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McArdle E, Bulbul M, Collins C, Duvvuri U, Gross N, Turner M. Surgery for the Treatment of HPV-Negative Oropharyngeal Squamous Cell Carcinoma-A Systematic Review and Meta-Analysis. Head Neck 2025; 47:1749-1757. [PMID: 39866097 DOI: 10.1002/hed.28088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 12/26/2024] [Accepted: 01/14/2025] [Indexed: 01/28/2025] Open
Abstract
BACKGROUND Human papillomavirus (HPV) negative oropharyngeal squamous cell carcinoma (OPSCC) is associated with worse survival when compared to HPV-positive OPSCC. Primary surgery is one option to intensify therapy in this high-risk group of patients. Unfortunately, the only randomized trial to explore this approach (RTOG 1221) failed to accrue and the role of primary surgery in the treatment of HPV-negative OPSCC remains unanswered. METHODS A systematic review and meta-analysis were performed to examine the outcomes of surgery in the treatment of HPV-negative OPSCC. We used the PRISMA statement for reporting and queried Pubmed, Web of Science and the Cochrane databases for studies examining the use of primary surgery in the treatment of HPV-negative OPSCC. Excluded from analysis were reviews, commentaries, case series with fewer than 10 patients, and studies that included HPV-negative head and neck cancers of mixed sites. Our primary outcomes were 2-year and 5-year overall survival (OS) and disease-free survival (DFS). OS and DFS were pooled using meta-analysis of proportions. RESULTS A total of 15 studies were included in qualitative synthesis and 11 were included in the meta-analysis. There were 923 patients total included. Eight studies including 483 patients reported staging of HPV negative disease, of which 81.6% had T1/T2 tumors and 41.4% had N0 nodal disease. The average rate of positive margins was 12.6%. The average rate of patients who underwent risk-stratified adjuvant RT was 30.7% and CRT was 29.5%. The average follow-up was 32.7 months (SD = 12.47 months). Only two studies reported survival outcomes for HPV-negative disease based on overall staging: 5-year OS was improved for stage III versus stage IV and early versus late stage disease. The pooled 2- and 5-year OS were 84% (95% CI 77%-91%, I 2 = 52.4%; 5 studies) and 72% (95% CI 46%-92%, I 2 = 95.5%; 4 studies), respectively. The pooled 2- and 5-year DFS for the entire population were 77% (95% CI 66%-86%, I 2 = 55%; 6 studies) and 59% (95% CI 50%-69%, I 2 = 0%; 3 studies). Of the subgroup undergoing TOS alone, the pooled 2- and 5-year OS were 87% (95% CI 79%-93%, I 2 = 46.8%; 4 studies) and 82% (95% CI 69%-92%, I 2 = 74.2%; 3 studies). The pooled 2- and 5-year DFS for the subgroup of patients undergoing TOS alone were 78% (95% CI 63%-90%, I 2 = 56%; 4 studies) and 59% (95% CI 47%-71%, I 2 = undetermined; 2 studies). CONCLUSIONS The two- and five-year OS for patients with HPV-negative OPSCC treated with any surgical approach and pathology-directed adjuvant therapy is 84% and 72%, respectively. The two- and five-year OS for HPV-negative OPCSCC treated with transoral surgery and pathology-directed adjuvant therapy is 87% and 82%, respectively.
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Affiliation(s)
- Erica McArdle
- Department of Otolaryngology-Head and Neck Surgery, West Virginia University, Morgantown, West Virginia, USA
| | - Mustafa Bulbul
- Department of Otolaryngology-Head and Neck Surgery, West Virginia University, Morgantown, West Virginia, USA
| | - Chantz Collins
- Department of Health Sciences, West Virginia University, Morgantown, West Virginia, USA
| | - Umamaheswar Duvvuri
- Department of Otolaryngology-Head and Neck Surgery, New York Grossman School of Medicine, New York, New York, USA
| | - Neil Gross
- Department of Head and Neck Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Meghan Turner
- Department of Otolaryngology-Head and Neck Surgery, West Virginia University, Morgantown, West Virginia, USA
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Chennareddy S, Chen S, Levinson C, Genden EM, Posner MR, Roof SA. Circulating tumor DNA in human papillomavirus-associated oropharyngeal cancer management: A systematic review. Oral Oncol 2025; 164:107262. [PMID: 40163959 DOI: 10.1016/j.oraloncology.2025.107262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Accepted: 03/14/2025] [Indexed: 04/02/2025]
Abstract
OBJECTIVE Circulating tumor DNA (ctDNA) has emerged as a promising tool in the treatment of HPV-associated oropharyngeal squamous cell cancer (OPSCC). This systematic review sought to answer the question: what is the current role of ctDNA in the diagnosis, treatment, and surveillance of HPV-associated OPSCC? DATA SOURCES Medline (Ovid), Embase (Ovid), Scopus. REVIEW METHODS Original articles studying the role of ctDNA in the diagnosis or surveillance of HPV-associated OPSCC were eligible for inclusion. Two authors independently reviewed studies for inclusion and abstracted data, including study design, characterization of liquid biopsy technology, and diagnostic outcomes. RESULTS After a preliminary screening of 441 studies, 23 were selected for inclusion. Ten studies were conducted retrospectively, and 13 were conducted prospectively. In these studies, diagnostic testing included plasma-based droplet digital polymerase chain reaction (ddPCR, n = 13), quantitative PCR (qPCR, n = 4), digital PCR (dPCR, n = 3), next-generation sequencing (NGS) (n = 3), or a ctDNA detection kit (n = 1). Diagnostic outcomes were reported for pre-diagnosis (n = 1), pre-treatment (n = 17), during treatment (n = 6), and surveillance/recurrence (n = 11) timepoints. Test sensitivities ranged from 20.6 %-100 % pre-treatment and 72 %-100 % during surveillance, while test specificities ranged from 95 %-100 % pre-treatment and 87.2 %-100 % during surveillance. CONCLUSION The majority of studied ctDNA technologies allow for detection of HPV-associated OPSCC with high diagnostic accuracy. However, heterogeneity is introduced by test type and assay used. These findings highlight the utility, as well as limitations, of ctDNA in the diagnosis, treatment monitoring, and surveillance of HPV-associated OPSCC. Future studies and clinical consensus will need to address acceptable diagnostic accuracy thresholds for clinical use.
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Affiliation(s)
- Susmita Chennareddy
- Department of Otolaryngology-Head& Neck Surgery, Mount Sinai Hospital, New York, NY, USA.
| | - Sida Chen
- Department of Otolaryngology-Head& Neck Surgery, Mount Sinai Hospital, New York, NY, USA
| | - Carrie Levinson
- Gustave L. and Janet W. Levy Library, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Eric M Genden
- Department of Otolaryngology-Head& Neck Surgery, Mount Sinai Hospital, New York, NY, USA
| | - Marshall R Posner
- TGH/Cancer Center of South Florida, USA; University of Southern Florida, USA
| | - Scott A Roof
- Department of Otolaryngology-Head& Neck Surgery, Mount Sinai Hospital, New York, NY, USA
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Jhawar SR, Haring C, Pan X, Ma J, Bhateja P, Kubi EA, Limbach AL, Gogineni E, Mitchell D, Konieczkowski D, Grecula J, Ma SJ, Zhu S, Old M, Bonomi M, Rocco JW, Blakaj DM, Baliga S. Impact of circulating tumor human papillomavirus DNA kinetics on disease outcomes in HPV-associated oropharyngeal cancer. Int J Cancer 2025; 156:1656-1663. [PMID: 39679923 DOI: 10.1002/ijc.35291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 11/12/2024] [Accepted: 11/28/2024] [Indexed: 12/17/2024]
Abstract
Circulating tumor tissue modified (TTMV)-HPV DNA has emerged as a promising biomarker in human papillomavirus associated oropharyngeal squamous cell carcinoma (HPV-OPSCC). The objective of this study was to assess ctHPVDNA TTMV clearance kinetics during RT and its relationship with progression in HPV-OPSCC. We identified 80 non-metastatic HPV-OPSCC patients with 366 TTMV samples who underwent prospective plasma TTMV testing before, during and after curative intent RT or CRT between June 2021 and February 2023. Patients with rapid favorable clearance (>95% decline from pre-treatment value) of TTMV were compared to those with suboptimal clearance (<95%). The primary objective was to evaluate the relationship between TTMV clearance during CRT and its impact on progression free survival (PFS). The median follow-up was 14.7 months. Clinical nodal stage was associated with higher TTMV-HPV DNA scores at baseline, with a median score of 128, 778, and 1219 for N0/N1, N2a/b, and N2c/3 patients, respectively. Patients who had persistent TTMV at the end of RT had an inferior PFS compared to those who cleared their TTMV at 2 years (91.7% vs. 71.7%) (log rank, p = .042). Among patients who had complete clearance of their TTMV at 3 months, those who had a negative, equivocal, and incomplete PET response had a 2-year PFS of 94.3%, 77.8%, and 59.3%, respectively (log-rank, p = .029). Our study indicates that persistent TTMV-HPV DNA is associated with worse PFS and may portend unfavorable outcomes. Thus, monitoring TTMV clearance kinetics could be a valuable biomarker for guiding treatment decisions in patients with HPV-OPSCC.
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Affiliation(s)
- Sachin R Jhawar
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Catherine Haring
- Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Xueliang Pan
- Center for Biostatistics, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Jianing Ma
- Center for Biostatistics, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Priyanka Bhateja
- Department of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Emmanuel Appiah Kubi
- Division of Molecular Imaging and Nuclear Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Abberly Lott Limbach
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Emile Gogineni
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Darrion Mitchell
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - David Konieczkowski
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - John Grecula
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Sung Jun Ma
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Simeng Zhu
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Matthew Old
- Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Marcelo Bonomi
- Department of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - James W Rocco
- Department of Otolaryngology-Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Dukagjin M Blakaj
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Sujith Baliga
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
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Hieromnimon HM, Trzcinska A, Wen FT, Howard FM, Dolezal JM, Dyer E, Kochanny S, Schulte JJ, Wang C, Chen H, Chin J, Blair E, Agrawal N, Rosenberg A, Vokes E, Katipally R, Juloori A, Izumchenko E, Lingen MW, Cipriani N, Jalaly JB, Basu D, Riesenfeld SJ, Pearson AT. Analysis of AI foundation model features decodes the histopathologic landscape of HPV-positive head and neck squamous cell carcinomas. Oral Oncol 2025; 163:107207. [PMID: 40043423 DOI: 10.1016/j.oraloncology.2025.107207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 01/19/2025] [Accepted: 01/25/2025] [Indexed: 03/29/2025]
Abstract
OBJECTIVES Human papillomavirus (HPV) influences the pathobiology of Head and Neck Squamous Cell Carcinomas (HSNCCs). While deep learning shows promise in detecting HPV from hematoxylin and eosin (H&E) stained slides, the histologic features utilized remain unclear. This study leverages artificial intelligence (AI) foundation models to characterize histopathologic features associated with HPV presence and objectively describe patterns of variability in the HPV-positive space. MATERIALS AND METHODS H&E images from 981 HNSCC patients across public and institutional datasets were analyzed. We used UNI, a foundation model based on self-supervised learning (SSL), to map the landscape of HNSCC histology and identify the axes of SSL features that best separate HPV-positive and HPV-negative tumors. To interpret the histologic features that vary across different regions of this landscape, we used HistoXGAN, a pretrained generative adversarial network (GAN), to generate synthetic histology images from SSL features, which a pathologist rigorously assessed. RESULTS Analyzing AI-generated synthetic images found distinctive features of HPV-positive histology, such as smaller, paler, more monomorphic nuclei; purpler, amphophilic cytoplasm; and indistinct cell borders with rounded tumor contours. The SSL feature axes we identified enabled accurate prediction of HPV status from histology, achieving validation sensitivity and specificity of 0.81 and 0.92, respectively. Our analysis subdivided image tiles from HPV-positive histology into three overlapping subtypes: border, inflamed, and stroma. CONCLUSION Foundation-model-derived synthetic pathology images effectively capture HPV-related histology. Our analysis identifies distinct subtypes within HPV-positive HNSCCs and enables accurate, explainable detection of HPV presence directly from histology, offering a valuable approach for low-resource clinical settings.
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Affiliation(s)
- Hanna M Hieromnimon
- Graduate Program in Biophysical Sciences, University of Chicago, Chicago, IL 60637, USA
| | - Anna Trzcinska
- Department of Pathology, University of Chicago, Chicago, IL 60637, USA
| | - Frank T Wen
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | | | | | - Emma Dyer
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Sara Kochanny
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Jefree J Schulte
- Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53792, USA
| | - Cindy Wang
- Department of Pathology, Stanford University, Palo Alto, CA 94305, USA
| | - Heather Chen
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jeffrey Chin
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | | | | | - Ari Rosenberg
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Everett Vokes
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | | | | | - Evgeny Izumchenko
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Mark W Lingen
- Department of Pathology, University of Chicago, Chicago, IL 60637, USA; Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Nicole Cipriani
- Department of Pathology, University of Chicago, Chicago, IL 60637, USA
| | - Jalal B Jalaly
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Devraj Basu
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Samantha J Riesenfeld
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA; CZ Biohub Chicago, LLC, University of Chicago, Chicago, IL 60642, USA; NSF-Simons National Institute for Theory and Mathematics in Biology (NITMB), Chicago, IL 60637, USA.
| | - Alexander T Pearson
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA; CZ Biohub Chicago, LLC, University of Chicago, Chicago, IL 60642, USA.
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Azalmad K, Lambercy K, Beharry A, Piazzon N, Barbesier M, Dalla‐Vale M, Moraru M, Berezowska S, Simon C. Trans Oral Robotic Surgery for HPV-Negative Oropharyngeal Squamous Cell Carcinoma: Follow-Up on Oncological and Functional Outcomes. Head Neck 2025; 47:791-800. [PMID: 39400549 PMCID: PMC11816564 DOI: 10.1002/hed.27958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 07/22/2024] [Accepted: 09/26/2024] [Indexed: 10/15/2024] Open
Abstract
BACKGROUND The efficacy of transoral robotic surgery (TORS) for HPV-negative oropharyngeal cancers (OPSCC) is less explored, especially regarding long-term outcomes and prognostic factors. METHODS We conducted a retrospective monocentric study on 37 patients with HPV-negative OPSCC treated with TORS with a median follow-up of 3 years, assessing survival outcomes using Kaplan-Meyer statistics and swallowing function via the functional outcome swallowing scale (FOSS). Histopathological parameters were collected either from medical records or histology slides were re-evaluated. RESULTS Patients demonstrated high disease-specific survival (DSS) but lower overall survival (OS), with a cohort characterized by high comorbidity rates. Vascular invasion was a significant adverse factor for relapse-free survival (RFS) and OS, while lymphatic invasion was not. Most patients demonstrated significant preservation of swallowing function. CONCLUSIONS TORS for HPV-negative OPSCC demonstrates high DSS and preserved swallowing function. Vascular invasion is a key prognostic factor for survival outcomes.
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Affiliation(s)
- Khalid Azalmad
- Department of Otolaryngology—Head and Neck Surgery, CHUVUniversity of LausanneLausanneSwitzerland
| | - Karma Lambercy
- Department of Otolaryngology—Head and Neck Surgery, CHUVUniversity of LausanneLausanneSwitzerland
| | - Avinash Beharry
- Department of Otolaryngology—Head and Neck Surgery, CHUVUniversity of LausanneLausanneSwitzerland
| | - Nathalie Piazzon
- Department of Laboratory Medicine and Pathology, Institute of Pathology, CHUVUniversity of LausanneLausanneSwitzerland
| | - Marie Barbesier
- Department of Laboratory Medicine and Pathology, Institute of Pathology, CHUVUniversity of LausanneLausanneSwitzerland
| | - Margaux Dalla‐Vale
- Department of Otolaryngology—Head and Neck Surgery, CHUVUniversity of LausanneLausanneSwitzerland
| | - Manuela Moraru
- Department of Otolaryngology—Head and Neck Surgery, CHUVUniversity of LausanneLausanneSwitzerland
| | - Sabina Berezowska
- Department of Laboratory Medicine and Pathology, Institute of Pathology, CHUVUniversity of LausanneLausanneSwitzerland
| | - Christian Simon
- Department of Otolaryngology—Head and Neck Surgery, CHUVUniversity of LausanneLausanneSwitzerland
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Sadeghi N, Subramaniam T, Richardson K, Mascarella M, Zeitouni A, Shenouda G, Sultanem K, Mlynarek A, Caglar D, Esfahani K, Joshi A, Siegel R, Goodman J, Thakkar P, Lee E, Golabi N, Ramanakumar AV, Hier M, Bouganim N. Neoadjuvant Chemotherapy and Transoral Robotic Surgery for Human Papillomavirus-Related Oropharyngeal Cancer. JAMA Otolaryngol Head Neck Surg 2025; 151:128-134. [PMID: 39636629 PMCID: PMC11622064 DOI: 10.1001/jamaoto.2024.3303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 10/03/2024] [Indexed: 12/07/2024]
Abstract
Importance Distant metastasis (DM) remains the leading cause of death in patients treated for human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC). An effective treatment strategy needs to address DM while reducing treatment-related toxic effects. Objective To assess DM-free survival in patients with HPV-OPSCC treated with neoadjuvant chemotherapy followed by transoral robotic surgery (NECTORS) and neck dissection compared with standard of care, concurrent chemoradiation (CCRT). Design, Setting, and Participants This multicenter retrospective cohort study compares prospective data from the NECTORS treatment group with a historical cohort of patients treated with CCRT. Patients with American Joint Committee on Cancer seventh edition stage III and IVa HPV-OPSCC treated with NECTORS and CCRT between February 2010 and September 2021 were included. Data were analyzed in September 2024. Exposures Patients in the NECTORS arm were treated with 3 cycles of neoadjuvant docetaxel and cisplatin followed by TORS and neck dissection. Patients in the radiation therapy arm were treated with concurrent high-dose cisplatin and radiotherapy. Main Outcomes and Measures DM-free survival was analyzed with Kaplan-Meier and Cox regression after adjusting for age, sex, tobacco and alcohol use, site, and cancer stage. Results Of 342 included patients, 282 (82.5%) were male, and the mean (SD) age was 61.4 (9.4) years. A total of 232 patients were treated with CCRT and 110 patients were treated with NECTORS. Within the CCRT arm, 11 patients (4.7%) had locoregional recurrence (LRR), 5 (2.2%) had LRR and DM, and 28 (12.1%) developed distant-only metastasis. For patients treated with NECTORS, 5 (4.5%) developed LRR, 1 (0.9%) developed LRR plus DM, and no patients developed distant-only metastasis. With pseudorandomization matching for T and N stages, 209 patients were matched between the 2 treatment groups for further analysis (105 in the CCRT treatment arm and 104 in the NECTORS arm). The median (range) follow-up period for the CCRT and NECTORS groups were 5.8 (3.8-7.5) years and 5.1 (4.0-5.9) years, respectively. The hazard ratio of developing distant recurrence in the CCRT group was 10.77 (95% CI, 1.40-82.90) in univariate analysis and 9.98 (95% CI, 1.29-77.29) in multivariable analysis. In Kaplan-Meier survival analysis, the risk of developing DM was higher in the CCRT group. The hazard ratio for failure anywhere in the CCRT group was 3.32 (95% CI, 1.23-8.97) in univariate analysis and 3.21 (95% CI, 1.18-8.72) in multivariable analysis. Conclusions and Relevance In this study, neoadjuvant chemotherapy followed by transoral robotic surgery and neck dissection was an effective treatment option for patients with stage III and IVa HPV-OPSCC. Findings from our study suggest lower rates of DM with NECTORS worthy of further investigation in prospective randomized trials.
