pfister DG, Wong RJ, Shah JP, Kraus DH, Zhang Z, Schupak KD, Gelblum DY, Rao SD, Lee NY (2012) Intensity-modulated radiation therapy in oropharyngeal carcinoma: effect of tumor volume on clinical outcomes. Int J Radiat Oncol Biol Phys 82(5):1851–1857.  https://doi.org/10.1016/j.ijrobp.2011.03.029 CrossRefPubMedGoogle Scholar
  4. 4.
    He YX, Wang Y, Cao PF, Shen L, Zhao YJ, Zhang ZJ, Chen DM, Yang TB, Huang XQ, Qin Z, Dai YY, Shen LF (2016) Prognostic value and predictive threshold of tumor volume for patients with locally advanced nasopharyngeal carcinoma receiving intensity-modulated radiotherapy. Chin J Cancer 35(1):96.  https://doi.org/10.1186/s40880-016-0159-2 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Linge A, Lohaus F, Lock S, Nowak A, Gudziol V, Valentini C, von Neubeck C, Jutz M, Tinhofer I, Budach V, Sak A, Stuschke M, Balermpas P, Rodel C, Grosu AL, Abdollahi A, Debus J, Ganswindt U, Belka C, Pigorsch S, Combs SE, Monnich D, Zips D, Buchholz F, Aust DE, Baretton GB, Thames HD, Dubrovska A, Alsner J, Overgaard J, Krause M, Baumann M, DKTK-ROG (2016) HPV status, cancer stem cell marker expression, hypoxia gene signatures and tumour volume identify good prognosis subgroups in patients with HNSCC after primary radiochemotherapy: A multicentre retrospective study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG). Radiother Oncol 121(3):364–373.  https://doi.org/10.1016/j.radonc.2016.11.008 CrossRefPubMedGoogle Scholar
  6. 6.
    Studer G, Lutolf UM, El-Bassiouni M, Rousson V, Glanzmann C (2007) Volumetric staging (VS) is superior to TNM and AJCC staging in predicting outcome of head and neck cancer treated with IMRT. Acta Oncol 46(3):386–394.  https://doi.org/10.1080/02841860600815407 CrossRefPubMedGoogle Scholar
  7. 7.
    Doweck I, Denys D, Robbins KT (2002) Tumor volume predicts outcome for advanced head and neck cancer treated with targeted chemoradiotherapy. Laryngoscope 112(10):1742–1749.  https://doi.org/10.1097/00005537-200210000-00006 CrossRefPubMedGoogle Scholar
  8. 8.
    Rutkowski T (2014) The role of tumor volume in radiotherapy of patients with head and neck cancer. Radiat Oncol 9:23.  https://doi.org/10.1186/1748-717x-9-23 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Strongin A, Yovino S, Taylor R, Wolf J, Cullen K, Zimrin A, Strome S, Regine W, Suntharalingam M (2012) Primary tumor volume is an important predictor of clinical outcomes among patients with locally advanced squamous cell cancer of the head and neck treated with definitive chemoradiotherapy. Int J Radiat Oncol Biol Phys 82(5):1823–1830.  https://doi.org/10.1016/j.ijrobp.2010.10.053 CrossRefPubMedGoogle Scholar
  10. 10.
    Knegjens JL, Hauptmann M, Pameijer FA, Balm AJ, Hoebers FJ, de Bois JA, Kaanders JH, van Herpen CM, Verhoef CG, Wijers OB, Wiggenraad RG, Buter J, Rasch CR (2011) Tumor volume as prognostic factor in chemoradiation for advanced head and neck cancer. Head Neck 33(3):375–382.  https://doi.org/10.1002/hed.21459 PubMedGoogle Scholar
  11. 11.
    Brenner DJ (1993) Dose, volume, and tumor-control predictions in radiotherapy. Int J Radiat Oncol Biol Phys 26(1):171–179CrossRefPubMedGoogle Scholar
  12. 12.
