Advertisement

International Journal of Clinical Oncology

, Volume 24, Issue 6, pp 640–648 | Cite as

Radiotherapy alone as a possible de-intensified treatment for human papillomavirus-related locally advanced oropharyngeal squamous cell carcinoma

  • Yoshifumi Yamamoto
  • Norihiko Takemoto
  • Takahiro Michiba
  • Yuji Seo
  • Fumiaki Isohashi
  • Keisuke Otani
  • Motoyuki Suzuki
  • Takashi Fujii
  • Tadashi Yoshii
  • Kenji Mitani
  • Toshimichi Yasui
  • Hironori Cho
  • Yasuhiko Tomita
  • Eiichi Morii
  • Teruki Teshima
  • Kazuhiko Ogawa
  • Hidenori InoharaEmail author
Original Article
  • 137 Downloads

Abstract

Background

Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) is defined by p16 positivity and/or HPV DNA positivity. Because survival of patients with HPV-related OPSCC after chemoradiotherapy is favorable, a de-intensified treatment is expected to lead to less morbidity while maintaining low mortality. The association of tumor p16 and HPV DNA status with survival after radiotherapy alone remains unknown.

Methods

We retrospectively examined survival of 107 patients with locally advanced OPSCC after radiotherapy alone (n = 43) or chemoradiotherapy (n = 64) with respect to tumor p16 and HPV DNA status, using Cox’s proportional hazard model.

Results

Survival after radiotherapy alone was significantly worse in p16-positive/HPV DNA-negative locally advanced OPSCC than in p16-positive/HPV DNA-positive locally advanced OPSCC. In bivariable analyses that included T category, N category, TNM stage, and smoking history, the survival disadvantage of p16-positive/HPV DNA-negative locally advanced OPSCC remained significant. There was no significant difference in survival after chemoradiotherapy between p16-positive/HPV DNA-positive locally advanced OPSCC and p16-positive/HPV DNA-negative locally advanced OPSCC. Survival in p16-positive/HPV DNA-positive locally advanced OPSCC after radiotherapy alone was similar to that after chemoradiotherapy, which stayed unchanged in bivariable analyses after adjustment of every other covariable. Survival of p16-negative/HPV DNA-negative locally advanced OPSCC was poor irrespective of treatment modality.

Conclusions

Survival in p16-positive locally advanced OPSCC differs depending on HPV DNA status. Radiotherapy alone can serve as a de-intensified treatment for p16-positive/HPV DNA-positive locally advanced OPSCC, but not for p16-positive/HPV DNA-negative locally advanced OPSCC.

Keywords

Human papillomavirus Oropharyngeal carcinoma De-intensified treatment Radiotherapy alone 

Notes

Acknowledgements

We appreciate that Ms. Mayumi Aihara provided technical assistance. We thank Libby Cone, MD, MA, from Edanz Group Japan (http://www.edanzediting.com/ac) for editing a draft of this manuscript.

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest.

Supplementary material

10147_2019_1394_MOESM1_ESM.docx (36 kb)
Supplementary material 1 (DOCX 35 KB)