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Affiliation(s)
- Nader Sadeghi
- Department of Otolaryngology—Head and Neck Surgery, McGill University, Montreal, Quebec, Canada
- Department of Oncology, McGill University, Montreal, Quebec, Canada
- Research Institute of McGill University Health Centre, Montreal, Quebec, Canada
| | - Thavakumar Subramaniam
- Department of Otolaryngology—Head and Neck Surgery, McGill University, Montreal, Quebec, Canada
| | - Keith Richardson
- Department of Otolaryngology—Head and Neck Surgery, McGill University, Montreal, Quebec, Canada
| | - Marco Mascarella
- Department of Otolaryngology—Head and Neck Surgery, McGill University, Montreal, Quebec, Canada
- Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada
| | - Anthony Zeitouni
- Department of Otolaryngology—Head and Neck Surgery, McGill University, Montreal, Quebec, Canada
| | - George Shenouda
- Department of Oncology, McGill University, Montreal, Quebec, Canada
| | - Khalil Sultanem
- Department of Oncology, McGill University, Montreal, Quebec, Canada
- Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada
| | - Alex Mlynarek
- Department of Otolaryngology—Head and Neck Surgery, McGill University, Montreal, Quebec, Canada
- Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada
| | - Derin Caglar
- Department of Pathology, McGill University Health Centre, Montreal, Quebec, Canada
| | | | - Arjun Joshi
- George Washington University Hospital, Washington, DC
| | - Robert Siegel
- George Washington University Hospital, Washington, DC
| | | | - Punam Thakkar
- George Washington University Hospital, Washington, DC
| | - Esther Lee
- George Washington University Hospital, Washington, DC
| | - Nahid Golabi
- Department of Otolaryngology—Head and Neck Surgery, McGill University, Montreal, Quebec, Canada
| | | | - Michael Hier
- Department of Otolaryngology—Head and Neck Surgery, McGill University, Montreal, Quebec, Canada
- Department of Oncology, McGill University, Montreal, Quebec, Canada
- Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada
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Shin E, Choi J, Hung TKW, Poon C, Riaz N, Yu Y, Kang JJ. Prognosis of p16 and Human Papillomavirus Discordant Oropharyngeal Cancers and the Exploration of Using Natural Language Processing to Analyze Free-Text Pathology Reports. JCO Clin Cancer Inform 2025; 9:e2400177. [PMID: 39965177 DOI: 10.1200/cci-24-00177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 11/04/2024] [Accepted: 01/07/2025] [Indexed: 02/20/2025] Open
Abstract
PURPOSE Treatment deintensification for human papillomavirus-positive (HPV+)-associated oropharyngeal cancer (OPC) has been the catalyst of experts worldwide. In situ hybridization is optimal to identify HPV+ OPC, but immunohistochemistry for its surrogate p16INK4a (p16) is standard-of-care given its availability and sensitivity. HPV testing is not required for clinical management, so treatments are often administered on the basis of p16 status alone. However, the prognosis of p16/HPV discordant tumors is uncertain. MATERIALS AND METHODS This cohort study included 727 consecutive patients with OPC with digitized unstructured pathology reports receiving curative radiation therapy at an academic cancer center. Natural language processing (NLP) methods were used to classify biomarker status and compared against manually derived classification. Patients were excluded if either p16 or HPV testing was not performed or equivocal. Primary end points were progression-free survival (PFS), cancer-specific survival (CSS), and overall survival. RESULTS NLP classified p16 and HPV status from a majority (91%) of reports. Accuracy, positive predictive value, sensitivity, and F-score for NLP-derived p16/HPV were 84%/82%, 91%/87%, 90%/89%, and 90%/88%, respectively. Four groups were identified: p16-positive (p16+)/HPV+ (75%), p16+/HPV-negative (HPV-; 13%), p16-negative (p16-)/HPV- (10%), and p16-/HPV+ (2%). There was no statistically significant difference in outcomes between p16+/HPV- and p16-/HPV- patients (5-year PFS 76.1% v 68.9%; P = .12; 5-year CSS 81.5% v 84.9%; P = .22). Number needed to harm calculations estimated one excess cancer-related death for every 10 p16+/HPV- patients, compared with that expected with p16+/HPV+ patients. CONCLUSION NLP classified head and neck cancer pathology reports with high concordance with gold-standard categorization, but a conspicuous portion of reports could not be interpreted. p16/HPV discordant OPC constitutes a noteworthy minority of patients. The inferior prognosis of p16+/HPV- suggests that p16 alone for prognostication is insufficient-especially when considering treatment de-escalation.
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Affiliation(s)
| | - Justin Choi
- SUNY Downstate College of Medicine, Brooklyn, NY
| | - Tony K W Hung
- Memorial Sloan Kettering Cancer Center, New York, NY
| | - Chester Poon
- Memorial Sloan Kettering Cancer Center, New York, NY
| | - Nadeem Riaz
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Yao Yu
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jung Julie Kang
- Department of Therapeutic Radiology, Yale University, New Haven, CT
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Li R, Zhao Y, Wu K, Li H, Lin X, Zhu L, Zhu Y, Wang X. p16 status or response to induction chemotherapy, which predicts survival outcomes in Chinese oropharyngeal cancer treated with definitive radiotherapy? Radiother Oncol 2024; 201:110578. [PMID: 39395672 DOI: 10.1016/j.radonc.2024.110578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 09/25/2024] [Accepted: 10/02/2024] [Indexed: 10/14/2024]
Abstract
PURPOSE To identify whether p16 status or response to induction chemotherapy (IC) predicts the radiotherapy (RT) response and survival outcomes in Chinese oropharyngeal squamous cell carcinoma (OPSCC). METHODS A total of 211 patients, including 128 p16-positive and 83 p16-negative were analyzed. All patients underwent IC followed by definitive RT or concurrent chemoradiotherapy (CCRT). Propensity score matching (PSM) was used to eliminate the baseline variations. RESULTS Age, sex, smoking history, alcohol history, and primary site were unbalanced between different p16 status subgroups. Before PSM, the objective response rates to IC between p16-positive and p16-negative groups were 80.5 % and 85.5 % (p = 0.344). After RT, the complete response (CR) rates were 73.4 % and 66.3 %, respectively (p = 0.264). IC-sensitive (IC-s) subgroups had a higher percentage of RT-CR rate than the IC-resistant (IC-r) subgroups in both p16-positive and p16-negative patients. IC-s showed significant improvement in cancer-specific survival (CSS) (92.9 % vs. 53.6 %, p < 0.0001), progression-free survival (PFS) (p < 0.0001), locoregional relapse-free survival (LRFS) (p < 0.0001) and distant metastasis-free survival (DMFS) (p = 0.025). After PSM, the CR rates among different p16 groups remained comparable following RT (71.2 % vs. 65.8 %, p = 0.476). Before or after PSM, CSS, PFS, LRFS, and DMFS were similar between different p16 status either in IC-s or IC-r subgroups (p > 0.05). IC-r was independently associated with shorter PFS (HR = 2.661, p = 0.002) and LRFS (HR = 2.876, p = 0.002; HR = 2.78, p = 0.018). CONCLUSIONS Response to IC is an important predictor of prognosis in Chinese OPSCC treated with definitive RT. Poor response to IC is associated with unsatisfactory outcomes either in p16-positive or p16-negative OPSCC.
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Affiliation(s)
- Ruichen Li
- Department of Radiation Oncology, Eye & ENT Hospital of Fudan University, Shanghai 200031, China
| | - Yang Zhao
- Department of Radiation Oncology, Eye & ENT Hospital of Fudan University, Shanghai 200031, China
| | - Kangting Wu
- Department of Radiation Oncology, Eye & ENT Hospital of Fudan University, Shanghai 200031, China
| | - Huiqing Li
- Department of Radiation Oncology, Eye & ENT Hospital of Fudan University, Shanghai 200031, China
| | - Xinru Lin
- Department of Radiation Oncology, Eye & ENT Hospital of Fudan University, Shanghai 200031, China
| | - Liting Zhu
- Department of Radiation Oncology, Eye & ENT Hospital of Fudan University, Shanghai 200031, China
| | - Yi Zhu
- Department of Radiation Oncology, Eye & ENT Hospital of Fudan University, Shanghai 200031, China.
| | - Xiaoshen Wang
- Department of Radiation Oncology, Eye & ENT Hospital of Fudan University, Shanghai 200031, China.
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9
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Wotman MT, Ivic-Pavlicic T, Westra WH, Gold B, D’Andrea M, Genden EM, Misiukiewicz K, Roof SA, Taioli E, Posner M. Association of human papillomavirus genotype and phylogenic clade with oropharyngeal cancer outcomes. Oncologist 2024; 29:966-977. [PMID: 39137148 PMCID: PMC11546636 DOI: 10.1093/oncolo/oyae202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 07/05/2024] [Indexed: 08/15/2024] Open
Abstract
BACKGROUND Human papillomavirus (HPV)+ oropharynx cancer (OPC) has a more favorable prognosis than HPV-negative disease, but the impact of specific HPV genotype and phylogenic clade on patient outcomes is not well understood and has profound implications for treatment de-intensification. METHODS The objective of this single-institution cohort study was to investigate the association of HPV genotype (16 vs high-risk non-16) and clade (A9 vs A7) with OPC outcomes. The primary endpoints were overall survival (OS) and event-free survival (EFS) in patients with M0 disease treated with curative intent. RESULTS The cohort included 598 patients (87% HPV16, 98% A9). Compared to those with HPV16 OPC, individuals with non-HPV16 OPC had a higher age, comorbidity index, and proportion of non-whites, HIV+ patients, T4 tumors, and stage IV disease (AJCC 7th edition). Non-HPV16 genotype was associated with worse OS in univariate (HR = 2.17, 95% CI, 1.24-3.80, P = .0066), but not in multivariate analysis (HRadj = 0.84, 95% CI, 0.43-1.62, P = .5921). A7 clade was associated with worse OS in univariate (HR = 4.42, 95% CI, 1.60-12.30, P = .0041), but not in multivariate analysis (HRadj = 2.39, 95% CI, 0.57-9.99, P = .2325). Neither HPV genotype (HR = 1.60, 95% CI, 0.99-2.60, P = .0566) nor phylogenic clade (HR = 2.47, 95% CI, 0.91-6.72, P = .0761) was associated with EFS. CONCLUSION Non-HPV16 genotype and A7 clade were associated with worse OS and trended toward worse EFS in univariate analyses. The survival differences were more pronounced by phylogenic clade than by HPV16 status, suggesting that the former may be a more useful classification for future studies. However, neither HPV16 status nor phylogenic clade was prognostic when adjusting for patient and tumor covariates, raising the question as to whether possible differences in outcomes are related to distinct clinical profiles rather than inherent viral properties.
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Affiliation(s)
- Michael T Wotman
- Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Tara Ivic-Pavlicic
- Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - William H Westra
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Brandon Gold
- Department of Otolaryngology, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - Megan D’Andrea
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Eric M Genden
- Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Krzysztof Misiukiewicz
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Scott A Roof
- Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Emanuela Taioli
- Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Marshall Posner
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
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10
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Hanna GJ, Jabalee J, Lukens JN, Sun L, Rettig EM, Ferrandino R, Posner MR, Misiukiewicz KJ, Routman DM, Van Abel KM, Del Vecchio Fitz C, Roof SA. Circulating tumor tissue modified viral (TTMV)-HPV DNA in Recurrent, metastatic HPV-driven oropharyngeal cancer. Oral Oncol 2024; 158:107002. [PMID: 39159525 DOI: 10.1016/j.oraloncology.2024.107002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 08/14/2024] [Accepted: 08/14/2024] [Indexed: 08/21/2024]
Abstract
BACKGROUND Human papillomavirus (HPV) is causally linked to oropharyngeal squamous cell carcinoma (OPSCC). Testing for plasma tumor tissue modified viral (TTMV)-HPV DNA has emerged as a biomarker strategy for post-treatment surveillance to identify recurrent disease. We aimed to understand the prognostic and predictive potential of TTMV-HPV DNA when monitoring patients who had developed recurrent or metastatic (R/M) HPV+OPSCC. METHODS This retrospective observational cohort study included 80 patients from 4 academic centers with R/M HPV+OPSCC if they had ≥ 1 plasma TTMV-HPV DNA test obtained at any point during their R/M disease course. Physician-reported clinical data and treatment history were captured in a centralized database, along with investigator-assessed response to therapy and survival. Descriptive statistics and non-parametric tests of association were employed along with survival analyses (Kaplan-Meier method). RESULTS Sixteen (20 %) patients had ≥ 5 test results over time. Consecutive TTMV-HPV DNA tests were performed a median of 73 days apart. Median TTMV-HPV DNA scores were higher with an increasing per-patient number of metastatic sites (<2 vs. 2+; p < 0.01). Score changes over time were influenced by R/M treatment modality and became undetectable in 67 % (12/18) of patients who achieved a complete response to R/M therapy. Patients with detectable scores at last follow-up had significantly worse survival compared with those who were undetectable (log-rank test, p < 0.01). CONCLUSIONS TTMV-HPV DNA appears useful as a prognostic tool for monitoring response to therapy in the R/M setting. In the future, TTMV-HPV DNA could be explored as an exploratory clinical trial endpoint in the metastatic setting.
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Affiliation(s)
- Glenn J Hanna
- Center for Head & Neck Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
| | | | - John N Lukens
- Head & Neck Service, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Lova Sun
- Head & Neck Service, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Eleni M Rettig
- Center for Head & Neck Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Rocco Ferrandino
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Marshall R Posner
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | | | | | | | - Scott A Roof
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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11
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Krsek A, Baticic L, Braut T, Sotosek V. The Next Chapter in Cancer Diagnostics: Advances in HPV-Positive Head and Neck Cancer. Biomolecules 2024; 14:925. [PMID: 39199313 PMCID: PMC11352962 DOI: 10.3390/biom14080925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/24/2024] [Accepted: 07/29/2024] [Indexed: 09/01/2024] Open
Abstract
Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC), particularly oropharyngeal squamous cell carcinoma (OPSCC), is an increasingly prevalent pathology worldwide, especially in developed countries. For diagnosing HPV in HNSCC, the combination of p16 immunohistochemistry (IHC) and polymerase chain reaction (PCR) offers high sensitivity and specificity, with p16 IHC being a reliable initial screen and PCR confirming HPV presence. Advanced techniques like next-generation sequencing (NGS) and RNA-based assays provide detailed insights but are primarily used in research settings. Regardless of HPV status, standard oncological treatments currently include surgery, radiation, and/or chemotherapy. This conventional approach does not account for the typically better prognosis of HPV-positive HNSCC patients, leading to increased chemo/radiation-induced secondary morbidities and reduced quality of life. Therefore, it is crucial to identify and detect HPV positivity and other molecular characteristics of HNSCC to personalize treatment strategies. This comprehensive review aims to summarize current knowledge on various HPV detection techniques and evaluate their advantages and disadvantages, with a focus on developing methodologies to identify new biomarkers in HPV-positive HNSCC. The review discusses direct and indirect HPV examination in tumor tissue, DNA- and RNA-based detection techniques, protein-based markers, liquid biopsy potentials, immune-related markers, epigenetic markers, novel biomarkers, and emerging technologies, providing an overall insight into the current state of knowledge.
