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1
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Hu Q, Li F, Yang K. Systematic evaluation and meta-analysis of the prognosis of down-staging human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma using cetuximab combined with radiotherapy instead of cisplatin combined with radiotherapy. PeerJ 2024; 12:e17391. [PMID: 38784388 PMCID: PMC11114112 DOI: 10.7717/peerj.17391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 04/23/2024] [Indexed: 05/25/2024] Open
Abstract
Objective To evaluate the efficacy and safety of cetuximab instead of cisplatin in combination with downstaging radiotherapy for papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (HPV+ OPSCC). Design Meta-analysis and systematic evaluation. Data sources The PubMed, Embase, Web of Science, and Cochrane library databases were searched up to June 8, 2023, as well as Clinicaltrials.gov Clinical Trials Registry, China Knowledge Network, Wanfang Data Knowledge Service Platform, and Wiprojournal.com. Eligibility criteria for selecting studies Randomized controlled trials reporting results of standard regimens of cetuximab + radiotherapy vs cisplatin + radiotherapy in treating HPV+ OPSCC were included. The primary outcomes of interest were overall survival (OS), progression-free survival (PFS), local regional failure rate (LRF), distant metastasis rate (DM), and adverse events (AE). Data extraction and synthesis Two reviewers independently extracted data and assessed the risk of bias of the included studies. The HR and its 95% CI were used as the effect analysis statistic for survival analysis, while the OR and its 95% CI were used as the effect analysis statistic for dichotomous variables. These statistics were extracted by the reviewers and aggregated using a fixed-effects model to synthesise the data. Results A total of 874 relevant papers were obtained from the initial search, and five papers that met the inclusion criteria were included; a total of 1,617 patients with HPV+ OPSCC were enrolled in these studies. Meta-analysis showed that OS and PFS were significantly shorter in the cetuximab + radiotherapy group of patients with HPV+ OPSCC compared with those in the conventional cisplatin + radiotherapy group (HR = 2.10, 95% CI [1.39-3.15], P = 0.0004; HR = 1.79, 95% CI [1.40-2.29], P < 0.0001); LRF and DM were significantly increased (HR = 2.22, 95% CI [1.58-3.11], P < 0.0001; HR = 1.66, 95% CI [1.07-2.58], P = 0.02), but there was no significant difference in overall grade 3 to 4, acute and late AE overall (OR = 0.86, 95% CI [0.65-1.13], P = 0.28). Conclusions Cisplatin + radiotherapy remains the standard treatment for HPV+ OPSCC. According to the 7th edition AJCC/UICC criteria, low-risk HPV+ OPSCC patients with a smoking history of ≤ 10 packs/year and non-pharyngeal tumors not involved in lymphatic metastasis had similar survival outcomes with cetuximab/cisplatin + radiotherapy. However, further clinical trials are necessary to determine whether cetuximab + radiotherapy can replace cisplatin + radiotherapy for degraded treatment in individuals who meet the aforementioned characteristics, particularly those with platinum drug allergies. Prospero registration number CRD42023445619.
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Affiliation(s)
- Qiong Hu
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Feng Li
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Kai Yang
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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2
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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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3
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Argirion I, Arthur AE, Zarins KR, Bellile E, Crowder SL, Amlani L, Taylor JM, Wolf GT, McHugh J, Nguyen A, Mondul AM, Rozek LS. Pretreatment Dietary Patterns, Serum Carotenoids and Tocopherols Influence Tumor Immune Response in Head and Neck Squamous Cell Carcinoma. Nutr Cancer 2020; 73:2614-2626. [PMID: 33307825 DOI: 10.1080/01635581.2020.1842895] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Tumor infiltrating lymphocytes (TILs) aid in informing treatment for head and neck squamous cell carcinoma (HNSCC). Nevertheless, little is known about the role of diet on TILs. METHODS Immunohistologic expression of CD4, CD8, CD68, CD103, CD104 and FOXP3 were assessed in tissue microarrays from 233 previously untreated HNSCC patients. Associations between these markers and pretreatment dietary patterns were evaluated using linear regression. Associations between baseline serum carotenoids, tocopherols and TILs were assessed using logistic regression. Cox models evaluated the association between diet and TILs on overall and recurrence-free survival. RESULTS Consumption of a Western dietary pattern was associated with lower CD8+ and FOXP3+ infiltrates (p-value:0.03 and 0.02, respectively). Multivariable logistic regression models demonstrated significantly higher CD8+ (OR:2.21;p-value:0.001) and FOXP3+ (OR:4.26;p-value:<0.0001) among patients with high gamma tocopherol. Conversely, high levels of xanthophylls (OR:0.12;p-value:<0.0001), lycopene (OR:0.36;p-value:0.0001) and total carotenoids(OR:0.31;p-value: <0.0001) were associated with significantly lower CD68+. Among those with high CD4+ (HR:1.77;p-value:0.03), CD68+ (HR:2.42;p-value:0.004), CD103+ (HR:3.64;p-value:0.03) and FOXP3+ (HR:3.09;p-value:0.05), having a high Western dietary pattern increased the risk of overall mortality when compared to a low Western dietary pattern. CONCLUSION Dietary patterns and serum carotenoids may play an important role in modifying TILs, and ultimately, outcome after diagnosis with HNSCC.
