Abstract
Purpose of Review
Management paradigms for oropharyngeal carcinoma (OPC) have been rapidly evolving due to the recognition that cancers associated with the human papillomavirus (HPV) have a favorable prognosis. This is especially the case with radiation therapy as a principal curative modality, as it is associated with a number of significant treatment complications due to the anatomic density of the head and neck and the importance of the oropharyngeal organs in swallow function. This has consequently raised major questions as to whether management can be fundamentally de-intensified in terms of dose and volume, and thereby reduce injury to the surrounding normal tissue.
Recent Findings
Several phase I/II clinical trials have supported the hypothesis that early stage HPV-OPC can be effectively treated with de-intensified therapies from an oncologic perspective, although there remain many unanswered questions regarding the optimal de-escalation strategy from a toxicity perspective. Confounding these efforts remains our inability to quantify normal tissue injury and its relationship to swallow function. To date, existing tools largely quantify the degree of swallow injury with varying degrees of reproducibility and granularity. Analyses of the relationship between radiation dose and swallow outcomes have also typically been limited to the dose delivered to isolated normal structures and have not considered spatial radiation dose to the complex “systems” of organs that govern swallow function.
Summary
Treatment de-intensification for HPV-associated OPC represents a rapidly advancing field where early studies suggest that oncologic efficacy for early stage cancers may not be compromised with lower radiation dose and minimally invasive surgical techniques. Generalizing this conclusion remains limited by the number of patients evaluated in clinical trials. The ability to determine if these efforts are reducing normal tissue injury and swallow function is also limited by the existing instruments used to measure injury.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Centers for Disease Control and Prevention (CDC). HPV-associated cancer statistics. Division of Cancer Prevention and Control, Centers for Disease Control and Prevention. 2018.
Chaturvedi AK. Epidemiology and clinical aspects of HPV in head and neck cancers. Head Neck Pathol. 2012. https://doi.org/10.1007/s12105-012-0377-0.
Ang KK, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24–35. https://doi.org/10.1056/NEJMOA0912217.
Chen AM, et al. Differential response rates to irradiation among patients with human papillomavirus positive and negative oropharyngeal cancer. Laryngoscope. 2013. https://doi.org/10.1002/lary.23570.
Baudelet M, et al. Very late xerostomia, dysphagia, and neck fibrosis after head and neck radiotherapy. Head Neck. 2019. https://doi.org/10.1002/hed.25880.
Forastiere AA, et al. Long-term results of RTOG 91–11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol. 2013;31(7):845. https://doi.org/10.1200/JCO.2012.43.6097.
Cooper JS, et al. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 2012;84(5):1198–205. https://doi.org/10.1016/J.IJROBP.2012.05.008.
Gourin CG, et al. Treatment, survival, and costs of oropharyngeal cancer care in the elderly. Laryngoscope. 2018;128(5):1103–12. https://doi.org/10.1002/LARY.26887.
O’Hare J, et al. Laryngeal tumours and radiotherapy dose to the cricopharyngeus are predictive of death from aspiration pneumonia. Oral Oncol. 2017;64:9–14. https://doi.org/10.1016/J.ORALONCOLOGY.2016.11.010.
Patterson JM. Late effects of organ preservation treatment on swallowing and voice; presentation, assessment, and screening. Front Oncol. 2019. https://doi.org/10.3389/FONC.2019.00401.
McHorney CA, et al. The SWAL–QOL and SWAL–CARE outcomes tool for oropharyngeal dysphagia in adults: III. Documentation of reliability and validity. Dysphagia. 2002;17(2):97–114. https://doi.org/10.1007/S00455-001-0109-1.
Chen AY, et al. The development and validation of a dysphagia-specific quality-of-life questionnaire for patients with head and neck cancer: the M. D. Anderson dysphagia inventory. Arch Otolaryngol Head Neck Surg. 2001;127(7):870–6.
Rogers SN, Gwanne S, Lowe D, Humphris G, Yueh B, Weymuller EA. The addition of mood and anxiety domains to the University of Washington quality of life scale. Head Neck. 2002;24(6):521–9. https://doi.org/10.1002/HED.10106.
Bjordal K, et al. Quality of life in head and neck cancer patients: validation of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-H and N35. J Clin Oncol. 1999;17(3):1008–19. https://doi.org/10.1200/jco.1999.17.3.1008.
List MA, et al. The performance status scale for head and neck cancer patients and the functional assessment of cancer therapy-head and neck scale a study of utility and validity. https://doi.org/10.1002/(SICI)1097-0142(19960601)77:11.
Dwivedi RC, et al. Validation of the Sydney Swallow Questionnaire (SSQ) in a cohort of head and neck cancer patients. Oral Oncol. 2010. https://doi.org/10.1016/J.ORALONCOLOGY.2010.02.004.