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Affiliation(s)
- Antea Krsek
- Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia;
| | - Lara Baticic
- Department of Medical Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia
| | - Tamara Braut
- Department of Otorhinolaryngology and Head and Neck Surgery, Clinical Hospital Centre Rijeka, 51000 Rijeka, Croatia;
| | - Vlatka Sotosek
- Department of Anesthesiology, Reanimatology, Emergency and Intensive Care Medicine, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia;
- Department of Clinical Medical Sciences I, Faculty of Health Studies, University of Rijeka, 51000 Rijeka, Croatia
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12
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Laxague F, Zeng PYF, Zabihi D, Fnais N, Alshahrani M, Fung K, MacNeil D, Mendez A, Yoo J, Mymryk JS, Barrett JW, Palma DA, Nichols AC. A comparison of timing and patterns of treatment failure, and survival outcomes after progression between HPV+ and HPV- patients undergoing chemoradiation for oropharyngeal squamous cell carcinomas. Head Neck 2024; 46:503-512. [PMID: 38100227 DOI: 10.1002/hed.27600] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 10/17/2023] [Accepted: 12/01/2023] [Indexed: 02/13/2024] Open
Abstract
BACKGROUND We aimed to analyze and compare the timing and patterns of treatment failure, and survival after progression between HPV-positive (HPV+) and HPV-negative (HPV-) patients undergoing chemoradiation for oropharyngeal squamous cell carcinomas (OPSCC). METHODS A retrospective review was performed of all patients undergoing primary chemoradiation for OPSCC between 2008 and 2021. Demographic and clinical data were collected. Kaplan-Meier estimates for overall survival (OS), and time to recurrence/metastases (TTR) were compared using the log-rank test, with Cox regression used for multivariable modeling comparing HPV+ and HPV- patients. RESULTS HPV- patients developed recurrence or metastases at earlier time points than HPV+ patients (8.8 vs. 15.2 months, p < 0.05), due to earlier local/locoregional recurrence and distant metastases, but not isolated regional recurrences. HPV- distant metastases exclusively occurred in a single organ, most commonly the lungs or bone, while HPV+ metastases frequently had multi-organ involvement in a wide variety of locations (p < 0.05). Once progression (recurrence/metastases) was diagnosed, HPV+ patients experienced superior survival to HPV- patients on univariate and multivariate analysis, largely due to improved outcomes after treatment of local/locoregional recurrences (p < 0.05). There were no differences in survival after isolated regional recurrences or distant metastases. CONCLUSION HPV+ OPSCC patients relapse later compared to HPV- patients in local/locoregional and distant sites. HPV+ patients with local/locoregional recurrence experience superior survival after recurrence, which does not hold true for isolated regional recurrences or distant metastases. These data can be useful to inform prognosis and guide treatment decisions in patients with recurrent OPSCC.
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Affiliation(s)
- Francisco Laxague
- Department of Otolaryngology - Head and Neck Surgery, London Health Sciences Center Children's Hospital, London, Ontario, Canada
| | - Peter Y F Zeng
- Department of Otolaryngology - Head and Neck Surgery, London Health Sciences Center Children's Hospital, London, Ontario, Canada
| | - Dorsa Zabihi
- Department of Otolaryngology - Head and Neck Surgery, London Health Sciences Center Children's Hospital, London, Ontario, Canada
| | - Naif Fnais
- Department of Otolaryngology - Head and Neck Surgery, London Health Sciences Center Children's Hospital, London, Ontario, Canada
- Department of Otolaryngology - Head and Neck Surgery, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed Alshahrani
- Department of Otolaryngology - Head and Neck Surgery, London Health Sciences Center Children's Hospital, London, Ontario, Canada
| | - Kevin Fung
- Department of Otolaryngology - Head and Neck Surgery, London Health Sciences Center Children's Hospital, London, Ontario, Canada
| | - Danielle MacNeil
- Department of Otolaryngology - Head and Neck Surgery, London Health Sciences Center Children's Hospital, London, Ontario, Canada
| | - Adrian Mendez
- Department of Otolaryngology - Head and Neck Surgery, London Health Sciences Center Children's Hospital, London, Ontario, Canada
| | - John Yoo
- Department of Otolaryngology - Head and Neck Surgery, London Health Sciences Center Children's Hospital, London, Ontario, Canada
| | - Joseph S Mymryk
- Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada
- Department of Microbiology & Immunology, University of Western Ontario, London, Ontario, Canada
| | - John W Barrett
- Department of Otolaryngology - Head and Neck Surgery, London Health Sciences Center Children's Hospital, London, Ontario, Canada
| | - David A Palma
- Department of Oncology, University of Western Ontario, London, Ontario, Canada
| | - Anthony C Nichols
- Department of Otolaryngology - Head and Neck Surgery, London Health Sciences Center Children's Hospital, London, Ontario, Canada
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13
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Khoo A, Boyer M, Jafri Z, Makeham T, Pham T, Khachigian LM, Floros P, Dowling E, Fedder K, Shonka D, Garneau J, O'Meara CH. Human Papilloma Virus Positive Oropharyngeal Squamous Cell Carcinoma and the Immune System: Pathogenesis, Immunotherapy and Future Perspectives. Int J Mol Sci 2024; 25:2798. [PMID: 38474047 DOI: 10.3390/ijms25052798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 02/14/2024] [Accepted: 02/16/2024] [Indexed: 03/14/2024] Open
Abstract
Oropharyngeal squamous cell carcinoma (OPSCC), a subset of head and neck squamous cell carcinoma (HNSCC), involves the palatine tonsils, soft palate, base of tongue, and uvula, with the ability to spread to adjacent subsites. Personalized treatment strategies for Human Papillomavirus-associated squamous cell carcinoma of the oropharynx (HPV+OPSCC) are yet to be established. In this article, we summarise our current understanding of the pathogenesis of HPV+OPSCC, the intrinsic role of the immune system, current ICI clinical trials, and the potential role of small molecule immunotherapy in HPV+OPSCC.
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Affiliation(s)
- A Khoo
- Department of Otolaryngology, Head & Neck Surgery, Canberra Health Services, Canberra, ACT 2601, Australia
| | - M Boyer
- Chris O'Brien Lifehouse, Camperdown, NSW 2050, Australia
| | - Z Jafri
- Vascular Biology and Translational Research, Department of Pathology, School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
| | - T Makeham
- Department of Otolaryngology, Head & Neck Surgery, Canberra Health Services, Canberra, ACT 2601, Australia
- ANU School of Medicine & Psychology, Australian National University, Canberra, ACT 0200, Australia
| | - T Pham
- Department of Otolaryngology, Head & Neck Surgery, Canberra Health Services, Canberra, ACT 2601, Australia
- ANU School of Medicine & Psychology, Australian National University, Canberra, ACT 0200, Australia
| | - L M Khachigian
- Vascular Biology and Translational Research, Department of Pathology, School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia
| | - P Floros
- St Vincent's Hospital, 390 Victoria Street, Sydney, NSW 2010, Australia
| | - E Dowling
- Department of Otolaryngology, Head & Neck Surgery, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
| | - K Fedder
- Department of Otolaryngology, Head & Neck Surgery, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
| | - D Shonka
- Department of Otolaryngology, Head & Neck Surgery, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
| | - J Garneau
- Department of Otolaryngology, Head & Neck Surgery, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
| | - C H O'Meara
- Department of Otolaryngology, Head & Neck Surgery, Canberra Health Services, Canberra, ACT 2601, Australia
- ANU School of Medicine & Psychology, Australian National University, Canberra, ACT 0200, Australia
- Department of Otolaryngology, Head & Neck Surgery, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
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14
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Cossyleon R, Robinson K, Delfino K, Robbins KT, Rao K. Quality of life following treatment with intra-arterial cisplatin with concurrent radiation and erlotinib for locally advanced head and neck cancer. Support Care Cancer 2024; 32:93. [PMID: 38193937 PMCID: PMC10776718 DOI: 10.1007/s00520-023-08286-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 12/20/2023] [Indexed: 01/10/2024]
Abstract
OBJECTIVES Studies that focus on the feasibility of using erlotinib plus chemoradiation to treat locally advanced head and neck cancer have given hints of improved survival outcomes compared to chemoradiation alone. However, the influence of this treatment regimen on the quality of life of the patients has not been documented. We conducted a study of this triple combination and now have documented follow-up survival data as well as long-term quality of life (QoL) measures. METHODS Three sets of QoL questionnaires were given to patients with a diagnosis of head and neck cancer at two time points, pre- and post-treatment, to assess differences in quality of life after receiving chemotherapy with intra-arterial (IA) cisplatin (150 mg/m2), concomitant radiation (70 Gy), and oral erlotinib (150 mg/day). Additionally, patients were followed for a total of 5 years. RESULTS Treatment had a detrimental effect on appearance, taste, and saliva domain scores in their QoL questionnaires. Nonetheless, fewer patients reported pain and anxiety. SIGNIFICANCE OF RESULTS The combination of erlotinib with chemoradiation produced similar adverse effects on the QoL scores of patients with head and neck cancer as compared to chemoradiation alone.
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Affiliation(s)
- Ricardo Cossyleon
- Simmons Cancer Institute, Southern Illinois University School of Medicine, 315 W. Carpenter St., PO Box 19677, Springfield, IL, USA
- Center for Clinical Research, Southern Illinois University School of Medicine, Springfield, IL, USA
| | - Kathy Robinson
- Simmons Cancer Institute, Southern Illinois University School of Medicine, 315 W. Carpenter St., PO Box 19677, Springfield, IL, USA
- Center for Clinical Research, Southern Illinois University School of Medicine, Springfield, IL, USA
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL, USA
| | - Kristin Delfino
- Center for Clinical Research, Southern Illinois University School of Medicine, Springfield, IL, USA
| | - K Thomas Robbins
- Simmons Cancer Institute, Southern Illinois University School of Medicine, 315 W. Carpenter St., PO Box 19677, Springfield, IL, USA
- Division of Otolaryngology Head and Neck Surgery, Department of Surgery, Southern Illinois University School of Medicine, Springfield, IL, USA
| | - Krishna Rao
- Simmons Cancer Institute, Southern Illinois University School of Medicine, 315 W. Carpenter St., PO Box 19677, Springfield, IL, USA.
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL, USA.
- Department of Medical Microbiology, Southern Illinois University School of Medicine, Springfield, IL, USA.
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15
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von Witzleben A, Ellis M, Thomas GJ, Hoffmann TK, Jackson R, Laban S, Ottensmeier CH. Tumor-Infiltrating CD103+ Tissue-Resident Memory T Cells and CD103-CD8+ T Cells in HNSCC Are Linked to Outcome in Primary but not Metastatic Disease. Clin Cancer Res 2024; 30:224-234. [PMID: 37874322 DOI: 10.1158/1078-0432.ccr-23-0445] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 05/14/2023] [Accepted: 10/23/2023] [Indexed: 10/25/2023]
Abstract
PURPOSE High numbers of tumor-infiltrating lymphocytes (TIL) are linked to better survival in patients with cancer. Tissue-resident memory T cells (TRM; CD8+CD103+) are recognized as a key player of anticancer immune response. To assess TRM cells in primary, metastatic, and recurrent head and neck squamous cell carcinoma (HNSCC), we developed a tissue microarray (TMA) and used multiplex IHC (MxIHC). EXPERIMENTAL DESIGN Samples from primary tumors of 379 HNSCC cases treated at Southampton Hospitals between 2000 and 2016 were collected and analyzed. Of these, 105 cases had lymph node metastases and 82 recurrences. A TMA was generated with triplicate cores for each sample. MxIHC with a stain-and-strip approach was performed using CD8, CD103, and TIM3. Scanned slides were analyzed (digital image analysis) and quality checked (QC). RESULTS After QC, 194 primary tumors, 76 lymph node metastases, and 65 recurrences were evaluable. Alcohol consumption was statistically significantly correlated with a reduction of TRM cells in primary tumors (nondrinker vs. heavy drinker: P = 0.0036). The known survival benefit of TRM cell infiltration in primary tumors was not found for lymph node metastasis. In recurrences, a high TRM cell number led to a favorable outcome after 12 months. The checkpoint molecule TIM3, was expressed significantly higher on TRM and non-TRM cells in the lymph node compared with primary tumors (P < 0.0001), which was also seen in recurrences (P = 0.0134 and P = 0.0007, respectively). CONCLUSIONS We confirm the prognostic impact of TIL in primary tumors and in recurrences. TRM cell density in lymph node metastases was not linked to outcome. The role of TIM3, as a therapeutic target remains to be defined.
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Affiliation(s)
- Adrian von Witzleben
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Ulm, Ulm, Germany
- CRUK and NIHR Experimental Cancer Medicine Center and School of Cancer Sciences, Faculty of Medicine, H, Southampton, United Kingdom
| | - Matthew Ellis
- CRUK and NIHR Experimental Cancer Medicine Center and School of Cancer Sciences, Faculty of Medicine, H, Southampton, United Kingdom
| | - Gareth J Thomas
- CRUK and NIHR Experimental Cancer Medicine Center and School of Cancer Sciences, Faculty of Medicine, H, Southampton, United Kingdom
- Southampton University Hospitals NHS Foundation Trust, Southampton, United Kingdom
| | - Thomas K Hoffmann
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Ulm, Ulm, Germany
| | - Richard Jackson
- Liverpool Clinical Trials Center, University of Liverpool, Liverpool, United Kingdom
| | - Simon Laban
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Ulm, Ulm, Germany
| | - Christian H Ottensmeier
- Liverpool Head and Neck Center, Institute of Systems, Molecular and Integrative Biology and Liverpool CRUK and NIHR Experimental Cancer Medicine Center, UK University of Liverpool, Liverpool, United Kingdom
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16
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Xu T, Shen C, Zhou X, Zhu L, Xiang J, Wang Y, Zhu Y, He X, Ying H, Wang Y, Ji Q, Hu C, Lu X. Selective Treatment Deintensification by Reducing Radiation Dose and Omitting Concurrent Chemotherapy Based on Response to Induction Chemotherapy in Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma: A Single-Arm, Phase 2 Trial (IChoice-01). Int J Radiat Oncol Biol Phys 2024; 118:169-178. [PMID: 37574169 DOI: 10.1016/j.ijrobp.2023.07.037] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 07/18/2023] [Accepted: 07/29/2023] [Indexed: 08/15/2023]
Abstract
PURPOSE To demonstrate the feasibility of deintensification regimen in the light of the response to induction chemotherapy (IC) in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). METHODS AND MATERIALS Patients with p16+ OPSCC, T1-2/N1-3M0 (excluding T1N1M0 with single and ≤3 cm lymph node) or T3-4N0-3M0 were enrolled between January 2019 and July 2021. All patients received 2 cycles of IC with docetaxel 75 mg/m2 dL and cisplatin 75 mg/m2 dL every 3 weeks. Those with major responses (≥50% decrease in both primary and lymph nodes) to IC entered the deintensification cohort (cohort D), in which intensity modulated radiation therapy alone was given to a reduced dose of 60 Gy/30 fractions. Those who failed to meet major responsesentered the concurrent chemoradiotherapy cohort (cohort C), where the dose was simultaneously integrated boosted to a standard 70 Gy/35 fractions to nonmajor response sites, concurrently with cisplatin 80 mg/m2 dL,22. Patient-reported swallow function was documented using the MD Anderson Dysphagia Inventory. The primary endpoint was 2-year progression-free survival (PFS) using Simon's 2 stage design. RESULTS A total of 26 of 48 (54.2%) participants met the criteria to enter cohort D and 22 of 48 (45.8%) patients entered cohort C. With a median follow-up time of 29.7 months (6.9-48.0 months), 2-year PFS and OS rates were 85.4% and 93.6%, respectively for all enrolled patients. In cohort D, 2-year PFS and OS rates were both 100%. Grade 3 and 4 IC-related toxicities included leukopenia/neutropenia occurring in 41.7% and hyponatremia in 4.2% of patients. A higher incidence of grade 3 and 4 mucositis (61.9% vs 23.1% P = .022) was observed in cohort C. Consistent decline in longitudinal MD Anderson Dysphagia Inventory scores were observed at month 3 after radiation therapy between cohorts and both were found to recover to baseline at month 12. CONCLUSIONS Selective radiation therapy dose reduction and concurrent chemotherapy removal based on IC response in HPV + OPSCC was feasible and promising. Further study of this strategy to balance efficacy and toxicity is warranted in a prospective controlled trial.
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Affiliation(s)
- Tingting Xu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Radiation Oncology, Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China; Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Chunying Shen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Radiation Oncology, Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China; Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Xin Zhou
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Radiation Oncology, Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China; Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Lin Zhu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Radiation Oncology, Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China; Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Jun Xiang
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yulong Wang
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yongxue Zhu
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xiayun He
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Radiation Oncology, Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China; Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Hongmei Ying
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Radiation Oncology, Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China; Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Yu Wang
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Qinghai Ji
- Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
| | - Chaosu Hu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Radiation Oncology, Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China; Shanghai Key Laboratory of Radiation Oncology, Shanghai, China.
| | - Xueguan Lu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Radiation Oncology, Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China; Shanghai Key Laboratory of Radiation Oncology, Shanghai, China.