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Affiliation(s)
- Ilona Argirion
- Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan, USA
| | - Anna E Arthur
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.,Carle Cancer Center, Carle Foundation Hospital, Urbana, Illinois, USA
| | - Katie R Zarins
- Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan, USA
| | - Emily Bellile
- Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA
| | - Sylvia L Crowder
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA
| | - Lahin Amlani
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Jeremy Mg Taylor
- Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA
| | - Greg T Wolf
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Jonathan McHugh
- Pathology, The University of Michigan Health System, Ann Arbor, Michigan, USA
| | - Ariane Nguyen
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Alison M Mondul
- Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, USA
| | - Laura S Rozek
- Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan, USA
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Ishida K, Nakashima T, Shibata T, Hara A, Tomita H. Role of the DEK oncogene in the development of squamous cell carcinoma. Int J Clin Oncol 2020; 25:1563-1569. [PMID: 32656741 PMCID: PMC7441080 DOI: 10.1007/s10147-020-01735-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 06/21/2020] [Indexed: 01/21/2023]
Abstract
DEK is a highly conserved nuclear factor that plays an important role in the regulation of multiple cellular processes. DEK was discovered to be an oncogene as a fusion with NUP214 gene, which results in producing DEK-NUP214 proteins, in a subset of patients with acute myeloid leukemia. Subsequently, DEK overexpression was reported in many cancers, thus DEK itself is considered to be an oncoprotein. DEK has been reported to play important roles in the progression of early and late stage squamous cell carcinoma (SCC) and is useful for early diagnosis of the disease. These findings have made DEK an attractive therapeutic target, especially for human papillomavirus (HPV)-associated SCC. However, the mechanism of DEK in SCC remains unclear. In this review, we discuss human DEK oncogene-related SCC.
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Affiliation(s)
- Kazuhisa Ishida
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan
- Department of Oral Maxillofacial Surgery, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan
| | - Takayuki Nakashima
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan
- Department of Oral Maxillofacial Surgery, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan
| | - Toshiyuki Shibata
- Department of Oral Maxillofacial Surgery, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan
| | - Akira Hara
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan
| | - Hiroyuki Tomita
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan.
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5
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Wang HF, Wang SS, Tang YJ, Chen Y, Zheng M, Tang YL, Liang XH. The Double-Edged Sword-How Human Papillomaviruses Interact With Immunity in Head and Neck Cancer. Front Immunol 2019; 10:653. [PMID: 31001266 PMCID: PMC6454067 DOI: 10.3389/fimmu.2019.00653] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 03/11/2019] [Indexed: 02/05/2023] Open
Abstract
Patients with human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) have remarkably better prognosis, which differs from HPV-negative oropharyngeal squamous cell carcinoma (OPSCC) with respect to clinical, genomic, molecular, and immunological aspects, especially having the characteristics of high levels of immune cell infiltration and high degrees of immunosuppression. This review will summarize immune evasion mechanisms in HPV-positive HNSCC, analyze the host various immune responses to HPV and abundant numbers of infiltrating immune cell, and discuss the differences between HPV-positive HNSCC with cervical cancer. A deeper understanding of the immune landscape will help new concepts to emerge in immune-checkpoint oncology, which might be a valuable add-on to established concepts.
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Affiliation(s)
- Hao-Fan Wang
- State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
| | - Sha-Sha Wang
- State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
| | - Ya-Jie Tang
- Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Key Laboratory of Industrial Microbiology, Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, Hubei University of Technology, Wuhan, China
| | - Yu Chen
- State Key Laboratory of Oral Diseases, Department of Oral Pathology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
| | - Min Zheng
- Department of Stomatology, Zhoushan Hospital, Wenzhou Medical University, Zhoushan, China
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases, Department of Oral Pathology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
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6
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Evaluation and validation of HPV real-time PCR assay for the detection of HPV DNA in oral cytobrush and FFPE samples. Sci Rep 2018; 8:11313. [PMID: 30054550 PMCID: PMC6063863 DOI: 10.1038/s41598-018-29790-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 07/13/2018] [Indexed: 12/18/2022] Open
Abstract
Specific HPV genotypes have been recognized as risk factors inducing head and neck cancers (HNC). The aim of this study was to validate a real-time PCR assay to detect accurately High Risk HPV DNA in Formalin Fixed Paraffin Embedded (FFPE) and oral cytobrush samples and compare the results with conventional PCR. Repeatability, reproducibility and limit of detection of Cobas assay were estimated for oral cytobrush and FFPE samples of patients with HNC. 53 samples of patients with a HNC were then used for assay comparison with conventional PCR. Finally, 26 samples of patients with anogenital neoplasia cancer were analyzed as control and assays comparison. Among the 53 samples of patients with HNC, 12 (26.7%) were HPV positive, 33 (73.3%) were HPV negative and 8 (15.1%) were non contributive with the Cobas assay. Among the 26 samples of patients with anogenital neoplasia, 15 (57.7%) were HPV positive and 11 were HPV negative (42.3%). One sample was found with an HPV 16 and HPV 18 co-infection. Only 3 samples were found with discrepant results. Cobas assay was found suitable for routine HPV detection with a very good repeatability and reproducibility for all HPV genotypes (CV < 0.6% and <0.4% respectively). Sensitivity and specificity for Cobas assay were 91.7% [61.5%;99.8%] and 96.9% [83.8%;99.9%] respectively. Ten nanograms of DNA were sufficient for the detection of HPV 16, HPV 18 and HPV in FFPE and oral cytobrush samples. Cobas assay was found comparable to conventional PCR and can detect accurately and rapidly HPV DNA in FFPE and oral cytobrush samples for the management of HNC and other types of HPV-associated neoplasia.