References

  1. 1.
    Marur S, D’Souza G, Westra WH et al (2010) HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol 11:781–789CrossRefGoogle Scholar
  2. 2.
    Robinson M, Sloan P, Shaw R (2010) Refining the diagnosis of oropharyngeal squamous cell carcinoma using human papillomavirus testing. Oral Oncol 46:492–496CrossRefGoogle Scholar
  3. 3.
    Wiest T, Schwarz E, Enders C et al (2002) Involvement of intact HPV16 E6/E7 gene expression in head and neck cancers with unaltered p53 status and perturbed pRb cell cycle control. Oncogene 21:1510–1517CrossRefGoogle Scholar
  4. 4.
    Smeets SJ, Hesselink AT, Speel EJ et al (2007) A novel algorithm for reliable detection of human papillomavirus in paraffin embedded head and neck cancer specimen. Int J Cancer 121:2465–2472CrossRefGoogle Scholar
  5. 5.
    Rietbergen MM, Snijders PJ, Beekzada D et al (2014) Molecular characterization of p16-immunopositive but HPV DNA-negative oropharyngeal carcinomas. Int J Cancer 134:2366–2372CrossRefGoogle Scholar
  6. 6.
    Fakhry C, Westra WH, Li S et al (2008) Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 100:261–269CrossRefGoogle Scholar
  7. 7.
    Ang KK, Harris J, Wheeler R et al (2010) Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363:24–35CrossRefGoogle Scholar
  8. 8.
    Rischin D, Young RJ, Fisher R et al (2010) Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. J Clin Oncol 28:4142–4148CrossRefGoogle Scholar
  9. 9.
    Machtay M, Moughan J, Trotti A et al (2008) Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis. J Clin Oncol 26:3582–3589CrossRefGoogle Scholar
  10. 10.
    Bhatia A, Burtness B (2015) Human Papillomavirus-associated oropharyngeal cancer: defining risk groups and clinical trials. J Clin Oncol 33:3243–3250CrossRefGoogle Scholar
  11. 11.
    Albers AE, Qian X, Kaufmann AM et al (2017) Meta analysis: HPV and p16 pattern determines survival in patients with HNSCC and identifies potential new biologic subtype. Sci Rep 7:16715CrossRefGoogle Scholar
  12. 12.
    Inohara H, Takenaka Y, Yoshii T et al (2015) Phase 2 study of docetaxel, cisplatin, and concurrent radiation for technically resectable stage III-IV squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 91:934–941CrossRefGoogle Scholar
  13. 13.
    Sobin L, Gospodarowicz M, Wittekind C (eds) (2010) UICC TNM classification of malignant tumours, 7th edn. Wiley-Blackwell, ChichesterGoogle Scholar
  14. 14.
    Fuessel Haws AL, He Q, Rady PL et al (2004) Nested PCR with the PGMY09/11 and GP5+/6+ primer sets improves detection of HPV DNA in cervical samples. J Virol Methods 122:87–93CrossRefGoogle Scholar
  15. 15.
    Chang JT1, Kuo TF, Chen YJ et al (2010) Highly potent and specific siRNAs against E6 or E7 genes of HPV16- or HPV18-infected cervical cancers. Cancer Gene Ther 17:827–836CrossRefGoogle Scholar
  16. 16.
    Hu Z, Zhu D, Wang W et al (2015) Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism. Nat Genet 47:158–163CrossRefGoogle Scholar
  17. 17.
    Maruyama H, Yasui T, Ishikawa-Fujiwara T et al (2014) Human papillomavirus and p53 mutations in head and neck squamous cell carcinoma among Japanese population. Cancer Sci 105:409–417CrossRefGoogle Scholar
  18. 18.
    Nauta IH, Rietbergen MM, van Bokhoven AAJD et al (2018) Evaluation of the eighth TNM classification on p16-positive oropharyngeal squamous cell carcinomas in the Netherlands and the importance of additional HPV DNA testing. Ann Oncol 29:1273–1279CrossRefGoogle Scholar
  19. 19.
    O’Sullivan B, Huang SH, Perez-Ordonez B et al (2012) Outcomes of HPV-related oropharyngeal cancer patients treated by radiotherapy alone using altered fractionation. Radiother Oncol 103:49–56CrossRefGoogle Scholar
  20. 20.
    Rosenthal DI, Harari PM, Giralt J et al (2016) Association of human papillomavirus and p16 status with outcomes in the IMCL-9815 phase III registration trial for patients with locoregionally advanced oropharyngeal squamous cell carcinoma of the head and neck treated with radiotherapy with or without cetuximab. J Clin Oncol 34:1300–1308CrossRefGoogle Scholar
  21. 21.
    Rietbergen MM, Brakenhoff RH, Bloemena E et al (2013) Human papillomavirus detection and comorbidity: critical issues in selection of patients with oropharyngeal cancer for treatment De-escalation trials. Ann Oncol 24:2740–2745CrossRefGoogle Scholar
  22. 22.
    Pignon JP, Maitre AL, Maillard E et al (2009) Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomized trials and 17,346 patients. Radiother Oncol 92:4–14CrossRefGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2019

Authors and Affiliations

  • Yoshifumi Yamamoto
    • 1
  • Norihiko Takemoto
    • 1
  • Takahiro Michiba
    • 1
  • Yuji Seo
    • 2
  • Fumiaki Isohashi
    • 2
  • Keisuke Otani
    • 2
  • Motoyuki Suzuki
    • 1
  • Takashi Fujii
    • 3
  • Tadashi Yoshii
    • 3
  • Kenji Mitani
    • 4
  • Toshimichi Yasui
    • 1
  • Hironori Cho
    • 1
  • Yasuhiko Tomita
    • 5
    • 8
  • Eiichi Morii
    • 6
  • Teruki Teshima
    • 7
  • Kazuhiko Ogawa
    • 2
  • Hidenori Inohara
    • 1
    Email author
  1. 1.Department of Otorhinolaryngology-Head and Neck SurgeryOsaka University School of MedicineSuitaJapan
  2. 2.Department of Radiation OncologyOsaka University School of MedicineSuitaJapan
  3. 3.Department of Head and Neck SurgeryOsaka International Cancer InstituteOsakaJapan
  4. 4.Department of OtolaryngologyToyonaka Municipal HospitalToyonakaJapan
  5. 5.Department of PathologyOsaka Medical Center for Cancer and Cardiovascular DiseaseOsakaJapan
  6. 6.Department of PathologyOsaka University School of MedicineSuitaJapan
  7. 7.Department of Radiation OncologyOsaka International Cancer InstituteOsakaJapan
  8. 8.Department of PathologyInternational University of Health and Welfare Ichikawa HospitalIchikawaJapan

Personalised recommendations