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Rahimy E, Gensheimer MF, Beadle B, Le QT. Lessons and Opportunities for Biomarker-Driven Radiation Personalization in Head and Neck Cancer. Semin Radiat Oncol 2023; 33:336-347. [PMID: 37331788 DOI: 10.1016/j.semradonc.2023.03.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/20/2023]
Abstract
Head and neck cancer is notoriously challenging to treat in part because it constitutes an anatomically and biologically diverse group of cancers with heterogeneous prognoses. While treatment can be associated with significant late toxicities, recurrence is often difficult to salvage with poor survival rates and functional morbidity.1,2 Thus, achieving tumor control and cure at the initial diagnosis is the highest priority. Given the differing outcome expectations (even within a specific sub-site like oropharyngeal carcinoma), there has been growing interest in personalizing treatment: de-escalation in selected cancers to decrease the risk of late toxicity without compromising oncologic outcomes, and intensification for more aggressive cancers to improve oncologic outcomes without causing undue toxicity. This risk stratification is increasingly accomplished using biomarkers, which can represent molecular, clinicopathologic, and/or radiologic data. In this review, we will focus on biomarker-driven radiotherapy dose personalization with emphasis on oropharyngeal and nasopharyngeal carcinoma. This radiation personalization is largely performed on the population level by identifying patients with good prognosis via traditional clinicopathologic factors, although there are emerging studies supporting inter-tumor and intra-tumor level personalization via imaging and molecular biomarkers.
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Affiliation(s)
- Elham Rahimy
- Department of Radiation Oncology, Stanford University, Stanford, CA.
| | | | - Beth Beadle
- Department of Radiation Oncology, Stanford University, Stanford, CA
| | - Quynh-Thu Le
- Department of Radiation Oncology, Stanford University, Stanford, CA
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18
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Ferreira CC. The relation between human papillomavirus (HPV) and oropharyngeal cancer: a review. PeerJ 2023; 11:e15568. [PMID: 37397013 PMCID: PMC10309048 DOI: 10.7717/peerj.15568] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 05/25/2023] [Indexed: 07/04/2023] Open
Abstract
Oropharyngeal squamous cell carcinomas (OPSCC) represent a major public health challenge. In 2020, the international agency for research on cancer (IARC) recorded 98,421 cases of OPSCC worldwide. Over the past decade, the epidemiological profile of patients with OPSCC has shifted, mainly due to a change in etiological factors. Previously, alcohol and tobacco were considered the primary contributors, but the human papillomavirus (HPV) is now recognized as the leading cause of these tumors. This study aimed to conduct a literature review on the relationship between OPSCC and HPV for the general practitioner. The review examined the primary clinical differences between HPV+ and HPV- OPSCC, their prognosis and treatment. In addition, the various HPV diagnostic methods were analyzed. Although there is a vast amount of literature on HPV, this review is unique in its ability to present the key information in an organized and accessible way and enables healthcare professionals to gain a better understanding of the relationship between HPV and oropharyngeal cancer. This, in turn, can contribute to the prevention of various cancers caused by the HPV virus, including oropharyngeal cancer.
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Affiliation(s)
- Chrystiano Campos Ferreira
- Department of Medicine, Federal University of Rondonia, Porto Velho, Rondonia, Brazil
- Head and Neck Department, Barretos Cancer Hospital, Porto Velho, Rondonia, Brazil
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19
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Tran NA, Palotai M, Hanna GJ, Schoenfeld JD, Bay CP, Rettig EM, Bunch PM, Juliano AF, Kelly HR, Suh CH, Zander DA, Morales Pinzon A, Kann BH, Huang RY, Haddad RI, Guttmann CRG, Guenette JP. Diagnostic performance of computed tomography features in detecting oropharyngeal squamous cell carcinoma extranodal extension. Eur Radiol 2023; 33:3693-3703. [PMID: 36719493 DOI: 10.1007/s00330-023-09407-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 12/06/2022] [Accepted: 12/27/2022] [Indexed: 02/01/2023]
Abstract
OBJECTIVES Accurate pre-treatment imaging determination of extranodal extension (ENE) could facilitate the selection of appropriate initial therapy for HPV-positive oropharyngeal squamous cell carcinoma (HPV + OPSCC). Small studies have associated 7 CT features with ENE with varied results and agreement. This article seeks to determine the replicable diagnostic performance of these CT features for ENE. METHODS Five expert academic head/neck neuroradiologists from 5 institutions evaluate a single academic cancer center cohort of 75 consecutive HPV + OPSCC patients. In a web-based virtual laboratory for imaging research and education, the experts performed training on 7 published CT features associated with ENE and then independently identified the "single most (if any) suspicious" lymph node and presence/absence of each of the features. Inter-rater agreement was assessed using percentage agreement, Gwet's AC1, and Fleiss' kappa. Sensitivity, specificity, and positive and negative predictive values were calculated for each CT feature based on histologic ENE. RESULTS All 5 raters identified the same node in 52 cases (69%). In 15 cases (20%), at least one rater selected a node and at least one rater did not. In 8 cases (11%), all raters selected a node, but at least one rater selected a different node. Percentage agreement and Gwet's AC1 coefficients were > 0.80 for lesion identification, matted/conglomerated nodes, and central necrosis. Fleiss' kappa was always < 0.6. CT sensitivity for histologically confirmed ENE ranged 0.18-0.94, specificity 0.41-0.88, PPV 0.26-0.36, and NPV 0.78-0.96. CONCLUSIONS Previously described CT features appear to have poor reproducibility among expert head/neck neuroradiologists and poor predictive value for histologic ENE. KEY POINTS • Previously described CT imaging features appear to have poor reproducibility among expert head and neck subspecialized neuroradiologists as well as poor predictive value for histologic ENE. • Although it may still be appropriate to comment on the presence or absence of these CT features in imaging reports, the evidence indicates that caution is warranted when incorporating these features into clinical decision-making regarding the likelihood of ENE.
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Affiliation(s)
- Ngoc-Anh Tran
- Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Miklos Palotai
- Center for Neurological Imaging, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Glenn J Hanna
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jonathan D Schoenfeld
- Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Camden P Bay
- Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Eleni M Rettig
- Division of Otolaryngology-Head and Neck Surgery, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Paul M Bunch
- Division of Neuroradiology, Wake Forest School of Medicine, Winston Salem, NC, USA
| | - Amy F Juliano
- Department of Radiology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - Hillary R Kelly
- Department of Radiology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
- Division of Neuroradiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Chong Hyun Suh
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - David A Zander
- Division of Neuroradiology, University of Colorado, Aurora, CO, USA
| | - Alfredo Morales Pinzon
- Center for Neurological Imaging, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Benjamin H Kann
- Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Raymond Y Huang
- Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Division of Neuroradiology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, 75 Francis Street Boston, Boston, MA, 02115, USA
| | - Robert I Haddad
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Charles R G Guttmann
- Center for Neurological Imaging, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jeffrey P Guenette
- Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
- Division of Neuroradiology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, 75 Francis Street Boston, Boston, MA, 02115, USA.
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20
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Mercke C, Wickart-Johansson G, Sjödin H, Farrajota Neves da Silva P, Alexandersson von Döbeln G, Margolin G, Jonmarker Jaraj S, Carstens H, Berglund A, Lax I, Hellström M, Hammarstedt-Nordenvall L, Friesland S. Radiotherapy-Dose Escalated for Large Volume Primary Tumors-And Cetuximab with or without Induction Chemotherapy for HPV Associated Squamous Cell Carcinoma of the Head and Neck-A Randomized Phase II Trial. Cancers (Basel) 2023; 15:cancers15092543. [PMID: 37174008 PMCID: PMC10177265 DOI: 10.3390/cancers15092543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/22/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
The leading cause of death for patients with HPV associated squamous cell carcinoma of the head and neck (SCCHN) after treatment with chemoradiotherapy (CRT) nowadays is peripheral metastasis. This study investigated whether induction chemotherapy (IC) could improve progression free survival (PFS) and impact on relapse pattern after CRT. METHODS Eligible patients in this multicenter, randomized, controlled, phase 2 trial had p16-positive locoregionally advanced SCCHN. Patients were randomized in a 1:1 ratio to either RT with cetuximab (arm B) versus the same regimen preceded by two cycles of taxotere/cisplatin/5-FU (arm A). The RT dose was escalated to 74.8 Gy for large volume primary tumors. Eligibility criteria included patients of 18-75 years, an ECOG performance status 0-1, and adequate organ functions. RESULTS From January 2011 to February 2016, 152 patients, all with oropharyngeal tumors were enrolled, 77 in arm A and 75 in arm B. Two patients, one in each group, withdrew their consent after randomization, leaving 150 patients for the ITT analysis. PFS at 2 years was 84.2% (95% CI 76.4-92.8) in arm A and 78.4% (95% CI 69.5-88.3) in arm B (HR 1.39, 95% CI 0.69-2.79, p = 0.40). At the time of analysis, there were 26 disease failures, 9 in arm A and 17 in arm B. In arm A, 3 patients had local, 2 regional, and 4 distant relapses as first sites of recurrence, and in arm B, 4, 4, and 9 relapses in corresponding sites. Eight out of 26 patients with disease progression had salvage therapy and 7 were alive NED (no evidence of disease), at 2 years. Locoregional control was 96% in arm A and 97.3% in arm B and OS 93% and 90.5%, respectively. Local failure as first site of recurrence was low, in 4.6% of patients and was similar for T1/T2 and T3/T4 tumors (n.s). Nevertheless, out of 7 patients with primary local failures, 4 were treated with the escalated RT dose. Toxicity was low and similar in the treatment arms. There was one fatal event in arm A where the combined effects of the drugs used in chemotherapy and cetuximab could not be ruled out. CONCLUSIONS PFS, locoregional control and toxicity did not differ between the two arms, OS was high, and there were few local relapses. In arm B, more than twice as many patients had distant metastasis as the first site of relapse compared to arm A. The response to IC was found to define 29% of patients in arm A who did not have a tumor relapse during follow-up. An escalated dose of 74.8 Gy could mitigate the negative impact of large tumor volume but for some patients, even this intensified treatment was insufficient.
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Affiliation(s)
- Claes Mercke
- Theme Cancer, Medical Unit Head&Neck, Lung and Skin Cancer, Karolinska University Hospital, Comprehensive Cancer Center, 17176 Stockholm, Sweden
- Department of Oncology-Pathology, Karolinska Institutet, 17176 Stockholm, Sweden
| | - Gun Wickart-Johansson
- Theme Cancer, Medical Unit Head&Neck, Lung and Skin Cancer, Karolinska University Hospital, Comprehensive Cancer Center, 17176 Stockholm, Sweden
- Department of Oncology-Pathology, Karolinska Institutet, 17176 Stockholm, Sweden
| | - Helena Sjödin
- Theme Cancer, Medical Unit Head&Neck, Lung and Skin Cancer, Karolinska University Hospital, Comprehensive Cancer Center, 17176 Stockholm, Sweden
- Department of Oncology-Pathology, Karolinska Institutet, 17176 Stockholm, Sweden
| | - Pedro Farrajota Neves da Silva
- Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital and Department of Oncology-Pathology, Karolinska Institutet, 17176 Stockholm, Sweden
| | - Gabriella Alexandersson von Döbeln
- Theme Cancer, Medical Unit Head&Neck, Lung and Skin Cancer, Karolinska University Hospital, Comprehensive Cancer Center, 17176 Stockholm, Sweden
- Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, 17164 Stockholm, Sweden
| | - Gregori Margolin
- Theme Cancer, Medical Unit Head&Neck, Lung and Skin Cancer, Karolinska University Hospital, Comprehensive Cancer Center, 17176 Stockholm, Sweden
- Division of Ear, Nose and throat Diseases and Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, 17176 Stockholm, Sweden
| | - Sara Jonmarker Jaraj
- Department of Neuroradiology, Karolinska University Hospital, 17176 Stockholm, Sweden
| | - Hanna Carstens
- Theme Cancer, Medical Unit Head&Neck, Lung and Skin Cancer, Karolinska University Hospital, Comprehensive Cancer Center, 17176 Stockholm, Sweden
- Department of Oncology-Pathology, Karolinska Institutet, 17176 Stockholm, Sweden
| | | | - Ingmar Lax
- Department of Oncology-Pathology, Karolinska Institutet, 17176 Stockholm, Sweden
- Theme Cancer, Karolinska University Hospital, 17176 Stockholm, Sweden
| | - Mats Hellström
- Theme Cancer, Karolinska University Hospital, 17176 Stockholm, Sweden
| | - Lalle Hammarstedt-Nordenvall
- Theme Cancer, Medical Unit Head&Neck, Lung and Skin Cancer, Karolinska University Hospital, Comprehensive Cancer Center, 17176 Stockholm, Sweden
- Division of Ear, Nose and throat Diseases and Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, 17176 Stockholm, Sweden
| | - Signe Friesland
- Theme Cancer, Medical Unit Head&Neck, Lung and Skin Cancer, Karolinska University Hospital, Comprehensive Cancer Center, 17176 Stockholm, Sweden
- Department of Oncology-Pathology, Karolinska Institutet, 17176 Stockholm, Sweden
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Shinomiya H, Nibu KI. Etiology, diagnosis, treatment, and prevention of human papilloma virus-associated oropharyngeal squamous cell carcinoma. Int J Clin Oncol 2023:10.1007/s10147-023-02336-8. [PMID: 37093464 PMCID: PMC10390603 DOI: 10.1007/s10147-023-02336-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Accepted: 03/30/2023] [Indexed: 04/25/2023]
Abstract
Classical oropharyngeal squamous cell carcinoma (OPSCC) caused by alcohol consumption and smoking and HPV-associated OPSCC caused by human papillomavirus (HPV) infection have different etiologies, incidences, and prognoses. Therefore, the 8th American Joint committee on Cancer (AJCC) and Union for International Cancer Control (UICC) TNM classifications propose distinguishing HPV-associated OPSCC from classical OPSCC and classifying it as an independent disease. Therefore, this review provides an overview of HPV-associated OPSCC from the perspectives of epidemiology, carcinogenesis, development, diagnosis, treatment, and prevention. The incidence of HPV-associated OPSCC is increasing. Although HPV vaccination has been shown to be effective at reducing the incidence of cervical cancer, it is still unclear how it affects the incidence of HPV-associated OPSCC. Additionally, the prognosis of patients with HPV-associated OPSCC is extremely favorable compared to that of patients with classical OPSCC. Therefore, patients with HPV-associated OPSCC may undergo reduced-dose therapy, although attempts to reduce treatment intensity should be carefully planned to ensure they do not compromise oncological outcomes, and large-scale trials aimed at reducing treatment intensity are ongoing.
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Affiliation(s)
- Hirotaka Shinomiya
- Department of Otolaryngology-Head and Neck Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan.
| | - Ken-Ichi Nibu
- Department of Otolaryngology-Head and Neck Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
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22
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Kaur V, Rooney A, Horton B. Prognostic significance of extra-nodal extension and positive surgical margins in HPV positive oropharyngeal squamous cell carcinoma. Am J Otolaryngol 2023; 44:103877. [PMID: 37030131 DOI: 10.1016/j.amjoto.2023.103877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 03/25/2023] [Indexed: 04/01/2023]
Abstract
BACKGROUND Whether extra-nodal extension (ENE+) and surgical margin positivity (margin+) are poor prognostic factors in HPV-associated (HPV+) oropharyngeal carcinoma (OPC) remains uncertain. RESULTS Our study evaluated if microscopic ENE+ and/or margin+ are associated poorer recurrence free survival (RFS) and overall survival (OS) in HPV+ OPC. Patients were classified as high risk (ENE+ and/or margin+) or low risk (ENE- and margins-). Of a total of 176 patients HPV+ OPC, 81 underwent primary surgery and dad data on ENE and margin status. There was no statistically significant difference in RFS (p = 0.35) or OS (p = 0.13) for high-risk versus low-risk groups. Ongoing smoking (p = 0.023), alcohol use (p = 0.044) and advanced stage (p = 0.019) were associated with higher risk of recurrence. Only advanced stage (p-value <0.0001) was associated poorer overall survival. CONCLUSIONS The presence of ENE+ and/or margin+ was not an independent predictor of poor RFS or OS in HPV+ OPC.
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23
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Varatanovic S, Maier T, Al-Gboore S, Stoiber S, Kandathil SA, Quint C, Brennus C, Heiduschka G, Kadletz-Wanke L, Brkic FF. In vitro effects of gamma-secretase inhibition in HPV-positive and HPV-negative head and neck squamous cell carcinoma. Invest New Drugs 2023; 41:193-201. [PMID: 36809443 PMCID: PMC10140088 DOI: 10.1007/s10637-023-01334-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 01/25/2023] [Indexed: 02/23/2023]
Abstract
BACKGROUND New chemotherapy agents are warranted for head and neck squamous cell carcinoma (HNSCC), particularly for incidence-rising HPV-positive tumors. Based on the evidence of Notch pathway involvement in cancer promotion and progression, we aimed to gain insights into the in vitro antineoplastic effects of gamma-secretase inhibition in HPV-positive and -negative HNSCC models. METHODS All in vitro experiments were conducted in two HPV-negative (Cal27 and FaDu) and one HPV-associated HNSCC cell line (SCC154). The influence of the gamma-secretase inhibitor PF03084014 (PF) on proliferation, migration, colony forming, and apoptosis was assessed. RESULTS We observed significant anti-proliferative, anti-migratory, anti-clonogenic, and pro-apoptotic effects in all three HNSCC cell lines. Furthermore, synergistic effects with concomitant radiation were observable in the proliferation assay. Interestingly, effects were slightly more potent in the HPV-positive cells. CONCLUSION We provided novel insights into the potential therapeutic relevance of gamma-secretase inhibition in HNSCC cell lines in vitro. Therefore, PF may become a viable treatment option for patients with HNSCC, particularly for patients with HPV-induced malignancy. Indeed, further in vitro and in vivo experiments should be conducted to validate our results and decipher the mechanism behind the observed anti-neoplastic effects.