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7
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Makkouk A, Sundaram V, Chester C, Chang S, Colevas AD, Sunwoo JB, Maecker H, Desai M, Kohrt HE. Characterizing CD137 upregulation on NK cells in patients receiving monoclonal antibody therapy. Ann Oncol 2017; 28:415-420. [PMID: 27831501 DOI: 10.1093/annonc/mdw570] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Background In the era of personalized cancer medicine, identifying techniques for effectively matching patients to efficacious treatments is a critical step in the treatment process. The advent of anti-cancer immunotherapies necessitates novel approaches to biomarker identification beyond traditional genomic profiling. One promising approach is incorporation of nomograms into treatment decisions. Nomograms are prediction tools, based on statistical modeling, designed to predict treatment outcomes. As a first step toward developing a nomogram, we conducted analyses to predict CD137 expression of natural killer cells after monoclonal antibody (mAb) treatment. Patients and methods Patient, tumor and immune characteristics were collected from 199 patients with breast cancer (N = 62), head/neck cancers (N = 46) and non-Hodgkin's lymphoma (NHL) (N = 91), who were receiving mAb therapy as part of clinical trials. The difference in CD137 expression before and after mAb therapy was assessed by flow cytometry. To evaluate those who respond to mAb therapy via increased CD137 expression, we applied classification and regression trees (CART), multivariable lasso regression tools and Random Forest. Results The CD137 expression was significantly different for each cancer type [mean (SD): Breast: 6.6 (6.5); Head/Neck: 11.0 (7.0); NHL: 7.5 (7.1), P < 0.0001]. For breast cancer and NHL, FcR polymorphism and baseline CD137 expression were significant predictors of increased CD137 expression; for head/neck cancer, FcR polymorphism and age were significant predictors of increased expression. Conclusions Our preliminary results suggest that FcR polymorphism, pre-treatment CD137 expression and age are significant predictors of CD137 upregulation in patients. This study demonstrates that the development of a nomogram for therapy response is feasible. Further work validating our models in an independent cohort will provide the next steps in developing a nomogram that may be used to individualize this therapeutic approach for patients (NCT01114256).
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Affiliation(s)
- A Makkouk
- Department of Medicine, Division of Oncology, Stanford University , Stanford, CA, USA
| | - V Sundaram
- Quantitative Sciences Unit, Department of Medicine, Stanford University School of Medicine, CA, USA
| | - C Chester
- Department of Medicine, Division of Oncology, Stanford University , Stanford, CA, USA.,Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA
| | - S Chang
- Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA
| | - A D Colevas
- Department of Medicine, Division of Oncology, Stanford University , Stanford, CA, USA
| | - J B Sunwoo
- Department of Otorhinolaryngology, Stanford University, Stanford, USA
| | - H Maecker
- Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA
| | - M Desai
- Quantitative Sciences Unit, Department of Medicine, Stanford University School of Medicine, CA, USA
| | - H E Kohrt
- Department of Medicine, Division of Oncology, Stanford University , Stanford, CA, USA
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8
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Lei Y, Xie Y, Tan YS, Prince ME, Moyer JS, Nör J, Wolf GT. Telltale tumor infiltrating lymphocytes (TIL) in oral, head & neck cancer. Oral Oncol 2016; 61:159-65. [PMID: 27553942 DOI: 10.1016/j.oraloncology.2016.08.003] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Revised: 07/11/2016] [Accepted: 08/15/2016] [Indexed: 12/13/2022]
Abstract
Evidence gleaned from recent studies on the role of tumor-infiltrating lymphocytes (TILs) suggests that cancer is not only a genetic disease but also an immunologic disease. Head and Neck Squamous Cell Carcinoma (HNSCC) has been a significant model to study cancer cell-immune cell interactions. First, immune cell infiltration is an important feature of these tumors. Second, HNSCC frequently develops resistance to immunogenic cytotoxicity, which provides a window to decipher how tumors engage the immune system to establish immune tolerance. Finally, chemoradiation therapy, as a central modality for HNSCC treatment, has been shown to elicit immune activation. The presence of effector immune cells in the tumor microenvironment is often associated with superior clinical response to adjuvant therapy. On the other hand, an activated immune system, in addition to limiting tumor initiation and progression, could also exert selective pressure to promote the growth of less immunogenic tumors, as a pivotal immunoediting process. But it remains unclear how cancer cell signaling regulates tumor immunogenicity and how to mitigate HNSCC-potentiated TIL suppression. In this review, we will revisit the prognostic role of TILs in HNSCC, and collectively discuss how cancer cell machinery impacts upon the plasticity of TILs.
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Affiliation(s)
- Yu Lei
- Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, MI 48109, United States; Department of Otolaryngology - Head and Neck Surgery, University of Michigan, School of Medicine, Ann Arbor, MI 48109, United States; Translational Oncology Program, U-M Comprehensive Cancer Center, Ann Arbor, MI 48109, United States; Graduate Program in Immunology, University of Michigan, School of Medicine, Ann Arbor, MI 48109, United States.
| | - Yuying Xie
- Department of Computational Mathematics, Science, and Engineering, Michigan State University, East Lansing 48824, United States
| | - Yee Sun Tan
- Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, MI 48109, United States; Translational Oncology Program, U-M Comprehensive Cancer Center, Ann Arbor, MI 48109, United States
| | - Mark E Prince
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan, School of Medicine, Ann Arbor, MI 48109, United States
| | - Jeffrey S Moyer
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan, School of Medicine, Ann Arbor, MI 48109, United States
| | - Jacques Nör
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan, School of Medicine, Ann Arbor, MI 48109, United States; Translational Oncology Program, U-M Comprehensive Cancer Center, Ann Arbor, MI 48109, United States; Department of Cariology, Restorative Sciences, and Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI 48109, United States
| | - Gregory T Wolf
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan, School of Medicine, Ann Arbor, MI 48109, United States; Translational Oncology Program, U-M Comprehensive Cancer Center, Ann Arbor, MI 48109, United States.