Deek MP, et al. Long term toxicity and oncologic outcomes of de-intensified chemoradiation in early stage oropharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2019;105(1):S215–6. https://doi.org/10.1016/j.ijrobp.2019.06.296.
• Chera BS, et al. Phase II trial of de-intensified chemoradiotherapy for human papillomavirus-associated oropharyngeal squamous cell carcinoma. J Clin Oncol Off J Am Soc Clin Oncol. 2019;37(29):2661–9. https://doi.org/10.1200/JCO.19.01007. This study demonstrates the feasibility of radiation dose de-escalation from the standard 70Gy to 60Gy as a de-intensification strategy for patients with HPV-associated tumors up to T3N2 (AJCC 7), conferring 2 year locoregional control and survival rates of 95%.
Chera BS, et al. Rapid clearance profile of plasma circulating tumor HPV type 16 DNA during chemoradiotherapy correlates with disease control in HPV-associated oropharyngeal cancer. Clin Cancer Res. 2019. https://doi.org/10.1158/1078-0432.CCR-19-0211.
Riaz N, et al. Precision radiotherapy: reduction in radiation for oropharyngeal cancer in the 30 ROC Trial. J Natl Cancer Inst. 2021;113(6):742–51. https://doi.org/10.1093/JNCI/DJAA184.
•• Ferris RL, et al. Phase II randomized trial of transoral surgery and low-dose intensity modulated radiation therapy in resectable p16+ locally advanced oropharynx cancer: an ECOG-ACRIN Cancer Research Group Trial (E3311). 2021. https://doi.org/10.1200/JCO.21.01752. Large multi-institutional phase 2 trial demonstrating that transoral surgery is effective and that patients with intermediate pathologically defined risk of recurrence can be effectively)(treated with a lower postoperative radiotherapy dose of 50 Gy alone.
Miles BA, et al. De-escalated adjuvant therapy after transoral robotic surgery for human papillomavirus-related oropharyngeal carcinoma: the Sinai Robotic Surgery (SIRS) Trial. Oncologist. 2021;26(6):504. https://doi.org/10.1002/ONCO.13742.
Ma DJ, et al. Long-term results for MC1273, a phase II evaluation of de-escalated adjuvant radiation therapy for human papillomavirus associated oropharyngeal squamous cell cArcinoma (HPV+ OPSCC). Int J Radiat Oncol Biol Phys. 2021;111(3):S61. https://doi.org/10.1016/J.IJROBP.2021.07.155.
Ma DJ, et al. Phase II evaluation of aggressive dose de-escalation for adjuvant chemoradiotherapy in human papillomavirus–associated oropharynx squamous cell carcinoma. J Clin Oncol. 2019;37(22):1909–18. https://doi.org/10.1200/JCO.19.00463.
Baliga S, et al. Identification of clinical and socioeconomic predictors of adjuvant therapy after trans-oral robotic surgery in patients with oropharyngeal squamous cell carcinoma. Cancers. 2020;12(9):1–16. https://doi.org/10.3390/CANCERS12092474.
• Nichols AC, et al. Radiotherapy versus transoral robotic surgery and neck dissection for oropharyngeal squamous cell carcinoma (ORATOR): an open-label, phase 2, randomised trial. Lancet Oncol. 2019;20(10):1349–59. https://doi.org/10.1016/S1470-2045(19)30410-3. Randomized phase 2 trial comparing radiotherapy to a surgical approach for HPV associated carcinoma demonstrating non-significant difference in swallowquality of life as measured by the MD Anderson Dysphagia Inventory.
Nichols AC, et al. Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial. BMC Cancer. 2020;20(1):1–13. https://doi.org/10.1186/S12885-020-6607-Z.
Hutcheson KA, Barrow MP, Lisec A, Barringer DA, Gries K, Lewin JS. What is a clinically relevant difference in MDADI scores between groups of head and neck cancer patients? Laryngoscope. 2016;126(5):1108–13. https://doi.org/10.1002/LARY.25778.
Swisher-McClure S, et al. A phase 2 trial of alternative volumes of oropharyngeal irradiation for de-intensification (AVOID): omission of the resected primary tumor bed after transoral robotic surgery for human papilloma virus–related squamous cell carcinoma of the oropharynx. Int J Radiat Oncol Biol Phys. 2020;106(4):725–32. https://doi.org/10.1016/J.IJROBP.2019.11.021.
Sher DJ, et al. Prospective phase 2 study of radiation therapy dose and volume de-escalation for elective neck treatment of oropharyngeal and laryngeal cancer. Int J Radiat Oncol Biol Phys. 2021;109(4):932–40. https://doi.org/10.1016/J.IJROBP.2020.09.063.