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Affiliation(s)
- Sara Varatanovic
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Tobias Maier
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Sega Al-Gboore
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Stefan Stoiber
- Department of Pathology, Medical University of Vienna, Vienna, Austria.,Christian Doppler Laboratory for Applied Metabolomics, Medical University of Vienna, Vienna, Austria
| | - Sam Augustine Kandathil
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria.,Division of Anatomy, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Clemens Quint
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Charlotte Brennus
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Gregor Heiduschka
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Lorenz Kadletz-Wanke
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Faris F Brkic
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria.
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Mazurek AM, Rutkowski TW. Practical Application of Circulating Tumor-Related DNA of Human Papillomavirus in Liquid Biopsy to Evaluate the Molecular Response in Patients with Oropharyngeal Cancer. Cancers (Basel) 2023; 15:1047. [PMID: 36831390 PMCID: PMC9953792 DOI: 10.3390/cancers15041047] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 01/31/2023] [Accepted: 02/03/2023] [Indexed: 02/10/2023] Open
Abstract
Recent findings have shown that human papillomavirus (HPV) DNA is present in the blood as a tumor-specific biomarker (circulating tumor-related HPV; ctHPV) in patients with HPV-related oropharyngeal cancer (HPV-related OPC). The molecular response (MR) in patients with HPV-related OPC can be defined as the change in the number of ctHPV copies in relation to its initial quantity. The optimal model for assessing the MR using a liquid biopsy (LB) should be based on the E6/E7 sequences of the viral genome. MR assessment can help to evaluate the intensity of ongoing treatments in relation to the tumor response. The evaluation of the residual disease at the end of therapy may also be performed by MR assessment. If a partial MR (pMR) is found, caution is indicated and a subsequent LB should be considered, due to the likelihood of disease progression. Complete radiological and clinical responses together with a complete MR (cMR) convincingly indicate a low risk of treatment failure. Moreover, molecular recurrence (Mrec) during a follow-up, confirmed in two consecutive assays, even despite the lack of any other clinical or radiological symptoms of progression, indicates patients at high risk of disease recurrence. In conclusion, MR by ctHPV assessment may hasten the early detection of disease progression, at any stage of the management of the patient with HPV-related OPC.
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Affiliation(s)
- Agnieszka M. Mazurek
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Wybrzeże Armii Krajowej 15, 44-102 Gliwice, Poland
| | - Tomasz W. Rutkowski
- I Radiation and Clinical Oncology Department, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Wybrzeże Armii Krajowej 15, 44-102 Gliwice, Poland
- Radiotherapy Department, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Wybrzeże Armii Krajowej 15, 44-102 Gliwice, Poland
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25
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Li H, Zhang X, Chen W, Zhang Q, Li Q, Chen S, Yang Z, Su X, Yan S, Yang A, Song M. Analysis of T1-T2 stage oropharyngeal squamous cell carcinoma treated with transoral robotic surgery. Laryngoscope Investig Otolaryngol 2023; 8:103-112. [PMID: 36846425 PMCID: PMC9948596 DOI: 10.1002/lio2.1005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 11/07/2022] [Accepted: 11/15/2022] [Indexed: 01/12/2023] Open
Abstract
Objective Transoral robotic surgery (TORS) has become an effective treatment for early-stage oropharyngeal squamous cell carcinomas (OPSCCs). We aimed to analyze the clinical safety and efficacy of TORS for human papilloma virus (HPV)-positive and HPV-negative OPSCC in China. Methods Patients with OPSCC of pT1-T2 stage who underwent TORS from March 2017 to December 2021 were analyzed. Results A total of 83 patients (HPV-positive, n = 25; HPV-negative, n = 58) were included. The median age of the patients was 57.0 years and 71 were men. The majority of primary tumor sites were palatine tonsils (52, 62.7%) and base of tongues (20, 24.1%). Three patients have a positive margin. A total of 12 (14.5%) patients received tracheotomies, the average duration of tracheostomy tube use was 9.4 days, and nasogastric tube was 14.5 days. No patient had a long-term tracheotomy. The 3-year overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS) for all 83 patients were 89.5%, 80.1%, and 83.3%, respectively. The OS at 3 years between the HPV-positive group and HPV-negative group were 100% versus 84.3% (P = .07), while the DFS and RFS between two groups also showed no significant difference. Among multivariate cox regression analysis of all potential risk factors, smoking was the significant risk factors for disease recurrence (P < .05). Conclusion Transoral robotic surgery achieved encouraging oncologic outcomes and safety in T1-T2 stage OPSCC treatment, regardless of HPV status. Level of Evidence 4.
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Affiliation(s)
- Hui Li
- Collaborative Innovation Center for Cancer MedicineState Key Laboratory of Oncology in South China, Sun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Head and Neck SurgerySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Xing Zhang
- Collaborative Innovation Center for Cancer MedicineState Key Laboratory of Oncology in South China, Sun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Head and Neck SurgerySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Wenkuan Chen
- Collaborative Innovation Center for Cancer MedicineState Key Laboratory of Oncology in South China, Sun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Head and Neck SurgerySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Quan Zhang
- Collaborative Innovation Center for Cancer MedicineState Key Laboratory of Oncology in South China, Sun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Head and Neck SurgerySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Qiuli Li
- Collaborative Innovation Center for Cancer MedicineState Key Laboratory of Oncology in South China, Sun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Head and Neck SurgerySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Shuwei Chen
- Collaborative Innovation Center for Cancer MedicineState Key Laboratory of Oncology in South China, Sun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Head and Neck SurgerySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Zhongyuan Yang
- Collaborative Innovation Center for Cancer MedicineState Key Laboratory of Oncology in South China, Sun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Head and Neck SurgerySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Xuan Su
- Collaborative Innovation Center for Cancer MedicineState Key Laboratory of Oncology in South China, Sun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Head and Neck SurgerySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Shida Yan
- Collaborative Innovation Center for Cancer MedicineState Key Laboratory of Oncology in South China, Sun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Head and Neck SurgerySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Ankui Yang
- Collaborative Innovation Center for Cancer MedicineState Key Laboratory of Oncology in South China, Sun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Head and Neck SurgerySun Yat‐sen University Cancer CenterGuangzhouChina
| | - Ming Song
- Collaborative Innovation Center for Cancer MedicineState Key Laboratory of Oncology in South China, Sun Yat‐sen University Cancer CenterGuangzhouChina
- Department of Head and Neck SurgerySun Yat‐sen University Cancer CenterGuangzhouChina
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26
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Kang JJ, Ko A, Kil SH, Mallen-St Clair J, Shin DS, Wang MB, Srivatsan ES. EGFR pathway targeting drugs in head and neck cancer in the era of immunotherapy. Biochim Biophys Acta Rev Cancer 2023; 1878:188827. [PMID: 36309124 DOI: 10.1016/j.bbcan.2022.188827] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 09/30/2022] [Accepted: 10/16/2022] [Indexed: 11/12/2022]
Abstract
Receptor tyrosine kinases (RTKs) are cell surface receptors that bind growth factor ligands and initiate cellular signaling. Of the 20 classes of RTKs, 7 classes, I-V, VIII, and X, are linked to head and neck cancers (HNCs). We focus on the first class of RTK, epidermal growth factor receptor (EGFR), as it is the most thoroughly studied class. EGFR overexpression is observed in 20% of tumors, and expression of EGFR variant III is seen in 15% of aggressive chemoradiotherapy resistant HNCs. Currently, the EGFR monoclonal antibody (mAb) cetuximab is the only FDA approved RTK-targeting drug for the treatment of HNCs. Clinical trials have also included EGFR mAbs, with tyrosine kinase inhibitors, and small molecule inhibitors targeting the EGFR, MAPK, and mTOR pathways. Additionally, Immunotherapy has been found to be effective in 15 to 20% of patients with recurrent or metastatic HNC as a monotherapy. Thus, attempts are underway for the combinatorial treatment of immunotherapy and EGFR mAbs to determine if the recruitment of immune cells in the tumor microenvironment can overcome EGFR resistance.
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Affiliation(s)
- James J Kang
- Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Albert Ko
- Department of Surgery, VA Greater Los Angeles Healthcare System/UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Sang Hoon Kil
- Department of Surgery, VA Greater Los Angeles Healthcare System/UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Jon Mallen-St Clair
- Department of Otolaryngology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Daniel Sanghoon Shin
- Department of Medicine, VA Greater Los Angeles Healthcare System/UCLA David Geffen School of Medicine, Los Angeles, CA, USA; Molecular Biology Institute, UCLA, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA
| | - Marilene B Wang
- Department of Surgery, VA Greater Los Angeles Healthcare System/UCLA David Geffen School of Medicine, Los Angeles, CA, USA; Molecular Biology Institute, UCLA, Los Angeles, CA, USA; Department of Head and Neck Surgery, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Eri S Srivatsan
- Department of Surgery, VA Greater Los Angeles Healthcare System/UCLA David Geffen School of Medicine, Los Angeles, CA, USA; Molecular Biology Institute, UCLA, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA.
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27
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Morey T, Hodge J, Stern C, Krishnan S, Foreman A. Correlation between radiologic and pathologic extranodal extension in HPV-associated oropharyngeal cancer: Systematic review. Head Neck 2022; 44:2875-2885. [PMID: 36071683 PMCID: PMC9826216 DOI: 10.1002/hed.27183] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 08/02/2022] [Accepted: 08/18/2022] [Indexed: 01/11/2023] Open
Abstract
Pretreatment determination of extranodal extension (ENE) has significant clinical implications in human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC). Unfortunately there is no gold-standard imaging modality for radiological assessment of ENE in HPV+ OPSCC, leading to subjective assessments and complex decision making concerning ENE. A systematic review of diagnostic test accuracy was therefore undertaken, with five databases systemically searched to evaluate the diagnostic performance of an imaging modality for detection of ENE in HPV+ OPSCC. A meta-analysis was conducted on four CT studies using a random-effects model. While a narrative synthesis was provided for the studies using PET/CT and "CT and MRI." Out of 1772 hits, six studies were included in the review. Meta-analysis on four CT studies showed CT had an overall sensitivity of 77% and specificity of 60%. PET/CT had a sensitivity of 37.5% and specificity of 97%. "CT and MRI" had a sensitivity of 62% and specificity of 78%. Further diagnostic studies involving CT, PET/CT and MRI are ultimately required.
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Affiliation(s)
- Tristan Morey
- JBI, Faculty of Health and Medical SciencesThe University of AdelaideAdelaideSouth AustraliaAustralia
| | - John‐Charles Hodge
- Department of Otolaryngology ‐ Head and Neck SurgeryRoyal Adelaide HospitalAdelaideSouth AustraliaAustralia
| | - Cindy Stern
- JBI, Faculty of Health and Medical SciencesThe University of AdelaideAdelaideSouth AustraliaAustralia
| | - Suren Krishnan
- Department of Otolaryngology ‐ Head and Neck SurgeryRoyal Adelaide HospitalAdelaideSouth AustraliaAustralia
| | - Andrew Foreman
- Department of Otolaryngology ‐ Head and Neck SurgeryRoyal Adelaide HospitalAdelaideSouth AustraliaAustralia
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28
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Genetic deletion of HPV E7 oncogene effectively regresses HPV driven oral squamous carcinoma tumour growth. Biomed Pharmacother 2022; 155:113782. [DOI: 10.1016/j.biopha.2022.113782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 09/26/2022] [Accepted: 09/28/2022] [Indexed: 11/21/2022] Open
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29
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Sharkey Ochoa I, O’Regan E, Toner M, Kay E, Faul P, O’Keane C, O’Connor R, Mullen D, Nur M, O’Murchu E, Barry-O’Crowley J, Kernan N, Tewari P, Keegan H, O’Toole S, Woods R, Kennedy S, Feeley K, Sharp L, Gheit T, Tommasino M, O’Leary JJ, Martin CM. The Role of HPV in Determining Treatment, Survival, and Prognosis of Head and Neck Squamous Cell Carcinoma. Cancers (Basel) 2022; 14:4321. [PMID: 36077856 PMCID: PMC9454666 DOI: 10.3390/cancers14174321] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/29/2022] [Accepted: 09/01/2022] [Indexed: 12/02/2022] Open
Abstract
Human papillomavirus (HPV) infection has been identified as a significant etiological agent in the development of head and neck squamous cell carcinoma (HNSCC). HPV's involvement has alluded to better survival and prognosis in patients and suggests that different treatment strategies may be appropriate for them. Only some data on the epidemiology of HPV infection in the oropharyngeal, oral cavity, and laryngeal SCC exists in Europe. Thus, this study was carried out to investigate HPV's impact on HNSCC patient outcomes in the Irish population, one of the largest studies of its kind using consistent HPV testing techniques. A total of 861 primary oropharyngeal, oral cavity, and laryngeal SCC (OPSCC, OSCC, LSCC) cases diagnosed between 1994 and 2013, identified through the National Cancer Registry of Ireland (NCRI), were obtained from hospitals across Ireland and tested for HPV DNA using Multiplex PCR Luminex technology based in and sanctioned by the International Agency for Research on Cancer (IARC). Both overall and cancer-specific survival were significantly improved amongst all HPV-positive patients together, though HPV status was only a significant predictor of survival in the oropharynx. Amongst HPV-positive patients in the oropharynx, surgery alone was associated with prolonged survival, alluding to the potential for de-escalation of treatment in HPV-related OPSCC in particular. Cumulatively, these findings highlight the need for continued investigation into treatment pathways for HPV-related OPSCC, the relevance of introducing boys into national HPV vaccination programs, and the relevance of the nona-valent Gardasil-9 vaccine to HNSCC prevention.
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Affiliation(s)
- Imogen Sharkey Ochoa
- TCD CERVIVA Molecular Pathology Laboratory, The Coombe Women and Infants University Hospital, D08 XW7X Dublin, Ireland
| | - Esther O’Regan
- Trinity St James Cancer Institute, Trinity College Dublin, D08 NHY1 Dublin, Ireland
- Discipline of Histopathology, St. James’ University Hospital, Trinity College Dublin, D08 NHY1 Dublin, Ireland
| | - Mary Toner
- Discipline of Histopathology, St. James’ University Hospital, Trinity College Dublin, D08 NHY1 Dublin, Ireland
| | - Elaine Kay
- Department of Pathology, Beaumont University Hospital, D09 V2N0 Dublin, Ireland
| | - Peter Faul
- Department of Pathology, University Hospital Limerick, V94 F858 Limerick, Ireland
| | - Connor O’Keane
- Department of Pathology, Mater University Hospital, D07 R2WY Dublin, Ireland
| | - Roisin O’Connor
- Discipline of Histopathology, St. James’ University Hospital, Trinity College Dublin, D08 NHY1 Dublin, Ireland
| | - Dorinda Mullen
- Discipline of Histopathology, St. James’ University Hospital, Trinity College Dublin, D08 NHY1 Dublin, Ireland
| | - Mataz Nur
- Discipline of Histopathology, St. James’ University Hospital, Trinity College Dublin, D08 NHY1 Dublin, Ireland
| | - Eamon O’Murchu
- National Cancer Registry of Ireland, T12 CDF7 Cork, Ireland
| | - Jacqui Barry-O’Crowley
- TCD CERVIVA Molecular Pathology Laboratory, The Coombe Women and Infants University Hospital, D08 XW7X Dublin, Ireland
| | - Niamh Kernan
- TCD CERVIVA Molecular Pathology Laboratory, The Coombe Women and Infants University Hospital, D08 XW7X Dublin, Ireland
| | - Prerna Tewari
- TCD CERVIVA Molecular Pathology Laboratory, The Coombe Women and Infants University Hospital, D08 XW7X Dublin, Ireland
| | - Helen Keegan
- TCD CERVIVA Molecular Pathology Laboratory, The Coombe Women and Infants University Hospital, D08 XW7X Dublin, Ireland
| | - Sharon O’Toole
- TCD CERVIVA Molecular Pathology Laboratory, The Coombe Women and Infants University Hospital, D08 XW7X Dublin, Ireland
- Trinity St James Cancer Institute, Trinity College Dublin, D08 NHY1 Dublin, Ireland
| | - Robbie Woods
- TCD CERVIVA Molecular Pathology Laboratory, The Coombe Women and Infants University Hospital, D08 XW7X Dublin, Ireland
| | - Susan Kennedy
- Department of Pathology, St Vincent’s University Hospital, D04 T6F4 Dublin, Ireland
| | - Kenneth Feeley
- Department of Pathology, University Hospital Kerry, V92 NX94 Tralee, Ireland
| | - Linda Sharp
- Faculty of Medical Sciences, Newcastle University, Newcastle NE1 7RU, UK
| | - Tarik Gheit
- Infections and Cancer Biology Laboratory, International Agency for Research on Cancer, 69008 Lyon, France
| | - Massimo Tommasino
- Dipartimento di Farmacia-Scienze del Farmaco, University of Bari, 70121 Bari, Italy
| | - John J. O’Leary
- TCD CERVIVA Molecular Pathology Laboratory, The Coombe Women and Infants University Hospital, D08 XW7X Dublin, Ireland
- Trinity St James Cancer Institute, Trinity College Dublin, D08 NHY1 Dublin, Ireland
- Discipline of Histopathology, St. James’ University Hospital, Trinity College Dublin, D08 NHY1 Dublin, Ireland
| | - Cara M. Martin
- TCD CERVIVA Molecular Pathology Laboratory, The Coombe Women and Infants University Hospital, D08 XW7X Dublin, Ireland
- Trinity St James Cancer Institute, Trinity College Dublin, D08 NHY1 Dublin, Ireland
- Discipline of Histopathology, St. James’ University Hospital, Trinity College Dublin, D08 NHY1 Dublin, Ireland
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Abstract
ABSTRACT Head and neck squamous cell carcinomas are rising in incidence worldwide, and despite the advent of improved surgical and radiation techniques, a substantial proportion of patients have disease recurrence, where systemic therapies are the mainstay of management. Recent advances in systemic therapy include the development of epidermal growth factor receptor- and programmed death 1-targeting drugs, which have produced incremental improvements in disease outcomes. However, for most patients, responses to treatment remain elusive because of primary or acquired resistance. Novel drugs and rational drug combinations need to be tested based on biomarker identification and preclinical science that will ultimately advance outcomes for our patients. This review focuses on efforts untaken for epidermal growth factor receptor targeting in head and neck squamous cell carcinoma to date.