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9
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Masterson L, Sorgeloos F, Winder D, Lechner M, Marker A, Malhotra S, Sudhoff H, Jani P, Goon P, Sterling J. Deregulation of SYCP2 predicts early stage human papillomavirus-positive oropharyngeal carcinoma: A prospective whole transcriptome analysis. Cancer Sci 2015; 106:1568-75. [PMID: 26334652 PMCID: PMC4714680 DOI: 10.1111/cas.12809] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 08/20/2015] [Accepted: 08/29/2015] [Indexed: 12/31/2022] Open
Abstract
This study was designed to identify significant differences in gene expression profiles of human papillomavirus (HPV)‐positive and HPV‐negative oropharyngeal squamous cell carcinomas (OPSCC) and to better understand the functional and biological effects of HPV infection in the premalignant pathway. Twenty‐four consecutive patients with locally advanced primary OPSCC were included in a prospective clinical trial. Fresh tissue samples (tumor vs. matched normal epithelium) were subjected to whole transcriptome analysis and the results validated on the same cohort with RT–quantitative real‐time PCR. In a separate retrospective cohort of 27 OPSCC patients, laser capture microdissection of formalin‐fixed, paraffin‐embedded tissue allowed RNA extraction from adjacent regions of normal epithelium, carcinoma in situ (premalignant) and invasive SCC tissue. The majority of patients showed evidence of high‐risk HPV16 positivity (80.4%). Predictable fold changes of RNA expression in HPV‐associated disease included multiple transcripts within the p53 oncogenic pathway (e.g. CDKN2A/CCND1). Other candidate transcripts found to have altered levels of expression in this study have not previously been established (SFRP1, CRCT1, DLG2, SYCP2, and CRNN). Of these, SYCP2 showed the most consistent fold change from baseline in premalignant tissue; aberrant expression of this protein may contribute to genetic instability during HPV‐associated cancer development. If further corroborated, this data may contribute to the development of a non‐invasive screening tool. This study is registered with the UK Clinical Research Network (ref.: 11945).
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Affiliation(s)
- Liam Masterson
- Department of Pathology, University of Cambridge, Cambridge, UK.,Department of Otorhinolaryngology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK
| | | | - David Winder
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - Matt Lechner
- University College London Cancer Institute, London, UK
| | - Alison Marker
- Department of Histopathology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK
| | - Shalini Malhotra
- Department of Histopathology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK
| | - Holger Sudhoff
- Department of Otolaryngology, Head and Neck Surgery, Bielefeld Academic Teaching Hospital, Bielefeld, Germany
| | - Piyush Jani
- Department of Otorhinolaryngology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK
| | - Peter Goon
- Department of Pathology, University of Cambridge, Cambridge, UK
| | - Jane Sterling
- Department of Pathology, University of Cambridge, Cambridge, UK.,Department of Dermatology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK
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10
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Whang SN, Filippova M, Duerksen-Hughes P. Recent Progress in Therapeutic Treatments and Screening Strategies for the Prevention and Treatment of HPV-Associated Head and Neck Cancer. Viruses 2015; 7:5040-65. [PMID: 26393639 PMCID: PMC4584304 DOI: 10.3390/v7092860] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Revised: 08/17/2015] [Accepted: 08/27/2015] [Indexed: 12/11/2022] Open
Abstract
The rise in human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) has elicited significant interest in the role of high-risk HPV in tumorigenesis. Because patients with HPV-positive HNSCC have better prognoses than do their HPV-negative counterparts, current therapeutic strategies for HPV+ HNSCC are increasingly considered to be overly aggressive, highlighting a need for customized treatment guidelines for this cohort. Additional issues include the unmet need for a reliable screening strategy for HNSCC, as well as the ongoing assessment of the efficacy of prophylactic vaccines for the prevention of HPV infections in the head and neck regions. This review also outlines a number of emerging prospects for therapeutic vaccines, as well as for targeted, molecular-based therapies for HPV-associated head and neck cancers. Overall, the future for developing novel and effective therapeutic agents for HPV-associated head and neck tumors is promising; continued progress is critical in order to meet the challenges posed by the growing epidemic.
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Affiliation(s)
- Sonia N Whang
- Department of Basic Science, Loma Linda University, Loma Linda, CA 92354, USA.
| | - Maria Filippova
- Department of Basic Science, Loma Linda University, Loma Linda, CA 92354, USA.