Taku N, et al. Proton therapy for HPV-associated oropharyngeal cancers of the head and neck: a de-intensification strategy. Curr Treat Options Oncol. 2021;22(6):54. https://doi.org/10.1007/S11864-021-00847-Y.
Rischin D, et al. Randomized trial of radiation therapy with weekly cisplatin or cetuximab in low-risk HPV-associated oropharyngeal cancer (TROG 12.01) – a Trans-Tasman Radiation Oncology Group Study. Int J Radiat Oncol Biol Phys. 2021;111(4):876–86. https://doi.org/10.1016/J.IJROBP.2021.04.015.
Gillison ML, et al. Radiotherapy plus cetuximab or cisplatin for human papillomavirus (HPV)-positive oropharyngeal cancer: a randomized, multicenter, non-inferiority clinical trial. Lancet (London, England). 2019;393(10166):40. https://doi.org/10.1016/S0140-6736(18)32779-X.
Mehanna H, et al. Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial. The Lancet. 2019;393(10166):51–60. https://doi.org/10.1016/S0140-6736(18)32752-1.
Yom SS, et al. Reduced-dose radiation therapy for HPV-associated oropharyngeal carcinoma (NRG Oncology HN002). J Clin Oncol. 2021;39(9):956–65. https://doi.org/10.1200/JCO.20.03128.
Ensley JF, et al. Correlation between response to cisplatinum-combination chemotherapy and subsequent radiotherapy in previously untreated patients with advanced squamous cell cancers of the head and neck. Cancer. 1984. https://doi.org/10.1002/1097-0142(19840901)54:5%3c811::AID-CNCR2820540508%3e3.0.CO;2-E.
Marur S, et al. E1308: phase II trial of induction chemotherapy followed by reduced-dose radiation and weekly cetuximab in patients with HPV-associated resectable squamous cell carcinoma of the oropharynx— ECOG-ACRIN Cancer Research Group. J Clin Oncol. 2017;35(5):490. https://doi.org/10.1200/JCO.2016.68.3300.
Chen AM, et al. Phase II trial of radiation dose de-escalation for human papillomavirus-associated squamous cell carcinoma of the oropharynx. Lancet Oncol. 2017;18(6):803. https://doi.org/10.1016/S1470-2045(17)30246-2.
Seiwert TY, et al. Optima: a phase II dose and volume de-escalation trial for human papillomavirus-positive oropharyngeal cancer. Ann Oncol. 2019. https://doi.org/10.1093/annonc/mdy522.
Margalit DN, Lin A. Two sides of the same coin: head and neck cancer treatment de-intensification and intensification with induction chemotherapy. Int J Radiat Oncol Biol Phys. 2018;102(1):1–4. https://doi.org/10.1016/J.IJROBP.2018.04.002.
Weiss JM, et al. Phase 2 trial of neoadjuvant chemotherapy and transoral endoscopic surgery with risk-adapted adjuvant therapy for squamous cell carcinoma of the head and neck. Cancer. 2018. https://doi.org/10.1002/cncr.31526.
Sadeghi N, et al. Pathologic response to neoadjuvant chemotherapy in HPV-associated oropharynx cancer. Head Neck. 2020;42(3):417–25. https://doi.org/10.1002/hed.26022.
Sadeghi N, et al. Neoadjuvant chemotherapy followed by surgery for HPV-associated locoregionally advanced oropharynx cancer. Head Neck. 2020;42(8):2145–54. https://doi.org/10.1002/hed.26147.
Leichter DM, Stark NE, Leary OP, Brodsky MB, Gilbert RJ, Nicosia MA. Two dimensional computational model coupling myoarchitecture-based lingual tissue mechanics with liquid bolus flow during oropharyngeal swallowing. Comput Biol Med. 2022;145:105446. https://doi.org/10.1016/j.compbiomed.2022.105446.
Cheng Z, et al. Voxel dose pattern for patient-reported dysphagia among head and neck cancer patients receiving definitive radiotherapy. Int J Radiat Oncol Biol Phys. 2019;105(1):S118. https://doi.org/10.1016/J.IJROBP.2019.06.085.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Yilin Cao reports non-financial support from Sysmex Inostics (In-kind research support [assays]), outside the submitted work. Harry Quon reports he is Co-Founder, Chief Medical Officer for Pistevo Decision, LLC; and he is a consultant with equity for Oncospace, LLC, outside the submitted work. Richard J. Gilbert declares no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on HEAD AND NECK: Human Papilloma Virus Associated Head and Neck Squamous Cell Carcinoma
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Cao, Y., Gilbert, R.J. & Quon, H. Advances and Challenges in Treatment De-Intensification of HPV-Associated Oropharyngeal Squamous Cell Carcinoma. Curr Otorhinolaryngol Rep 10, 464–474 (2022). https://doi.org/10.1007/s40136-022-00425-2
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40136-022-00425-2