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31
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Lopez DC, Hoke AT, Rooper LM, London NR. Human Papillomavirus-Related Carcinomas of the Sinonasal Tract. CURRENT OTORHINOLARYNGOLOGY REPORTS 2022; 10:291-302. [PMID: 36311560 PMCID: PMC9610077 DOI: 10.1007/s40136-022-00404-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/19/2022] [Indexed: 11/26/2022]
Abstract
Purpose of review The sinonasal tract is home to a uniquely heterogenous collection of malignant tumors. Human papillomavirus (HPV) has been detected in a number of these, but the virus' role as an oncogenic driver or coincidental finding remains unclear. We aim to highlight five sinonasal tumor types and synthesize the prevalence, etiologic role, and known clinicopathologic relevance of HPV in each. Recent findings The last decade has seen an expansion of investigation into HPV's oncogenic and prognostic significance within sinonasal malignancies. The sinonasal tract poses challenges to HPV detection where p16 lacks value as an accurate surrogate. A growing body of data supports a potentially favorable clinical profile for certain sinonasal HPV-positive lesions. Summary HPV represents a potential biologically and clinically relevant factor for some sinonasal malignancies. Definitive conclusions regarding HPV's role as a potential oncogenic agent require routine testing using validated methodologies, genomic interrogation, and large-scale prospective studies.
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Affiliation(s)
- Diana C. Lopez
- Sinonasal and Skull Base Tumor Program, National Institute on Deafness and Other Communication Disorders, National Institutes of Health; Bethesda, MD, USA
- Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio, USA
| | - Austin T.K. Hoke
- Sinonasal and Skull Base Tumor Program, National Institute on Deafness and Other Communication Disorders, National Institutes of Health; Bethesda, MD, USA
- University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Lisa M. Rooper
- Department of Pathology, Johns Hopkins University School of Medicine; Baltimore, MD, USA
| | - Nyall R. London
- Sinonasal and Skull Base Tumor Program, National Institute on Deafness and Other Communication Disorders, National Institutes of Health; Bethesda, MD, USA
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine; Baltimore, MD, USA
- Department of Neurosurgery, Johns Hopkins University School of Medicine; Baltimore, MD, USA
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32
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Chai RL, Ferrandino RM, Barron C, Donboli K, Roof SA, Khan MN, Teng MS, Posner MR, Bakst RL, Genden EM. The Sinai Robotic Surgery Trial in HPV-related oropharyngeal squamous cell carcinoma (SIRS 2.0 trial) – study protocol for a phase II non-randomized non-inferiority trial. Front Oncol 2022; 12:965578. [PMID: 36091121 PMCID: PMC9453550 DOI: 10.3389/fonc.2022.965578] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 08/08/2022] [Indexed: 11/19/2022] Open
Abstract
Background Human papillomavirus associated oropharyngeal squamous cell carcinoma (HPVOPSCC) usually affects a younger patient population. As such, the risk for long term toxicity associated with therapy is an important consideration. Multiple trials focused on de-escalation of therapy to preserve survival outcomes while minimizing treatment toxicity are currently in progress, however the question of which patients are ideal candidates for de-escalation remains unanswered. Circulating tumor DNA (cfHPVDNA) has emerged as a means of monitoring disease in patients with HPVOPSCC. Undetectable postoperative cfHPVDNA levels portend a better prognosis and by extension, may identify ideal candidates for de-escalation therapy. We propose an overview and rationale for a new institutional clinical trial protocol focusing on the use of cfHPVDNA to risk stratify patients for adjuvant therapy. We hypothesize that many surgical patients currently receiving radiation therapy may be clinically observed without adjuvant therapy. Methods Patients with measurable cfHPVDNA and clinically resectable HPVOPSCC will undergo TORS resection of tumors and neck dissection. Patients with undetectable cfHPVDNA at 3 weeks post-op will be allocated to low or high-risk treatment protocol groups. The low risk group consists of patients with <4 positive lymph nodes, ≤2 mm extranodal extension (ENE), and perineural invasion (PNI) or lymphovascular invasion (LVI) alone. The high-risk group is made up of patients with ≥4 positive lymph nodes, gross ENE, positive margins, N2c disease and/or the combination of both PNI and LVI. The low-risk group will be allocated to an observation arm, while the high-risk group will receive 46 Gy of adjuvant radiotherapy and weekly cisplatin therapy. The primary outcome of interest is 2-year disease recurrence with secondary outcomes of 2-year disease free survival, locoregional control, overall survival, and quality of life measures. A sample of 126 patients in the low-risk group and 73 patients in the high-risk group will be required to evaluate non-inferiority to the standard of care. Discussion This study will provide much needed recurrence and survival data for patients that undergo primary TORS followed by observation or de-escalated adjuvant therapy. Additionally, it will help delineate the role of cfHPVDNA in the risk stratification of patients that undergo treatment de-intensification.
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Affiliation(s)
- Raymond L. Chai
- Department of Otolaryngology – Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- *Correspondence: Raymond L. Chai,
| | - Rocco M. Ferrandino
- Department of Otolaryngology – Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Christine Barron
- Department of Otolaryngology – Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Kianoush Donboli
- Department of Otolaryngology – Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Scott A. Roof
- Department of Otolaryngology – Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Mohemmed N. Khan
- Department of Otolaryngology – Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Marita S. Teng
- Department of Otolaryngology – Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Marshall R. Posner
- Department of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Richard L. Bakst
- Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Eric M. Genden
- Department of Otolaryngology – Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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Fan J, Li P, Fang Q, Yang Y, Zhang H, Du W, Liu S, Luo R. Heterotypic neutrophil-in-tumor structure: A novel pathological feature first discovered in the tissues of OPSCC. Front Oncol 2022; 12:807597. [PMID: 36052249 PMCID: PMC9425089 DOI: 10.3389/fonc.2022.807597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 07/15/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE To reveal a novel pathological feature: heterotypic neutrophil-in-tumor structure (hNiT) first discovered in patients with oropharyngeal squamous cell carcinoma (OPSCC), to analyze the prognostic role of hNiT in OPSCC patients and to explore the role of p16 in the formation of hNiT structures. METHODS Clinically, 197 patients were enrolled. Clinicopathological information was extracted and analyzed. All pathologic sections made from primary tumors were re-evaluated by immunohistochemistry and immunostaining. In vitro, we cocultured OPSCC cell line SCC-15 with neutrophils to form hNiT structures, which were then subject to fluorescence staining. By RNAi and overexpression techniques, we investigated the role of CDKN2A in the formation of hNiTs. We validated the two techniques by qPCR and Western Blot. RESULTS The hNiT as a novel pathological feature was first discovered in the tissues of OPSCC. The FNiT was significantly associated with tumor stage, disease stage, p16 and tumor grade. A total of 119 patients died of the disease, and the 5-year disease-specific survival (DSS) rate was 36%. The median survival time was 52.6 months. In patients with an FNiT<0.5%, the 5-year DSS rate was 40%; in patients with an FNiT>=0.5%, the 5-year DSS was 28%, and the difference was significant (p=0.001). Cox model analysis showed that FNiT along with disease stage, p16 and tumor grade was an independent prognostic factor for DSS. Immunostaining results of p16 expression showed hNiT formation was negatively correlated to p16 in OPSCC as well as in the hNiT formation assays in vitro indicated by fluorescent staining. Function assays of CDKN2A implied that reduce CDKN2A promoted the formation of hNiT while elevated CDKN2A impeded the hNiT formation. CONCLUSION The hNiT as a novel pathological feature is associated with the adverse prognosis of OPSCC patients with p16 inhibiting the formation of hNiT structures.
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Affiliation(s)
- Jie Fan
- Department of Head Neck and Thyroid Surgery, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Peng Li
- Department of Head Neck and Thyroid Surgery, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Qigen Fang
- Department of Head Neck and Thyroid Surgery, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yang Yang
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - He Zhang
- Department of Pathology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Wei Du
- Department of Head Neck and Thyroid Surgery, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
- Department of Anatomy, Zhengzhou University, Zhengzhou, China
| | - Shanting Liu
- Department of Head Neck and Thyroid Surgery, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Ruihua Luo
- Department of Head Neck and Thyroid Surgery, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
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Choi KH, Song JH, Hong JH, Lee YS, Kang JH, Sun DI, Kim MS, Kim YS. Importance of lymph node ratio in HPV-related oropharyngeal cancer patients treated with surgery and adjuvant treatment. PLoS One 2022; 17:e0273059. [PMID: 35960785 PMCID: PMC9374241 DOI: 10.1371/journal.pone.0273059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 08/01/2022] [Indexed: 12/03/2022] Open
Abstract
OBJECTIVES The pathologic nodal stage of human papillomavirus (HPV)-related oropharyngeal cancer (OPC) patients is classified according to the number of lymph nodes (LNs), as revised in 2018. Previous studies showed that the LN ratio (LNR) could be also a significant prognostic factor in head and neck cancer, but there are few studies on the LNR in HPV-related [HPV(+)] OPC. The aim of the present study was to analyze the predictive value of the LNR for survival and recurrence in HPV(+) OPC patients. MATERIALS AND METHODS HPV(+) OPC patients treated with surgery with or without postoperative radiotherapy from January 2000 to March 2019 were evaluated. The patients were divided into two sets of three groups, according to LN numbers based on pathologic nodal stages, and LNRs by a cutoff value of 0.05. The medical records were reviewed, and the overall survival (OS), disease-free survival, locoregional recurrence, and distant metastasis incidence were analyzed. RESULTS Ninty patients were included and the median follow-up period was 38.2 months. There were no significant differences in OS in the LN number groups. However, there was a significant difference in OS in the LNR groups (P = 0.010). The incidence of distant metastasis in the LNR groups was significantly different (P = 0.005). CONCLUSION The LNR in HPV(+) OPC patients may be a more useful tool to predict survival and distant metastasis than the LN number. Additional research and consensus on surgical pathology are needed before applying the LNR to adjuvant treatment decisions and pathologic nodal staging.
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Affiliation(s)
- Kyu Hye Choi
- Department of Radiation Oncology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jin Ho Song
- Department of Radiation Oncology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ji Hyun Hong
- Department of Radiation Oncology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Youn Soo Lee
- Department of Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jin Hyoung Kang
- Department of Medical Oncology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Dong-Il Sun
- Department of Otolaryngology–Head and Neck Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Min-Sik Kim
- Department of Otolaryngology–Head and Neck Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yeon-Sil Kim
- Department of Radiation Oncology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Bahig H, Huang SH, O’Sullivan B. Oligometastatic Head and Neck Cancer: Challenges and Perspectives. Cancers (Basel) 2022; 14:cancers14163894. [PMID: 36010888 PMCID: PMC9405984 DOI: 10.3390/cancers14163894] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/09/2022] [Accepted: 08/10/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Oligometastasis represents a disease state and an opportunity for cure when metastases emerge. Emerging evidence supports that most head and neck cancer patients with oligometastatic disease are likely to benefit from curative intent local ablative therapy if appropriate selection criteria are applied. Biomarkers to predict development of oligometastasis, as well as to identify which patients could benefit from a radical intent approach, are under investigation. This review summarizes recent knowledge about the characteristics, investigational efforts, and evidence for local ablation regarding oligometastasis in head and neck cancer. We also describe the challenges and opportunities in patient selection and discuss the role of radiotherapy and immunotherapy combinations to enhance anti-tumor immunity. Abstract A minority of patients with metastatic head and neck squamous cell carcinoma (HNSCC) present with oligometastatic disease. Oligometastasis not only reflects a disease state, but might also present an opportunity for cure in the metastatic setting. Radical ablation of all oligometastatic sites may confer prolonged survival and possibly achieve cure in some patients. However, substantial debate remains about whether patients with oligometastatic disease could benefit from curative intent therapy or whether aggressive treatments expose some patients to futile toxicity. Optimal selection of patients, carefully balancing the currently known prognostic factors against the risks of toxicity is critical. Emerging evidence suggests that patients with a limited burden of disease, viral-related pharyngeal cancer, metachronous metastasis and lung-only metastasis may benefit most from this approach. Efforts are underway to identify biomarkers that can detect oligometastasis and better select patients who would derive the maximum benefit from an aggressive radical approach. The combination of radiotherapy and immunotherapy promises to enhance the anti-tumoral immune response and help overcome resistance. However, optimization of management algorithms, including patient selection, radiation dose and sequencing, will be critical in upcoming clinical trials. This review summarizes recent knowledge about the characteristics and investigational efforts regarding oligometastasis in HNSCC.
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Affiliation(s)
- Houda Bahig
- Department of Radiation Oncology, University of Montreal, Montreal, QC H2X 3E4, Canada
| | - Shao Hui Huang
- Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G 2M9, Canada
- Department of Otolaryngology-Head and Neck Surgery, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G 2M9, Canada
| | - Brian O’Sullivan
- Department of Radiation Oncology, University of Montreal, Montreal, QC H2X 3E4, Canada
- Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G 2M9, Canada
- Department of Otolaryngology-Head and Neck Surgery, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G 2M9, Canada
- Correspondence:
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Preissner SH, Nahles S, Preissner S, Heiland M, Koerdt S. Influence of sex on survival rates of HPV-positive oropharyngeal cancers. Front Oncol 2022; 12:917890. [PMID: 36119465 PMCID: PMC9472547 DOI: 10.3389/fonc.2022.917890] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 07/15/2022] [Indexed: 11/14/2022] Open
Abstract
The role of human papillomavirus (HPV) status for the prognosis of oropharyngeal cancers (OPCs) is discussed controversially. Here, we present an analysis of 144,969 head and neck cancer cases (ICD-10 codes: C00–C13) with a sub-cohort of 62,775 tumor cases of the oropharynx (C01, C09, and C10). To this end, de-identified data from electronic health records of about 60 healthcare organizations from 30 different countries were used. Odds ratios, hazard ratios (HRs), and Kaplan–Meier analyses were used to compare outcomes between different cancer entities of neoplasms of the base of the tongue (C01), of tonsils (C09), and of the oropharynx (C10) of women and men with and without HPV infection. To avoid the bias from different age distributions, the cohorts were balanced using propensity score matching. The 5-year survival rate for HPV-positive patients is somewhat better than that for HPV-negative patients, but for age- and sex-balanced cohorts, there remains no significant advantage for HPV-positive patients [HR, 1.126 (0.897–1.413)]. Looking at the different entities and HPV status for age-matched male and female patients separately, HPV is a significantly positive prognostic factor for female patients in some entities, whereas for male patients, it is only a positive prognostic factor for malignant neoplasms of oropharynx (C10) [HR, 1.077 (0.602–1.926)].
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Jager L, Felicelli C, Alexiev B, Samant S, Johnson DN. Anaplasia and multinucleation in metastases of oropharyngeal squamous cell carcinoma is associated with poorer outcomes. J Am Soc Cytopathol 2022; 11:201-209. [PMID: 35474265 DOI: 10.1016/j.jasc.2022.03.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 03/28/2022] [Accepted: 03/29/2022] [Indexed: 06/14/2023]
Abstract
INTRODUCTION The presence of tumor cell anaplasia and multinucleation (A/M) in oropharyngeal squamous cell carcinoma (OPSCC) has recently been found to be associated with increased disease recurrence and poorer disease-specific survival, regardless of human papillomavirus status. We studied the detection of A/M in cytology specimens. MATERIALS AND METHODS We performed a comprehensive data search for all patients with OPSCC diagnosed and treated at Northwestern Memorial Hospital between January 2013 and April 2020. All cytology and histopathologic slides were reviewed for the presence of A/M in patients with both surgical resection or biopsy specimens and fine needle aspiration cytology of a metastatic site. RESULTS A total of 87 patients were identified with both surgical and cytology specimens available for review. A/M was identified in 21 cytology specimens and 14 surgical specimens. Cytologic A/M was seen in 11 of the 14 patients (78.5%) with corresponding histologic A/M and in 10 of the 73 patients (13.7%) without histologic A/M. Disease-specific survival was significantly worse for the patients with cytologic A/M regardless of the presence of histologic A/M (P = 0.0064) and for the patients with cytologic A/M only (P = 0.0271). In patients with p16-positive/human papillomavirus-associated carcinoma, disease-specific survival was significantly worse for the patients with both histologic and cytologic A/M (P = 0.0305). CONCLUSIONS A/M can be reliably identified in cytology specimens among all the various stains and preparations, irrespective of the primary tumor histologic type. Identification of A/M on cytology specimens could indicate more aggressive clinical behavior and help guide patient management.