    Dubben HH, Thames HD, Beck-Bornholdt HP (1998) Tumor volume: a basic and specific response predictor in radiotherapy. Radiother Oncol 47(2):167–174CrossRefPubMedGoogle Scholar
  13. 13.
    Johnson CR, Thames HD, Huang DT, Schmidt-Ullrich RK (1995) The tumor volume and clonogen number relationship: tumor control predictions based upon tumor volume estimates derived from computed tomography. Int J Radiat Oncol Biol Phys 33(2):281–287CrossRefPubMedGoogle Scholar
  14. 14.
    Yang SN, Chiou YR, Zhang GG, Chou KT, Huang TC (2017) The clinical outcome correlations between radiation dose and pretreatment metabolic tumor volume for radiotherapy in head and neck cancer: a retrospective analysis. Medicine (Baltimore) 96(26):e7186.  https://doi.org/10.1097/MD.0000000000007186 CrossRefGoogle Scholar
  15. 15.
    Edge SBBD, Compton CC, Fritz AG, Greene FL, Trotti A (2010) AJCC cancer staging manual, 7th edn. Springer, New YorkGoogle Scholar
  16. 16.
    Edge SB, Compton CC (2010) The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 17(6):1471–1474.  https://doi.org/10.1245/s10434-010-0985-4 CrossRefPubMedGoogle Scholar
  17. 17.
    Davis KS, Lim CM, Clump DA, Heron DE, Ohr JP, Kim S, Duvvuri U, Johnson JT, Ferris RL (2016) Tumor volume as a predictor of survival in human papillomavirus-positive oropharyngeal cancer. Head Neck 38(Suppl 1):E1613–1617.  https://doi.org/10.1002/hed.24287 CrossRefPubMedGoogle Scholar
  18. 18.
    Hermans R, Op de beeck K, Van den Bogaert W, Rijnders A, Staelens L, Feron M, Bellon E (2001) The relation of CT-determined tumor parameters and local and regional outcome of tonsillar cancer after definitive radiation treatment. Int J Radiat Oncol Biol Phys 50(1):37–45CrossRefPubMedGoogle Scholar
  19. 19.
    Lydiatt WM, Patel SG, O’Sullivan B, Brandwein MS, Ridge JA, Migliacci JC, Loomis AM, Shah JP (2017) Head and Neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin 67(2):122–137.  https://doi.org/10.3322/caac.21389 CrossRefPubMedGoogle Scholar
  20. 20.
    Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, Sullivan DC, Jessup JM, Brierley JD, Gaspar LE, Schilsky RL, Balch CM, Winchester DP, Asare EA, Madera M, Gress DM, Meyer LR (2017) AJCC cancer staging manual, 8th edn. Springer, New YorkCrossRefGoogle Scholar
  21. 21.
    Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, Westra WH, Chung CH, Jordan RC, Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP, Gillison ML (2010) Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363(1):24–35.  https://doi.org/10.1056/NEJMoa0912217 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Gillison ML, D’Souza G, Westra W, Sugar E, Xiao W, Begum S, Viscidi R (2008) Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst 100(6):407–420.  https://doi.org/10.1093/jnci/djn025 CrossRefPubMedGoogle Scholar
  23. 23.
    Mehanna H, Beech T, Nicholson T, El-Hariry I, McConkey C, Paleri V, Roberts S (2013) Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer—systematic review and meta-analysis of trends by time and region. Head Neck 35(5):747–755.  https://doi.org/10.1002/hed.22015 CrossRefPubMedGoogle Scholar
  24. 24.
    D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM, Westra WH, Gillison ML (2007) Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 356(19):1944–1956.  https://doi.org/10.1056/NEJMoa065497 CrossRefPubMedGoogle Scholar
  25. 25.
    Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, Forastiere A, Gillison ML (2008) Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 100(4):261–269.  https://doi.org/10.1093/jnci/djn011 CrossRefPubMedGoogle Scholar
  26. 26.