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11
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Ludmir EB, Palta M, Zhang X, Wu Y, Willett CG, Czito BG. Incidence and prognostic impact of high-risk HPV tumor infection in cervical esophageal carcinoma. J Gastrointest Oncol 2014; 5:401-7. [PMID: 25436117 DOI: 10.3978/j.issn.2078-6891.2014.053] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Accepted: 07/06/2014] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Cervical esophageal carcinoma (CEC) is an uncommon malignancy. Limited data supports the use of definitive chemoradiotherapy (CRT) as primary treatment. Furthermore, the role of human papillomavirus (HPV) tumor infection in CEC remains unknown. This study retrospectively analyzes both outcomes of CEC patients treated with CRT and the incidence and potential role of HPV tumor infection in CEC lesions. METHODS A total of 37 CEC patients were treated with definitive CRT at our institution between 1987 and 2013. Of these, 19 had tumor samples available for high-risk HPV (types 16 and 18) pathological analysis. RESULTS For all patients (n=37), 5-year overall survival (OS), disease-free survival (DFS), and loco-regional control (LRC) rates were 34.1%, 40.2%, and 65.6%, respectively. On pathological analysis, 1/19 (5.3%) patients had an HPV-positive lesion. CONCLUSIONS Definitive CRT provides disease-related outcomes comparable to surgery. Moreover, HPV tumor infection in CEC is uncommon and its prognostic role is unclear. Our data contribute to the construction of an anatomical map of HPV tumor infection in squamous cell carcinomas (SCC) of the upper aerodigestive tract, and suggest a steep drop in viral infection rates at sites distal to the oropharynx, including the cervical esophagus.
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Affiliation(s)
- Ethan B Ludmir
- 1 Department of Radiation Oncology, 2 Department of Pathology, 3 Department of Biostatistics and Bioinformatics, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
| | - Manisha Palta
- 1 Department of Radiation Oncology, 2 Department of Pathology, 3 Department of Biostatistics and Bioinformatics, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
| | - Xuefeng Zhang
- 1 Department of Radiation Oncology, 2 Department of Pathology, 3 Department of Biostatistics and Bioinformatics, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
| | - Yuan Wu
- 1 Department of Radiation Oncology, 2 Department of Pathology, 3 Department of Biostatistics and Bioinformatics, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
| | - Christopher G Willett
- 1 Department of Radiation Oncology, 2 Department of Pathology, 3 Department of Biostatistics and Bioinformatics, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
| | - Brian G Czito
- 1 Department of Radiation Oncology, 2 Department of Pathology, 3 Department of Biostatistics and Bioinformatics, Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA
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12
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Goh AR, Shin SP, Jung NR, Ryu CH, Eom HS, Lee JH, Choi K, Lee SJ, Jung YS. Low-dose cisplatin converts the tumor microenvironment into a permissive state for HSVtk-induced antitumor immunity in HPV16-related tonsillar carcinoma. Cancer Lett 2014; 356:743-50. [PMID: 25449436 DOI: 10.1016/j.canlet.2014.10.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 10/20/2014] [Accepted: 10/22/2014] [Indexed: 02/05/2023]
Abstract
An adenovirus harboring the HSV thymidine kinase (HSVtk) gene under the regulation of a trans-splicing ribozyme that targets telomerase is cytotoxic to cancer cells because it inhibits DNA replication (Ad5mTR). Furthermore, it induces anti-tumor immunity by activating cytotoxic T cells. Because multiple chemotherapeutic agents also activate cytotoxic T-cell immunity during the direct killing process of tumor cells, we herein explored whether low-dose cisplatin could synergize with cytotoxic Ad5mTR to potentiate its therapeutic effect by boosting anti-tumor immunity in a murine HPV16-associated tonsillar carcinoma model. Tumor regression was enhanced when low-dose (1 mg/kg) cisplatin was added to suicide gene therapy using Ad5mTR. Meanwhile, 1 mg/kg cisplatin alone had no tumor-suppressive effects and did not result in any systemic toxicity. Thus, cisplatin along with Ad5mTR improved tumor clearance by increasing the number of E7-specific CD8+ T cells. Specifically, analysis of the tumors and lymph nodes supported improved immune clearance by increasing the number of E7-specific CD8+ T cells inside tumors (40%, P < 0.05) as a result of the combination of suicide gene and cisplatin therapy. These results suggest that a low dose of cisplatin potentiates CD8+ T-cell-mediated anti-tumor immunity, and its addition to the HSVtk-based adenovirus results in additional therapeutic benefits for HPV16-positive head and neck cancer patients.
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Affiliation(s)
| | | | | | - Chang-Hwan Ryu
- Specific Organs Cancer Branch, Department of Otolaryngology
| | - Hyeon Seok Eom
- Hematologic-Oncology, Research Institute & Hospital, National Cancer Center, Goyang, South Korea
| | - John H Lee
- Sanford Cancer Research Center, Sanford ENT - Head and Neck Surgery, Sioux Falls, South Dakota
| | - Kyungho Choi
- Seoul National University College of Medicine, Seoul, South Korea
| | | | - Yuh-S Jung
- Specific Organs Cancer Branch, Department of Otolaryngology.
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13
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HPV in oropharyngeal cancer: the basics to know in clinical practice. ACTA OTORHINOLARYNGOLOGICA ITALICA : ORGANO UFFICIALE DELLA SOCIETA ITALIANA DI OTORINOLARINGOLOGIA E CHIRURGIA CERVICO-FACCIALE 2014; 34:299-309. [PMID: 25709145 PMCID: PMC4299160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Accepted: 04/24/2014] [Indexed: 11/08/2022]
Abstract
The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is rising in contrast to the decreasing incidence of carcinomas in other subsites of the head and neck, in spite of the reduced prevalence of smoking. Human papilloma virus (HPV) infection, and in particular type 16 (HPV-16), is now recognized as a significant player in the onset of HPV positive OPSCC, with different epidemiological, clinical, anatomical, radiological, behavioural, biological and prognostic characteristics from HPV negative OPSCC. Indeed, the only subsite in the head and neck with a demonstrated aetiological viral link is, at present, the oropharynx. These observations lead to questions regarding management choices for patients based on tumour HPV status with important consequences on treatment, and on the role of vaccines and targeted therapy over the upcoming years.