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Affiliation(s)
- Lucy Jager
- Department of Pathology, Northwestern University Feinberg School of Medicine, Northwestern Memorial Hospital, Chicago, Illinois.
| | - Christopher Felicelli
- Department of Pathology, Northwestern University Feinberg School of Medicine, Northwestern Memorial Hospital, Chicago, Illinois
| | - Borislav Alexiev
- Department of Pathology, Northwestern University Feinberg School of Medicine, Northwestern Memorial Hospital, Chicago, Illinois
| | - Sandeep Samant
- Department of Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Northwestern Memorial Hospital, Chicago, Illinois
| | - Daniel N Johnson
- Department of Pathology, Northwestern University Feinberg School of Medicine, Northwestern Memorial Hospital, Chicago, Illinois
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Gama-Cuellar AG, Francisco ALN, Scarini JF, Mariano FV, Kowalski LP, Gondak R. Decreased CD1a + and CD83 + cells in tonsillar squamous cell carcinoma regardless of HPV status. J Appl Oral Sci 2022; 30:e20210702. [PMID: 35584505 PMCID: PMC9126112 DOI: 10.1590/1678-7757-2020-0702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 04/06/2022] [Indexed: 11/22/2022] Open
Abstract
Dendritic cells (DCs) are specialized antigen-presenting cells that play a critical role in the immune response against human papillomavirus (HPV) infection, and represent a therapeutic target in cancer.
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Affiliation(s)
| | | | - João Figueira Scarini
- Universidade Estadual de Campinas - UNICAMP, Departamento de Anatomia-Patológica, Faculdade de Ciências Médicas, Campinas, SP, Brasil
| | - Fernanda Viviane Mariano
- Universidade Estadual de Campinas - UNICAMP, Departamento de Anatomia-Patológica, Faculdade de Ciências Médicas, Campinas, SP, Brasil
| | | | - Rogério Gondak
- Universidade Federal de Santa Catarina - UFSC, Departamento de Patologia, Florianópolis, SC, Brasil
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Sex-Related Differences in Outcomes for Oropharyngeal Squamous Cell Carcinoma by HPV Status. Int J Otolaryngol 2022; 2022:4220434. [PMID: 35546963 PMCID: PMC9085342 DOI: 10.1155/2022/4220434] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 01/19/2022] [Accepted: 02/25/2022] [Indexed: 12/20/2022] Open
Abstract
Background Overall survival for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) has differed by sex, but little is known regarding cancer-specific outcomes. We assessed the independent association of sex with cancer-specific survival in patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Methods We identified 14,183 patients from the Surveillance, Epidemiology, and End Results (SEER) program with OPSCC and tumor HPV status. We used Kaplan–Meier methods to compare overall survival (OS) and OPSCC-specific survival (HNCSS) by patient sex and by tumor HPV status. We then separately fit multivariable survival and competing risk models evaluating the association of sex on these outcomes by tumor HPV status and stratified by the use of guideline-concordant OPSCC treatment. Results A total of 10,210 persons with HPV-positive tumors (72.0%) and 3,973 with HPV-negative tumors (28.0%) were identified. A larger proportion of women had HPV-negative tumors (24.0%) versus HPV-positive tumors (13.2%; p < 0.001). Women with HPV-positive tumors were less likely to receive guideline-concordant treatment compared to men. In unadjusted survival analyses, women did not differ in OS or HNCSS compared to men for HPV-positive tumors but had worse OS and HNCSS for HPV-negative tumors. After adjustment, men and women with HPV-positive OPSCC did not differ in OS or HNCSS. However, women with HPV-negative tumors faced worse overall survival (hazard ratio (HR) 1.15, 95% CI 1.02–1.29) that persisted even after stratifying for stage-appropriate treatment (HR 1.28, 95% CI 1.11–1.47). Conclusions Women with HPV-positive OPSCC had similar survival outcomes compared to men, but those with HPV-negative tumors have worse overall and cancer-specific survival.
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Petrelli F, Luciani A, Ghidini A, Cherri S, Gamba P, Maddalo M, Bossi P, Zaniboni A. Treatment de-escalation for HPV+ oropharyngeal cancer: A systematic review and meta-analysis. Head Neck 2022; 44:1255-1266. [PMID: 35238114 DOI: 10.1002/hed.27019] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 02/13/2022] [Accepted: 02/17/2022] [Indexed: 12/12/2022] Open
Abstract
Human Papillomavirus (HPV) related oropharyngeal carcinoma (OPC) carries a better prognosis compared with HPV-counterparts, thereby pushing the adoption of de-intensification treatment approaches as new strategies to preserve superior oncologic outcomes while minimizing toxicity. We evaluated the effect of treatment de-intensification in terms of overall survival (OS), progression-free survival (PFS), locoregional and distant control (LRC and DM) by selecting prospective or retrospective studies, providing outcome data with reduced intensification versus standard curative treatment in HPV+ OPC patients, with a systematic analysis till September 2020. The primary outcome of interest was OS. Secondary endpoints were PFS, LRC, and DM expressed as HR. A total of 55 studies (from 1393 screened references) were employed for quantitative synthesis for 38 929 patients. Among n = 48 studies with data available, de-intensified treatments reduced OS in HPV+ OPCs (HR = 1.33, 95% CI 1.17-1.52; p < 0.01). In de-escalated treatments, PFS was also decreased (HR = 2.11, 95% CI 1.65-2.69; p < 0.01). Compared with standard treatments, reduced intensity approaches were associated with reduced locoregional and distant disease control (HR = 2.51, 95% CI 1.75-3.59; p < 0.01; and HR = 1.9, 95% CI 1.25-2.9; p < 0.01). Chemoradiation improved survival in a definitive curative setting compared with radiotherapy alone (HR = 1.42, 95% CI 1.16-1.75; p < 0.01). When adjuvant treatments were compared, standard and de-escalation strategies provided similar OS. In conclusion, in patients with HPV+ OPC, de-escalation treatments should not be widely and agnostically adopted in clinical practice, as therein lies a concrete risk of offering a sub-optimal treatment to patients.
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Affiliation(s)
| | | | | | - Sara Cherri
- Oncology Unit, Fondazione Poliambulanza, Brescia, Italy
| | - Paolo Gamba
- Otolaryngology Unit, Fondazione Poliambulanza, Brescia, Italy
| | - Marta Maddalo
- Department of Radiation Oncology, University of Brescia and Spedali Civili, Brescia, Italy
| | - Paolo Bossi
- Medical Oncology, Department of Medical and Surgical Specialties, Radiological Sciences, Public Health, University of Brescia, Brescia, Italy
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Takahashi M, Hwang M, Misiukiewicz K, Gupta V, Miles BA, Bakst R, Genden E, Selkridge I, Botzler J, Virani V, Moshier E, Bonomi MR, Posner MR. Quality of Life Analysis of HPV-Positive Oropharyngeal Cancer Patients in a Randomized Trial of Reduced-Dose Versus Standard Chemoradiotherapy: 5-Year Follow-Up. Front Oncol 2022; 12:859992. [PMID: 35463348 PMCID: PMC9024140 DOI: 10.3389/fonc.2022.859992] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 03/07/2022] [Indexed: 11/13/2022] Open
Abstract
Background Human papillomavirus-positive oropharyngeal carcinoma (HPVOPC) portends a more favorable prognosis compared to environmentally related oropharynx cancer (EROPC). Patients with HPVOPC may be overtreated and endure unnecessary long-term toxicities. Methods Patients with untreated locally advanced HPVOPC received induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (TPF) and were randomized to standard chemoradiotherapy (sdCRT) (70 Gy) or reduced-dose chemoradiotherapy (rdCRT) (56 Gy) with weekly carboplatin. Patients were followed for changes in five validated quality of life (QoL) surveys: MD Anderson Dysphagia Inventory and Symptom Inventory for head and neck cancer (MDADI, MDASI-HN), Xerostomia Questionnaire (XQ), and European Organization for Research and Treatment of Cancer Questionnaire (EORTC) with head and neck module (EORTC HN). The secondary endpoints of this study were 5-year progression-free survival (PFS) and overall survival (OS). Results Twenty patients were enrolled and randomized to rdCRT (n = 12) or sdCRT (n = 8). Median follow-up was 88 months. At 5 years, difference in QoL changes all favored the rdCRT arm and two QoL scales reached statistical significance (EORTC global health score: 11.49 vs. -23.94, P = 0.014; EORTC symptom scale: -7.76 vs. 15.19, P = 0.015). The 5-year PFS and OS were 87.5% and 83.3% for sdCRT and rdCRT, respectively. Conclusions Therefore, rdCRT after TPF in HPVOPC is feasible in accordance with the earlier results of the Quarterback Trial and long-term follow-up. These limited results are more favorable in specific QoL domains compared to those of sdCRT and demonstrate equivalent long-term survival. Clinical Trial Registration https://clinicaltrials.gov/ct2/show/NCT01706939, The Quarterback Trial [NCT 01706939].
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Affiliation(s)
- Mai Takahashi
- The Department of Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai Beth Israel, New York, NY, United States
| | - Michael Hwang
- The Departments of Hematology/Oncology, Johns Hopkins Hospital, Baltimore, MD, United States
| | - Krysztof Misiukiewicz
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,The Departments of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Vishal Gupta
- Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Brett A Miles
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Richard Bakst
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Eric Genden
- Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Isaiah Selkridge
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - John Botzler
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Vruti Virani
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Erin Moshier
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Biostatistics in the Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Marcelo R Bonomi
- The Departments of Hematology/Oncology, The Ohio State University, Columbus, OH, United States
| | - Marshall R Posner
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,The Departments of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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Caudell JJ, Gillison ML, Maghami E, Spencer S, Pfister DG, Adkins D, Birkeland AC, Brizel DM, Busse PM, Cmelak AJ, Colevas AD, Eisele DW, Galloway T, Geiger JL, Haddad RI, Hicks WL, Hitchcock YJ, Jimeno A, Leizman D, Mell LK, Mittal BB, Pinto HA, Rocco JW, Rodriguez CP, Savvides PS, Schwartz D, Shah JP, Sher D, St John M, Weber RS, Weinstein G, Worden F, Yang Bruce J, Yom SS, Zhen W, Burns JL, Darlow SD. NCCN Guidelines® Insights: Head and Neck Cancers, Version 1.2022. J Natl Compr Canc Netw 2022; 20:224-234. [PMID: 35276673 DOI: 10.6004/jnccn.2022.0016] [Citation(s) in RCA: 293] [Impact Index Per Article: 97.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses. Occult primary cancer, salivary gland cancer, and mucosal melanoma (MM) are also addressed. The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding management of HPV-positive oropharynx cancer and ongoing research in this area.
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Affiliation(s)
| | | | | | | | | | - Douglas Adkins
- 6Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | | | | | | | | | | | - David W Eisele
- 12The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
| | | | - Jessica L Geiger
- 14Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | | | | | | | | | - Debra Leizman
- 14Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | | | - Bharat B Mittal
- 20Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | - James W Rocco
- 21The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | | | | | - David Schwartz
- 24St. Jude Children's Research Hospital/The University of Tennessee Health Science Center
| | | | - David Sher
- 25UT Southwestern Simmons Comprehensive Cancer Center
| | | | | | | | | | | | - Sue S Yom
- 30UCSF Helen Diller Family Comprehensive Cancer Center
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Haddad RI, Seiwert TY, Chow LQM, Gupta S, Weiss J, Gluck I, Eder JP, Burtness B, Tahara M, Keam B, Kang H, Muro K, Albright A, Mogg R, Ayers M, Huang L, Lunceford J, Cristescu R, Cheng J, Mehra R. Influence of tumor mutational burden, inflammatory gene expression profile, and PD-L1 expression on response to pembrolizumab in head and neck squamous cell carcinoma. J Immunother Cancer 2022; 10:jitc-2021-003026. [PMID: 35217573 PMCID: PMC8883256 DOI: 10.1136/jitc-2021-003026] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2022] [Indexed: 12/13/2022] Open
Abstract
Background To characterize genomic determinants of response to pembrolizumab in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 study. Methods Associations between biomarkers (tumor mutational burden (TMB), neoantigen load (NL), 18-gene T-cell-inflamed gene expression profile (TcellinfGEP), and PD-L1 combined positive score (CPS)) and clinical outcomes with pembrolizumab were assessed in patients with R/M HNSCC (n=192). Tumor human papillomavirus (HPV) status was also evaluated with the use of p16 immunohistochemistry and whole exome sequencing (WES; HPV+, mapping >20 HPV reads) in pretreatment tumor samples (n=106). Results TMB, clonality-weighted TMB, and TcellinfGEP were significantly associated with objective response (p=0.0276, p=0.0201, and p=0.006, respectively), and a positive trend was observed between NL and PD-L1 CPS and clinical response (p=0.0550 and p=0.0682, respectively). No correlation was observed between TMB and TcellinfGEP (Spearman ρ=–0.026) or TMB and PD-L1 (Spearman ρ=0.009); a correlation was observed between TcellinfGEP and PD-L1 (Spearman ρ=0.511). HPV status by WES and p16 immunohistochemistry showed concordance (84% ҡ=0.573) among patients whose HPV results were available using both methods. Conclusions TMB and inflammatory biomarkers (TcellinfGEP and PD-L1) may represent distinct and complementary biomarkers predicting response to anti-programmed death 1 therapies in HNSCC; further study of these relationships in randomized clinical trials is needed. Trial registration number NCT01848834.
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Affiliation(s)
- Robert I Haddad
- Department of Medical Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
| | - Tanguy Y Seiwert
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois, USA
| | - Laura Q M Chow
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Shilpa Gupta
- Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Jared Weiss
- Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill, North Carolina, USA
| | - Iris Gluck
- Department of Oncology, Sheba Medical Center at Tel HaShomer, Ramat Gan, Israel
| | - Joseph P Eder
- Department of Medicine, Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut, USA
| | - Barbara Burtness
- Division of Medical Oncology, Department of Internal Medicine, Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut, USA
| | - Makoto Tahara
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Bhumsuk Keam
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Hyunseok Kang
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland, USA
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | | | - Robin Mogg
- Merck & Co., Inc, Kenilworth, New Jersey, USA
| | - Mark Ayers
- Merck & Co., Inc, Kenilworth, New Jersey, USA
| | | | | | | | | | - Ranee Mehra
- Department of Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
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Gameiro SF, Evans AM, Mymryk JS. The tumor immune microenvironments of HPV + and HPV - head and neck cancers. WIREs Mech Dis 2022; 14:e1539. [PMID: 35030304 DOI: 10.1002/wsbm.1539] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 09/18/2021] [Accepted: 09/22/2021] [Indexed: 12/24/2022]
Abstract
Human papillomaviruses (HPVs) are the etiological agent of a significant, and increasing, fraction of head and neck squamous cell carcinomas (HNSCC)-a heterogenous group of malignancies in the head and neck region. HPV infection accounts for approximately 25% of all cases, with the remainder typically caused by smoking and excessive alcohol consumption. These distinct etiologies lead to profound clinical and immunological differences between HPV-positive (HPV+ ) and HPV-negative (HPV- ) HNSCC, likely related to the expression of exogenous viral antigens in the HPV+ subtype. Specifically, HPV+ HNSCC patients generally exhibit better treatment response compared to those with HPV- disease, leading to a more favorable prognosis, with lower recurrence rate, and longer overall survival time. Importantly, a plethora of studies have illustrated that the tumor immune microenvironment (TIME) of HPV+ HNSCC has a strikingly distinct immune composition to that of its HPV- counterpart. The HPV+ TIME is characterized as being immunologically "hot," with more immune infiltration, higher levels of T-cell activation, and higher levels of immunoregulation compared to the more immunologically "cold" HPV- TIME. In general, cancers with an immune "hot" TIME exhibit better treatment response and superior clinical outcomes in comparison to their immune "cold" counterparts. Indeed, this phenomenon has also been observed in HPV+ HNSCC patients, highlighting the critical role of the TIME in influencing prognosis, and further validating the use of cancer therapies that capitalize on the mobilization and/or modulation of the TIME. This article is categorized under: Cancer > Molecular and Cellular Physiology Infectious Diseases > Molecular and Cellular Physiology.
