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Consensuses, controversies, and future directions in treatment deintensification for human papillomavirus-associated oropharyngeal cancer.

Literature Information

DOI	10.3322/caac.21758
PMID	36305841
Journal	CA: a cancer journal for clinicians
Impact Factor	232.4
JCR Quartile	Q1
Publication Year	2023
Times Cited	22
Keywords	chemotherapy, deintensification, human papillomavirus, oral and oropharyngeal neoplasms, radiation oncology
Literature Type	Journal Article, Review, Research Support, N.I.H., Extramural
ISSN	0007-9235
Pages	164-197
Issue	73(2)
Authors	Jung Julie Kang, Yao Yu, Linda Chen, Kaveh Zakeri, Daphna Yael Gelblum, Sean Matthew McBride, Nadeem Riaz, C Jillian Tsai, Anuja Kriplani, Tony K W Hung, James V Fetten, Lara A Dunn, Alan L Ho, Jay O Boyle, Ian S Ganly, Bhuvanesh Singh, Eric J Sherman, David G Pfister, Richard J Wong, Nancy Y Lee

TL;DR

This review addresses the rising incidence of oropharyngeal cancer (OPC) linked to HPV infection and the challenges in optimizing deintensification strategies for treatment, as initial randomized trials have not led to changes in standard care despite significant long-term morbidities associated with chemoradiation. The authors emphasize the need for a synthesis of multidisciplinary data to guide best practices and advocate for incorporating intratreatment response assessments to advance personalized medicine in the management of HPV-positive OPC.

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chemotherapy · deintensification · human papillomavirus · oral and oropharyngeal neoplasms · radiation oncology

Abstract

The most common cancer caused by human papillomavirus (HPV) infection in the United States is oropharyngeal cancer (OPC), and its incidence has been rising since the turn of the century. Because of substantial long-term morbidities with chemoradiation and the favorable prognosis of HPV-positive OPC, identifying the optimal deintensification strategy for this group has been a keystone of academic head-and-neck surgery, radiation oncology, and medical oncology for over the past decade. However, the first generation of randomized chemotherapy deintensification trials failed to change the standard of care, triggering concern over the feasibility of de-escalation. National database studies estimate that up to one third of patients receive nonstandard de-escalated treatments, which have subspecialty-specific nuances. A synthesis of the multidisciplinary deintensification data and current treatment standards is important for the oncology community to reinforce best practices and ensure optimal patient outcomes. In this review, the authors present a summary and comparison of prospective HPV-positive OPC de-escalation trials. Chemotherapy attenuation compromises outcomes without reducing toxicity. Limited data comparing transoral robotic surgery (TORS) with radiation raise concern over toxicity and outcomes with TORS. There are promising data to support de-escalating adjuvant therapy after TORS, but consensus on treatment indications is needed. Encouraging radiation deintensification strategies have been reported (upfront dose reduction and induction chemotherapy-based patient selection), but level I evidence is years away. Ultimately, stage and HPV status may be insufficient to guide de-escalation. The future of deintensification may lie in incorporating intratreatment response assessments to harness the powers of personalized medicine and integrate real-time surveillance.

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Primary Questions Addressed

1. What are the specific challenges in establishing a consensus on deintensification strategies for HPV-positive oropharyngeal cancer?
2. How do different specialties perceive the risks and benefits of nonstandard de-escalated treatments for patients with HPV-associated oropharyngeal cancer?
3. In what ways could emerging personalized medicine approaches enhance the efficacy of deintensification strategies for HPV-positive oropharyngeal cancer?
4. What role does patient selection play in the success of adjuvant therapy de-escalation following transoral robotic surgery for oropharyngeal cancer?
5. How might future clinical trials address the gaps in evidence regarding the long-term outcomes of radiation deintensification strategies in HPV-positive oropharyngeal cancer patients?

Key Findings

Research Background and Purpose

Oropharyngeal cancer (OPC), primarily caused by human papillomavirus (HPV) infection, has seen a rising incidence in the United States since the early 2000s. Given the long-term morbidities associated with chemoradiation and the generally favorable prognosis for HPV-positive OPC patients, identifying optimal deintensification strategies has become a critical focus in head-and-neck oncology. This review aims to synthesize and compare existing data from various prospective de-escalation trials, highlighting the importance of standardizing treatment approaches to improve patient outcomes.

Main Methods/Materials/Experimental Design

The review encompasses a comprehensive analysis of multiple de-escalation trials and treatment standards for HPV-positive OPC. The following methodological framework outlines the approach taken in the review:

Key Results and Findings

• Chemotherapy Attenuation: Initial trials indicated that reducing chemotherapy does not significantly lower toxicity but compromises patient outcomes.
• Transoral Robotic Surgery (TORS): Limited comparative data suggest concerns regarding the efficacy and toxicity of TORS relative to traditional radiation therapy.
• Adjuvant Therapy: There is emerging evidence supporting the de-escalation of adjuvant therapy following TORS; however, consensus on treatment indications is lacking.
• Radiation Strategies: Promising approaches include upfront dose reduction and patient selection based on induction chemotherapy, though high-level evidence remains to be established.

Main Conclusions/Significance/Innovation

The review underscores the necessity for a cohesive understanding of de-escalation strategies in HPV-positive OPC to ensure optimal patient care. It highlights the potential for personalized medicine through intratreatment response assessments, which could refine de-escalation approaches. The integration of real-time surveillance in treatment protocols is posited as a future direction that may enhance treatment efficacy and patient safety.