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14
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Shah AA, Jeffus SK, Stelow EB. Squamous cell carcinoma variants of the upper aerodigestive tract: a comprehensive review with a focus on genetic alterations. Arch Pathol Lab Med 2014; 138:731-44. [PMID: 24878013 DOI: 10.5858/arpa.2013-0070-ra] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT Squamous cell carcinoma of the upper aerodigestive tract is a heterogenous entity. Although conventional squamous cell carcinomas are easily recognized, the morphologic variants of squamous cell carcinoma can present a diagnostic challenge. Familiarity with these variants is necessary because many are associated with unique risk factors and are characterized by specific molecular alterations (eg, nuclear protein in testis midline carcinomas). Perhaps the most important distinction is in identifying viral-related from nonviral-related carcinomas. The accurate diagnosis of these variants is necessary for prognostic and therapeutic reasons. OBJECTIVES To provide a clinicopathologic overview and summary of the molecular alterations of the common squamous cell carcinoma variants, including verrucous, spindle cell, acantholytic, adenosquamous, basaloid, and papillary squamous cell carcinoma, as well as nuclear protein in testis midline carcinoma, and to discuss the distinguishing features of human papillomavirus- and Epstein-Barr virus-related squamous cell carcinomas. DATA SOURCES Published peer-reviewed literature. CONCLUSIONS Familiarity with squamous cell carcinoma variants is essential for proper diagnosis and to guide appropriate clinical management. Further insight into the molecular alterations underlying those variants may lead to alterations in existing treatment approaches and to evolution of novel treatment modalities.
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Affiliation(s)
- Akeesha A Shah
- From the Department of Pathology, University of Virginia Health System, Charlottesville
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15
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Woods RSR, O’Regan EM, Kennedy S, Martin C, O’Leary JJ, Timon C. Role of human papillomavirus in oropharyngeal squamous cell carcinoma: A review. World J Clin Cases 2014; 2:172-193. [PMID: 24945004 PMCID: PMC4061306 DOI: 10.12998/wjcc.v2.i6.172] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Revised: 04/21/2014] [Accepted: 05/19/2014] [Indexed: 02/05/2023] Open
Abstract
Human papillomavirus (HPV) has been implicated in the pathogenesis of a subset of oropharyngeal squamous cell carcinoma. As a result, traditional paradigms in relation to the management of head and neck squamous cell carcinoma have been changing. Research into HPV-related oropharyngeal squamous cell carcinoma is rapidly expanding, however many molecular pathological and clinical aspects of the role of HPV remain uncertain and are the subject of ongoing investigation. A detailed search of the literature pertaining to HPV-related oropharyngeal squamous cell carcinoma was performed and information on the topic was gathered. In this article, we present an extensive review of the current literature on the role of HPV in oropharyngeal squamous cell carcinoma, particularly in relation to epidemiology, risk factors, carcinogenesis, biomarkers and clinical implications. HPV has been established as a causative agent in oropharyngeal squamous cell carcinoma and biologically active HPV can act as a prognosticator with better overall survival than HPV-negative tumours. A distinct group of younger patients with limited tobacco and alcohol exposure have emerged as characteristic of this HPV-related subset of squamous cell carcinoma of the head and neck. However, the exact molecular mechanisms of carcinogenesis are not completely understood and further studies are needed to assist development of optimal prevention and treatment modalities.
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16
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Hess CB, Rash DL, Daly ME, Farwell DG, Bishop J, Vaughan AT, Wilson MD, Chen AM. Competing causes of death and medical comorbidities among patients with human papillomavirus-positive vs human papillomavirus-negative oropharyngeal carcinoma and impact on adherence to radiotherapy. JAMA Otolaryngol Head Neck Surg 2014; 140:312-6. [PMID: 24526276 DOI: 10.1001/jamaoto.2013.6732] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
IMPORTANCE Survival of patients with head and neck cancer can be affected by competing causes of mortality, as well as comorbidities that result in radiation treatment interruptions. OBJECTIVE To discern how differences in preexisting medical and psychosocial comorbidities potentially influence adherence to radiation therapy according to human papillomavirus (HPV) status. DESIGN, SETTING, AND PARTICIPANTS Retrospective analysis at a comprehensive cancer center of 162 consecutive patients with locally advanced squamous cell carcinoma of the oropharynx treated with primary chemoradiation (n = 95) or primary surgery followed by adjuvant radiation (n = 67). Immunostaining for p16 was used to determine HPV status. MAIN OUTCOMES AND MEASURES Difference in alcohol, tobacco, and marijuana use was compared between patients with HPV-positive and HPV-negative tumors, as well as the prevalence of the following comorbidities: diabetes mellitus, chronic obstructive pulmonary disease (COPD), anxiety disorder, and major depression. The number of total missed treatment days was analyzed as both a continuous and categorical variable. RESULTS Rates of self-reported heavy alcohol use (47% vs 16%; P = .02) and any marijuana use (47% vs 23%; P = .003) were significantly higher among HPV-negative patients. Fifty-four percent of HPV-positive patients self-identified as never smokers, compared with only 12% of HPV-negative patients (P < .001). HPV-negative patients had more missed treatment days (mean, 2.8 vs 1.7 days; P = .02), as well as an increased rate of at least 5 missed days (24% vs 10%; P = .04), and higher prevalences of COPD (12% vs 7%; P = .37) and anxiety disorder (12% vs 6%; P = .35). CONCLUSIONS AND RELEVANCE Pronounced differences exist in lifestyle habits between patients with HPV-negative and HPV-positive oropharyngeal cancer at diagnosis. These differences, as well as those of medical and psychosocial burden, may contribute to observed discrepancies in treatment adherence and need to be considered in outcomes reporting and clinical trial design.