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Affiliation(s)
- Steven F Gameiro
- Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada
| | - Andris M Evans
- Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada
| | - Joe S Mymryk
- Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada.,Department of Otolaryngology, The University of Western Ontario, London, Ontario, Canada.,Department of Oncology, The University of Western Ontario, London, Ontario, Canada.,London Regional Cancer Program, Lawson Health Research Institute, London, Ontario, Canada
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Rosenberg AJ, Izumchenko E, Pearson A, Gooi Z, Blair E, Karrison T, Juloori A, Ginat D, Cipriani N, Lingen M, Sloane H, Edelstein DL, Keyser K, Fredebohm J, Holtrup F, Jones FS, Haraf D, Agrawal N, Vokes EE. Prospective study evaluating dynamic changes of cell-free HPV DNA in locoregional viral-associated oropharyngeal cancer treated with induction chemotherapy and response-adaptive treatment. BMC Cancer 2022; 22:17. [PMID: 34980038 PMCID: PMC8722316 DOI: 10.1186/s12885-021-09146-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Accepted: 12/23/2021] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) has a favorable prognosis which has led to efforts to de-intensify treatment. Response-adaptive de-escalated treatment is promising, however improved biomarkers are needed. Quantitative cell-free HPV-DNA (cfHPV-DNA) in plasma represents an attractive non-invasive biomarker for grading treatment response and post-treatment surveillance. This prospective study evaluates dynamic changes in cfHPV-DNA during induction therapy, definitive (chemo)radiotherapy, and post-treatment surveillance in the context of risk and response-adaptive treatment for HPV + OPC. METHODS Patients with locoregional HPV + OPC are stratified into two cohorts: High risk (HR) (T4, N3, [Formula: see text] 20 pack-year smoking history (PYH), or non-HPV16 subtype); Low risk (LR) (all other patients). All patients receive induction chemotherapy with three cycles of carboplatin and paclitaxel. LR with ≥ 50% response receive treatment on the single-modality arm (minimally-invasive surgery or radiation alone to 50 Gy). HR with ≥ 50% response or LR with ≥ 30% and < 50% response receive treatment on the intermediate de-escalation arm (chemoradiation to 50 Gy with cisplatin). All other patients receive treatment on the regular dose arm with chemoradiation to 70 Gy with concurrent cisplatin. Plasma cfHPV-DNA is assessed during induction, (chemo)radiation, and post-treatment surveillance. The primary endpoint is correlation of quantitative cfHPV-DNA with radiographic response. DISCUSSION A de-escalation treatment paradigm that reduces toxicity without compromising survival outcomes is urgently needed for HPV + OPC. Response to induction chemotherapy is predictive and prognostic and can select candidates for de-escalated definitive therapy. Assessment of quantitative cfHPV-DNA in the context of response-adaptive treatment of represents a promising reliable and convenient biomarker-driven strategy to guide personalized treatment in HPV + OPC. TRIAL REGISTRATION This trial is registered with ClinicalTrials.gov on October 1st, 2020 with Identifier: NCT04572100 .
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Affiliation(s)
- Ari J Rosenberg
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA.
| | - Evgeny Izumchenko
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA
| | - Alexander Pearson
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA
| | - Zhen Gooi
- Section of Otolaryngology-Head and Neck Surgery, University of Chicago, Chicago, IL, USA
| | - Elizabeth Blair
- Section of Otolaryngology-Head and Neck Surgery, University of Chicago, Chicago, IL, USA
| | - Theodore Karrison
- Department of Public Health Sciences, University of Chicago, Chicago, IL, USA
| | - Aditya Juloori
- Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA
| | - Daniel Ginat
- Department of Radiology, University of Chicago, Chicago, IL, USA
| | - Nicole Cipriani
- Department of Pathology, University of Chicago, Chicago, IL, USA
| | - Mark Lingen
- Department of Pathology, University of Chicago, Chicago, IL, USA
| | | | | | | | | | | | | | - Daniel Haraf
- Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USA
| | - Nishant Agrawal
- Section of Otolaryngology-Head and Neck Surgery, University of Chicago, Chicago, IL, USA
| | - Everett E Vokes
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA
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Hecht M, Eckstein M, Rutzner S, von der Grün J, Illmer T, Klautke G, Laban S, Hautmann MG, Brunner TB, Tamaskovics B, Hinke A, Zhou JG, Frey B, Donaubauer AJ, Becker I, Semrau S, Hartmann A, Balermpas P, Budach W, Gaipl US, Iro H, Gostian AO, Fietkau R. Induction chemoimmunotherapy followed by CD8+ immune cell-based patient selection for chemotherapy-free radioimmunotherapy in locally advanced head and neck cancer. J Immunother Cancer 2022; 10:e003747. [PMID: 35078923 PMCID: PMC8796267 DOI: 10.1136/jitc-2021-003747] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/25/2021] [Indexed: 01/05/2023] Open
Abstract
PURPOSE The first aim of the trial is to study feasibility of combined programmed death protein ligand 1/cytotoxic T-lymphocyte-associated protein 4 inhibition concomitant to radiotherapy. In addition, efficacy of the entire treatment scheme consisting of induction chemoimmunotherapy followed by chemotherapy-free radioimmunotherapy (RIT) after intratumoral CD8 +immune cell-based patient selection will be analyzed. METHODS Patients with stage III-IVB head and neck squamous cell carcinoma were eligible for this multicenter phase II trial. Treatment consisted of a single cycle of cisplatin 30 mg/m² days 1-3, docetaxel 75 mg/m² day 1, durvalumab 1500 mg fix dose day 5 and tremelimumab 75 mg fix dose day 5. Patients with increased intratumoral CD8 +immune cell density or pathological complete response (pCR) in the rebiopsy entered RIT up to a total dose of 70 Gy. Patients received further three cycles of durvalumab/tremelimumab followed by eight cycles of durvalumab mono (every 4 weeks). The intended treatment for patients not meeting these criteria was standard radiochemotherapy outside the trial. Primary endpoint was a feasibility rate of patients entering RIT to receive treatment until at least cycle 6 of immunotherapy of ≥80%. RESULTS Between September 2018 and May 2020, 80 patients were enrolled (one excluded). Out of these, 23 patients had human papilloma virus (HPV)-positive oropharyngeal cancer. Median follow-up was 17.2 months. After induction chemoimmunotherapy 41 patients had pCR and 31 had increased intratumoral CD8 +immune cells. Of 60 patients entering RIT (primary endpoint cohort), 10 experienced imiting toxic (mainly hepatitis) and four discontinued for other reasons, resulting in a feasibility rate of 82%. The RIT cohort (n=60) had a progression-free survival (PFS) rate at one and 2 years of 78% and 72%, respectively, and an overall survival rate at one and 2 years of 90% and 84%, respectively. Patients with HPV-positive oropharyngeal cancers had greater benefit from RIT with a 2-year PFS rate of 94% compared with 64% for HPV-negative oropharyngeal cancers and other locations. In the entire study cohort (n=79) the 2-year PFS rate was 68% (91% for HPV-positive oropharynx vs 59% for others). Toxicity grade 3-4 mainly consisted of dysphagia (53%), leukopenia (52%) and infections (32%). CONCLUSIONS The trial met the primary endpoint feasibility of RIT. Induction chemo-immunotherapy followed by chemotherapy-free RIT after intratumoral CD8 +immune cell-based patient selection has promising PFS. TRIAL REGISTRATION NUMBER The trial was registered with ClinicalTrials.gov (identifier: NCT03426657). The trial was conducted as investigator-sponsored trial (IST).
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Affiliation(s)
- Markus Hecht
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Markus Eckstein
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Sandra Rutzner
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Jens von der Grün
- Department of Radiation Oncology, University Hospital Frankfurt, Goethe-Universitat Frankfurt am Main, Frankfurt am Main, Germany
| | - Thomas Illmer
- Private Praxis Oncology, Arnoldstraße, Dresden, Germany
| | - Gunther Klautke
- Department of Radiation Oncology, Chemnitz Hospital, Chemnitz, Germany
| | - Simon Laban
- Department of Otolaryngology - Head & Neck Surgery, Universität Ulm, Ulm, Germany
| | - Matthias G Hautmann
- Department of Radiotherapy, University Hospital Regensburg, Universität Regensburg, Regensburg, Germany
| | - Thomas B Brunner
- Department of Radiation Oncology, University Hospital Magdeburg, Otto von Guericke Universität Magdeburg, Magdeburg, Germany
| | - Bálint Tamaskovics
- Department of Radiation Oncology, University Hospital Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Dusseldorf, Germany
| | - Axel Hinke
- Clinical Cancer Research Consulting (CCRC), Düsseldorf, Germany
| | - Jian-Guo Zhou
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Benjamin Frey
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Anna-Jasmina Donaubauer
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Ina Becker
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Sabine Semrau
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Arndt Hartmann
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Panagiotis Balermpas
- Department of Radiation Oncology, University Hospital Frankfurt, Goethe-Universitat Frankfurt am Main, Frankfurt am Main, Germany
| | - Wilfried Budach
- Department of Radiation Oncology, University Hospital Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Dusseldorf, Germany
| | - Udo S Gaipl
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Heinrich Iro
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
- Department of Otolaryngology - Head & Neck Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Antoniu-Oreste Gostian
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
- Department of Otolaryngology - Head & Neck Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Rainer Fietkau
- Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
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Crane J, Shi Q, Xi Y, Lai J, Pham K, Wang H. Emerging Trends in the Pathological Research of Human Papillomavirus-positive Oropharyngeal Squamous Cell Carcinoma. JOURNAL OF CLINICAL AND TRANSLATIONAL PATHOLOGY 2022; 2:31-36. [PMID: 36275841 PMCID: PMC9585478 DOI: 10.14218/jctp.2022.00004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Oropharyngeal squamous cell carcinomas (OPSCCs) have shown an alarming rate of increase in incidence over the past several decades, markedly in men. In the United States, transcriptionally-active human papillomavirus (HPV), particularly HPV 16, has become the highest contributive agent of OPSCCs, affecting approximately 16,000 people a year. Compared to patients with HPV-negative OPSCCs, patients with HPV-positive OPSCCs exhibit better health responses to chemoradiotherapy and an overall increase in long-term survival. Despite promising treatment options, many OPSCCs are discovered at an advanced stage, and ~20% of cases will recur after definitive treatment. Therefore, extensive research is ongoing to identify new targets for precision treatment and to stratify tumor prognosis. The aim of this review is to capture the most updated research on HPV-positive OPSCCs, emphasizing their relevance as potential new targets for precision medicine and survival prognosis.
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Affiliation(s)
- Joshua Crane
- Department of Laboratory Medicine and Pathology, Yale University School of Medicine, New Haven, CT, USA
| | | | - Yibo Xi
- Department of Laboratory Medicine and Pathology, Yale University School of Medicine, New Haven, CT, USA
| | | | - Kien Pham
- Department of Laboratory Medicine and Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - He Wang
- Department of Laboratory Medicine and Pathology, Yale University School of Medicine, New Haven, CT, USA
- Correspondence to: He Wang, Department of Laboratory Medicine and Pathology, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06510, USA. Tel: +1-203-214-2786, Fax: +1-203-214-2764,
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Morey T, Stern C, Foreman A, Hodge JC. Accuracy of imaging modalities at detecting extracapsular spread of cervical lymph node metastases in HPV-associated oropharyngeal cancer: a systematic review protocol of diagnostic test accuracy. JBI Evid Synth 2022; 20:189-195. [PMID: 34555838 DOI: 10.11124/jbies-21-00164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
OBJECTIVE The objective of this review is to evaluate the accuracy of different imaging modalities in detecting extracapsular spread (ECS) of cervical lymph node metastases in human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC). INTRODUCTION Extracapsular spread of lymph node metastases is associated with poor prognosis, and its detection in head and neck cancer is crucial for treatment planning. Commonly used imaging modalities to detect ECS in OPSCC include computed tomography, magnetic resonance imaging, positron emission tomography, and ultrasonography. Currently there is no gold standard imaging modality to detect ECS in OPSCC. INCLUSION CRITERIA This review will consider published studies examining the diagnostic accuracy (including sensitivity and specificity) of an imaging modality used to detect ECS in HPV+ OPSCC. Participants will have a diagnosis of HPV+ OPSCC and suspected diagnosis of ECS of cervical lymph node metastases. The index test will be different imaging modalities used to detect ECS, and the reference test will be histopathology. METHODS A three-step search strategy will be undertaken to identify relevant studies in MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus. A standardized critical appraisal tool (QUADAS-2) will be used to assess the methodological quality of the studies. The main outcomes will be sensitivity and specificity measures reported with 95% confidence intervals. Meta-analysis will be conducted using a bivariate model approach after pooling the studies according to imaging modality. Meta-regression will be used to explore heterogeneity. Meta-regression and subgroup analyses will be used to compare studies and imaging modalities. The results will be presented using either paired forest plots, summary receiver operator characteristic curves, or a narrative synthesis. A GRADE Summary of Findings will be provided. SYSTEMATIC REVIEW REGISTRATION NUMBER PROSPERO CRD42021250626.
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Affiliation(s)
- Tristan Morey
- JBI, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia
| | - Cindy Stern
- JBI, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia
| | - Andrew Foreman
- Department of Otolaryngology, Head and Neck Surgery, Royal Adelaide Hospital, University of Adelaide, Adelaide, SA, Australia
| | - John-Charles Hodge
- Department of Otolaryngology, Head and Neck Surgery, Royal Adelaide Hospital, University of Adelaide, Adelaide, SA, Australia
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Vaccine Strategies for Human Papillomavirus-Associated Head and Neck Cancers. Cancers (Basel) 2021; 14:cancers14010033. [PMID: 35008197 PMCID: PMC8750601 DOI: 10.3390/cancers14010033] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/15/2021] [Accepted: 12/20/2021] [Indexed: 12/25/2022] Open
Abstract
Simple Summary Human papillomavirus (HPV) is recognized as a significant risk factor for head and neck cancers worldwide, and it is the most common cause of oropharyngeal cancers in the United States. Here, we review the incidence and pathogenesis of HPV-related cancers, the development and approval of HPV prophylactic vaccines, and the use and effectiveness of HPV vaccines around the world. Furthermore, we discuss advances in the development of HPV therapeutic vaccines as well as its associated challenges. Abstract The rising incidence of oropharyngeal squamous cell cancers (OPSCC) in the United States is largely attributed to HPV. Prophylactic HPV vaccines have demonstrated effectiveness against oral infection of HPV 16 and HPV 18. We review the global epidemiology and biology of HPV-related cancers as well as the development of HPV vaccines and their use worldwide. We also review the various strategies and challenges in development of therapeutic HPV vaccines.
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Azzimonti B, Raimondo L, Squarzanti DF, Rosso T, Zanetta P, Aluffi Valletti P, Chiusa L, Masini L, Pecorari G, Airoldi M, Krengli M, Giovarelli M, Valente G. Macrophages expressing TREM-1 are involved in the progression of HPV16-related oropharyngeal squamous cell carcinoma. Ann Med 2021; 53:541-550. [PMID: 33769181 PMCID: PMC8008925 DOI: 10.1080/07853890.2021.1905872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 03/25/2021] [Indexed: 11/04/2022] Open
Abstract
INTRODUCTION Many types of research have been performed to improve the diagnosis, therapy, and prognosis of oropharyngeal carcinomas (OP-SCCs). Since they arise in lymphoid-rich areas and intense lymphocytic infiltration has been related to a better prognosis, a TREM-1 putative function in tumour progression and survival has been hypothesized. MATERIALS AND METHODS Twenty-seven human papillomavirus (HPV) 16+ OP-SCC specimens have been analyzed to relate TREM-1 expression with histiocytic and lymphocytic markers, HPV presence and patients' outcome. RESULTS No differences have been shown between intratumoral and stromal CD4+ cells, while intratumoral CD8+ lymphocytes are higher with respect to the tumour stroma (p = .0005). CD68+ cells are more than CD35+ and TREM-1+; their presence is related to CD35± and TREM-1± histiocytes (p = .005 and .026, respectively). Intratumoral CD4+ lymphocytes are higher in p16+ cases (11/27) than in p16- (p = .042); moreover, p16 positivity correlates to a better survival (p = .034). CD4+, CD8+ and CD35+ cells have no impact on survival, while CD68 expression heavily influences progression and bad outcome (p = .037). TREM-1 positivity also leads to worst overall survival (p = .001): peritumoral expression and death-cause relationship are always significant, particularly when the cause is OP-SCC (p = .000). CONCLUSION While p16 shows to better stratify HPV16+ patients' outcome, TREM-1+ macrophages suggest their key importance in HPV-related OP-SCCs progression.KEY MESSAGESTREM-1 positivity correlates to the worst overall survival of HPV16-positive OPSCCs-affected patients.p16-positive HPV16 related OPSCCs patients have a better prognosis with respect to p16-negative ones.
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Affiliation(s)
- Barbara Azzimonti
- Center for Translational Research on Autoimmune and Allergic Diseases (CAAD), Department of Health Sciences (DiSS), University of Piemonte Orientale (UPO), Novara, Italy
| | - Luca Raimondo
- Otorhinolaryngology Division, Department of Surgical Sciences, University of Turin, Turin, Italy
| | - Diletta Francesca Squarzanti
- Center for Translational Research on Autoimmune and Allergic Diseases (CAAD), Department of Health Sciences (DiSS), University of Piemonte Orientale (UPO), Novara, Italy
| | - Tiziana Rosso
- Clinical Epidemiology Unit, “Città della Salute e della Scienza” Hospital – CPO Piemonte, Torino, Italy
| | - Paola Zanetta
- Center for Translational Research on Autoimmune and Allergic Diseases (CAAD), Department of Health Sciences (DiSS), University of Piemonte Orientale (UPO), Novara, Italy
| | - Paolo Aluffi Valletti
- Division of Ear Nose and Throat Department-Head and Neck Surgery, DiSS, University of Piemonte Orientale (UPO), Novara, Italy
| | - Luigi Chiusa
- Department of Biomedical Sciences and Human Oncology, University of Turin, Turin, Italy
| | - Laura Masini
- Radiotherapy Unit, Department of Translational Medicine (DiMeT), University of Piemonte Orientale (UPO), Novara, Italy
| | - Giancarlo Pecorari
- Otorhinolaryngology Division, Department of Surgical Sciences, University of Turin, Turin, Italy
| | - Mario Airoldi
- Department of Oncology, Azienda Ospedaliera Universitaria Citta’ della Salute e della Scienza di Torino, Turin, Italy
| | - Marco Krengli
- Radiotherapy Unit, Department of Translational Medicine (DiMeT), University of Piemonte Orientale (UPO), Novara, Italy
| | - Mirella Giovarelli
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
- Center for Experimental Research and Medical Studies (CERMS), AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Guido Valente
- Pathology Unit, Ospedale “Sant’Andrea”, DiMeT, University of Piemonte Orientale (UPO), Vercelli, Italy
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