    Bird D, Scarsbrook AF, Sykes J, Ramasamy S, Subesinghe M, Carey B, Wilson DJ, Roberts N, McDermott G, Karakaya E, Bayman E, Sen M, Speight R, Prestwich RJ (2015) Multimodality imaging with CT, MR and FDG-PET for radiotherapy target volume delineation in oropharyngeal squamous cell carcinoma. BMC Cancer 15:844.  https://doi.org/10.1186/s12885-015-1867-8 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Emami B, Sethi A, Petruzzelli GJ (2003) Influence of MRI on target volume delineation and IMRT planning in nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 57(2):481–488.  https://doi.org/10.1016/s0360-3016(03)00570-4 CrossRefPubMedGoogle Scholar
  28. 28.
    van den Brekel MW, Stel HV, Castelijns JA, Nauta JJ, van der Waal I, Valk J, Meyer CJ, Snow GB (1990) Cervical lymph node metastasis: assessment of radiologic criteria. Radiology 177(2):379–384.  https://doi.org/10.1148/radiology.177.2.2217772 CrossRefPubMedGoogle Scholar
  29. 29.
    Cantrell SC, Peck BW, Li G, Wei Q, Sturgis EM, Ginsberg LE (2013) Differences in imaging characteristics of HPV-positive and HPV-Negative oropharyngeal cancers: a blinded matched-pair analysis. AJNR Am J Neuroradiol 34(10):2005–2009.  https://doi.org/10.3174/ajnr.A3524 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    McIlwain WR, Sood AJ, Nguyen SA, Day TA (2014) Initial symptoms in patients with HPV-positive and HPV-negative oropharyngeal cancer. JAMA Otolaryngol Head Neck Surg 140(5):441–447.  https://doi.org/10.1001/jamaoto.2014.141 CrossRefPubMedGoogle Scholar
  31. 31.
    Martinez I, Wang J, Hobson KF, Ferris RL, Khan SA (2007) Identification of differentially expressed genes in HPV-positive and HPV-negative oropharyngeal squamous cell carcinomas. Eur J Cancer 43(2):415–432. https://doi.org/10.1016/j.ejca .2006.09.001CrossRefPubMedGoogle Scholar
  32. 32.
    Huang SH, O’Sullivan B (2017) Overview of the 8th edition TNM classification for head and neck cancer. Curr Treat Options Oncol 18(7):40.  https://doi.org/10.1007/s11864-017-0484-y CrossRefPubMedGoogle Scholar
  33. 33.
    van den Broek GB, Rasch CR, Pameijer FA, Peter E, van den Brekel MW, Tan IB, Schornagel JH, de Bois JA, Zijp LJ, Balm AJ (2004) Pretreatment probability model for predicting outcome after intraarterial chemoradiation for advanced head and neck carcinoma. Cancer 101(8):1809–1817.  https://doi.org/10.1002/cncr.20556 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Timo Carpén
    • 1
  • Kauko Saarilahti
    • 2
  • Caj Haglund
    • 3
    • 4
  • Antti Markkola
    • 5
  • Jussi Tarkkanen
    • 6
  • Jaana Hagström
    • 4
    • 6
  • Petri Mattila
    • 1
  • Antti Mäkitie
    • 1
    • 7
  1. 1.Department of Otorhinolaryngology—Head and Neck SurgeryUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
  2. 2.Department of OncologyUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
  3. 3.Department of SurgeryUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
  4. 4.Research Program Unit, Translational Cancer BiologyUniversity of HelsinkiHelsinkiFinland
  5. 5.Department of RadiologyUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
  6. 6.Department of Pathology, Haartman Institute and HUSLABUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
  7. 7.Division of Ear, Nose and Throat Diseases, Department of Clinical Sciences, Intervention and TechnologyKarolinska Institutet and Karolinska HospitalStockholmSweden

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