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Affiliation(s)
- Clayton B Hess
- Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Sacramento
| | - Dominique L Rash
- Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Sacramento
| | - Megan E Daly
- Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Sacramento
| | - D Gregory Farwell
- Department of Otolaryngology-Head and Neck Surgery, University of California Davis Comprehensive Cancer Center, Sacramento
| | - John Bishop
- Department of Pathology, University of California Davis Comprehensive Cancer Center, Sacramento
| | - Andrew T Vaughan
- Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Sacramento
| | - Machelle D Wilson
- Division of Biostatistics, Department of Public Health Sciences, University of California Davis School of Medicine, Sacramento
| | - Allen M Chen
- Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Sacramento
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17
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Boeckx C, Weyn C, Vanden Bempt I, Deschoolmeester V, Wouters A, Specenier P, Van Laer C, Van den Weyngaert D, Kockx M, Vermorken JB, Peeters M, Pauwels P, Lardon F, Baay M. Mutation analysis of genes in the EGFR pathway in Head and Neck cancer patients: implications for anti-EGFR treatment response. BMC Res Notes 2014; 7:337. [PMID: 24899223 PMCID: PMC4067106 DOI: 10.1186/1756-0500-7-337] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2014] [Accepted: 05/29/2014] [Indexed: 11/14/2022] Open
Abstract
Background Targeted therapy against the Epidermal Growth Factor Receptor (EGFR) is among the most promising molecular therapeutics for Head and Neck Squamous Cell Carcinoma (HNSCC). However, drug resistance limits the clinical efficacy of anti-EGFR monoclonal antibodies and no predictive biomarker has entered the clinic yet. Methods A retrospective clinical study was performed utilizing pathological specimens from 52 newly diagnosed HNSCC patients. These patients were screened for mutations in EGFR and KRAS. Tyrosine kinase mutations in EGFR and KRAS mutations were evaluated by high resolution melting analysis (HRMA), whereas EGFRvIII was determined using one-step real-time PCR. Finally, patient samples were screened for HPV-DNA by GP5+/6+ PCR. Survival analysis was performed using Kaplan-Meier analysis and significance was calculated using log-rank statistic. Results In our study population no EGFRvIII mutations were present. However, two silent mutations were found; T785T in exon 20 and R836R in exon 21 of the EGFR gene. Additionally, HRMA revealed an abnormal KRAS melting pattern in 7.0% of the samples. However, the KRAS StripAssay could confirm only one sample with a G12S mutation and none of these samples could be confirmed by direct sequencing. HPV DNA was present in 3/25 larynx and 9/27 oropharynx tumors. Conclusion The low rate of EGFR and KRAS mutations in this Belgian HNSCC population suggests that these genes will probably not play a major role in predicting response to anti-EGFR therapy in HNSCC. Hence, other predictive markers need to be discovered in order to optimize EGFR targeting therapy.
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Affiliation(s)
- Carolien Boeckx
- Center for Oncological Research (CORE) Antwerp, Laboratory of Cancer Research and Clinical Oncology, University of Antwerp, Wilrijk, Belgium.
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18
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Selzer E, Kornek G. Targeted drugs in combination with radiotherapy for the treatment of solid tumors: current state and future developments. Expert Rev Clin Pharmacol 2014; 6:663-76. [PMID: 24164614 DOI: 10.1586/17512433.2013.841540] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The continuously rising use of novel drugs, especially of molecules belonging to the group of targeted drugs is now shaping the therapeutic landscape. However, treatment combinations of targeted drugs with radiotherapy are still rare. Only the monoclonal antibody cetuximab (Erbitux®) has been approved for the treatment of locally advanced squamous cell cancer of the head and neck in combination with radiotherapy. Several targeted compounds are in advanced stages of clinical development for combination treatments with radiotherapy, of which substances with either anti-EGFR or anti-angiogenic mechanisms, such as trastuzumab, panitumumab, erlotinib, cilengitide and bevacizumab are the most promising. Aim of this article is to provide, mainly from a radio-oncological point of view, an overview about the current state as well as to give an outlook on the near future of the most advanced targeted combined treatment concepts for solid tumors.