Research Limitations and Future Directions

• Limitations: The current evidence is limited by the variability in trial designs, small sample sizes, and the lack of consensus on treatment protocols. Additionally, existing studies often do not account for the complexity of patient responses based on individual characteristics.
• Future Directions: There is a need for further research to establish robust level I evidence regarding de-escalation strategies. Future studies should focus on personalized medicine approaches, including real-time monitoring of treatment responses, to optimize patient outcomes and refine clinical guidelines.

Aspect	Findings
Chemotherapy Attenuation	Compromises outcomes without reducing toxicity.
TORS vs Radiation	Limited data raises concerns over efficacy and toxicity.
Adjuvant Therapy	Promising de-escalation strategies post-TORS, but lack of consensus on indications.
Radiation Deintensification	Upfront dose reduction and induction chemotherapy selection show promise, but require further evidence.
Future Research	Focus on personalized medicine and real-time surveillance to enhance treatment protocols.

References

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Literatures Citing This Work

1. Development of a Novel Anti-CD44 Variant 7/8 Monoclonal Antibody, C44Mab-34, for Multiple Applications against Oral Carcinomas. - Hiroyuki Suzuki;Kazuki Ozawa;Tomohiro Tanaka;Mika K Kaneko;Yukinari Kato - Biomedicines (2023)
2. Prognostic values of systemic inflammation and nutrition-based prognostic indices in oropharyngeal carcinoma. - Tsunehiro Oka;Fumihiko Sato;Takeharu Ono;Toshihiko Kawaguchi;Kenta Murotani;Shintaro Sueyoshi;Taikai Kuroiwa;Takashi Kurita;Mioko Fukahori;Toshiyuki Mitsuhashi;Kiminobu Sato;Shun-Ichi Chitose;Hirohito Umeno - Laryngoscope investigative otolaryngology (2023)
3. Concurrent carboplatin and paclitaxel definitive radiation therapy for locally advanced head and neck cancer. - James Han;Kaveh Zakeri;Gabriel Raab;Jennifer Hesse;Achraf Shamseddine;Linda Chen;Yao Yu;Jung Julie Kang;Sean M McBride;Nadeem Riaz;C Jillian Tsai;Daphna Gelblum;Eric J Sherman;Richard J Wong;Loren Michel;Nancy Y Lee - Head & neck (2023)
4. Review of RM-1929 Near-Infrared Photoimmunotherapy Clinical Efficacy for Unresectable and/or Recurrent Head and Neck Squamous Cell Carcinoma. - Nanami L Miyazaki;Aki Furusawa;Peter L Choyke;Hisataka Kobayashi - Cancers (2023)
5. Neoadjuvant chemoimmunotherapy shows major pathological response and low recurrence in head and neck squamous cell carcinoma. - Shida Yan;Lili Liu;Xing Zhang;Lijun Wei;Wenmei Jiang;Xianlu Gao;Ankui Yang;Xuekui Liu;Wenkuan Chen;Yanfeng Chen;Hui Li;Qiaohong Lin;Menghua Li;Jingtao Chen;Quan Zhang;Shuwei Chen;Ming Song - Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico (2024)
6. A Radiomics-Based Machine Learning Perspective on the Parotid Gland as a Potential Surrogate Marker for HPV in Oropharyngeal Cancer. - Gordian Prasse;Agnes Glaas;Hans-Jonas Meyer;Veit Zebralla;Andreas Dietz;Kathrin Hering;Thomas Kuhnt;Timm Denecke - Cancers (2023)
7. Tongue electrical impedance myography correlates with functional, neurophysiologic, and clinical outcome measures in long-term oropharyngeal cancer survivors with and without hypoglossal neuropathy: An exploratory study. - Nathan J Hansen;Karin Woodman;Sheila Buoy;Shitong Mao;Carly E A Barbon;Stephen Y Lai;C David Fuller;Katherine A Hutcheson;Benjamin Sanchez - Head & neck (2024)
8. Hypoxia-Directed Treatment of Human Papillomavirus-Related Oropharyngeal Carcinoma. - Nancy Y Lee;Eric J Sherman;HeiKo Schöder;Rick Wray;Jay O Boyle;Bhuvanesh Singh;Milan Grkovski;Ramesh Paudyal;Louise Cunningham;Zhigang Zhang;Vaios Hatzoglou;Nora Katabi;Bill H Diplas;James Han;Brandon S Imber;Khoi Pham;Yao Yu;Kaveh Zakeri;Sean M McBride;Jung J Kang;C Jillian Tsai;Linda C Chen;Daphna Y Gelblum;Jatin P Shah;Ian Ganly;Marc A Cohen;Jennifer R Cracchiolo;Luc G T Morris;Lara A Dunn;Loren S Michel;James V Fetten;Anuja Kripani;David G Pfister;Alan L Ho;Amita Shukla-Dave;John L Humm;Simon N Powell;Bob T Li;Jorge S Reis-Filho;Luis A Diaz;Richard J Wong;Nadeem Riaz - Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2024)
9. The role of surgery and deescalation for HPV-related oropharyngeal cancer. - Kevin J Contrera;Mihir R Patel;Barbara Burtness;Ranee Mehra;Robert L Ferris - Cancer (2025)
10. "Why am I still suffering?": Experience of long-term fatigue and neurocognitive changes in oropharyngeal cancer survivors following (chemo)radiotherapy. - Zsuzsanna Iyizoba-Ebozue;Emma Nicklin;James Price;Robin Prestwich;Sarah Brown;Emma Hall;John Lilley;Matthew Lowe;David J Thomson;Finbar Slevin;Louise Murray;Florien Boele - Technical innovations & patient support in radiation oncology (2024)

... (12 more literatures)

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