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Affiliation(s)
- Edgar Selzer
- Department of Radiation Oncology, Medical University of Vienna, Vienna, Austria
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19
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Jiang N, Wang D, Hu Z, Shin HJC, Qian G, Rahman MA, Zhang H, Amin ARMR, Nannapaneni S, Wang X, Chen Z, Garcia G, MacBeath G, Shin DM, Khuri FR, Ma J, Chen ZG, Saba NF. Combination of anti-HER3 antibody MM-121/SAR256212 and cetuximab inhibits tumor growth in preclinical models of head and neck squamous cell carcinoma. Mol Cancer Ther 2014; 13:1826-36. [PMID: 24748655 DOI: 10.1158/1535-7163.mct-13-1093] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
The EGFR monoclonal antibody cetuximab is the only approved targeted agent for treating head and neck squamous cell carcinoma (HNSCC). Yet resistance to cetuximab has hindered its activity in this disease. Intrinsic or compensatory HER3 signaling may contribute to cetuximab resistance. To investigate the therapeutic benefit of combining MM-121/SAR256212, an anti-HER3 monoclonal antibody, with cetuximab in HNSCC, we initially screened 12 HNSCC cell lines for total and phosphorylated levels of the four HER receptors. We also investigated the combination of MM-121 with cetuximab in preclinical models of HNSCC. Our results revealed that HER3 is widely expressed and activated in HNSCC cell lines. MM-121 strongly inhibited phosphorylation of HER3 and AKT. When combined with cetuximab, MM-121 exerted a more potent antitumor activity through simultaneously inhibiting the activation of HER3 and EGFR and consequently the downstream PI3K/AKT and ERK pathways in vitro. Both high and low doses of MM-121 in combination with cetuximab significantly suppressed tumor growth in xenograft models and inhibited activations of HER3, EGFR, AKT, and ERK in vivo. Our work is the first report on this new combination in HNSCC and supports the concept that HER3 inhibition may play an important role in future therapy of HNSCC. Our results open the door for further mechanistic studies to better understand the role of HER3 in resistance to EGFR inhibitors in HNSCC.
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MESH Headings
- Animals
- Antibodies, Monoclonal/immunology
- Antibodies, Monoclonal/pharmacology
- Antibodies, Monoclonal, Humanized/pharmacology
- Antineoplastic Agents/pharmacology
- Apoptosis/drug effects
- Apoptosis/immunology
- Carcinoma, Squamous Cell/drug therapy
- Carcinoma, Squamous Cell/immunology
- Carcinoma, Squamous Cell/therapy
- Cell Growth Processes/drug effects
- Cell Growth Processes/immunology
- Cell Line, Tumor
- Cetuximab
- Combined Modality Therapy
- Disease Models, Animal
- Female
- Head and Neck Neoplasms/drug therapy
- Head and Neck Neoplasms/immunology
- Head and Neck Neoplasms/therapy
- Humans
- Immunohistochemistry
- Mice
- Mice, Nude
- Random Allocation
- Receptor, ErbB-3/antagonists & inhibitors
- Receptor, ErbB-3/immunology
- Signal Transduction
- Squamous Cell Carcinoma of Head and Neck
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Ning Jiang
- Authors' Affiliations: State Key Laboratory of Oncology in Southern China, Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China; Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine
| | - Dongsheng Wang
- Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine
| | - Zhongliang Hu
- Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine
| | | | - Guoqing Qian
- Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine
| | - Mohammad Aminur Rahman
- Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine
| | - Hongzheng Zhang
- Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine
| | - A R M Ruhul Amin
- Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine
| | - Sreenivas Nannapaneni
- Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine
| | - Xiaojing Wang
- Department of Biostatistics and Bioinformatics, Emory School of Public Health, Atlanta, Georgia
| | - Zhengjia Chen
- Department of Biostatistics and Bioinformatics, Emory School of Public Health, Atlanta, Georgia
| | | | - Gavin MacBeath
- Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts
| | - Dong M Shin
- Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine
| | - Fadlo R Khuri
- Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine
| | - Jun Ma
- Authors' Affiliations: State Key Laboratory of Oncology in Southern China, Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China
| | - Zhuo G Chen
- Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine;
| | - Nabil F Saba
- Department of Hematology and Medical Oncology, Winship Cancer Institute Emory University School of Medicine;
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20
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Mirghani H, Amen F, Blanchard P, Moreau F, Guigay J, Hartl DM, Lacau St Guily J. Treatment de-escalation in HPV-positive oropharyngeal carcinoma: ongoing trials, critical issues and perspectives. Int J Cancer 2014; 136:1494-503. [PMID: 24622970 DOI: 10.1002/ijc.28847] [Citation(s) in RCA: 174] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Accepted: 03/05/2014] [Indexed: 01/22/2023]
Abstract
Due to the generally poor prognosis of head and neck squamous cell carcinoma (HNSCC), treatment has been intensified, these last decades, leading to an increase of serious side effects. High-risk human papillomavirus (HR-HPV) infection has been recently etiologically linked to a subset of oropharyngeal squamous cell carcinoma (OPSCC), which is on the increase. These tumors are different, at the clinical and molecular level, when compared to tumors caused by traditional risk factors. Additionally, their prognosis is much more favorable which has led the medical community to consider new treatment strategies. Indeed, it is possible that less intensive treatment regimens could achieve similar efficacy with less toxicity and improved quality of life. Several clinical trials, investigating different ways to de-escalate treatment, are currently ongoing. In this article, we review these main approaches, discuss the rationale behind them and the issues raised by treatment de-escalation in HPV-positive OPSCC.
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Affiliation(s)
- H Mirghani
- Department of Head and Neck surgery, Institut de Cancérologie Gustave Roussy, Villejuif, France
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21
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Mirghani H, Amen F, Moreau F, Guigay J, Hartl DM, Lacau St Guily J. Oropharyngeal cancers: relationship between epidermal growth factor receptor alterations and human papillomavirus status. Eur J Cancer 2014; 50:1100-11. [PMID: 24424107 DOI: 10.1016/j.ejca.2013.12.018] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 12/11/2013] [Accepted: 12/13/2013] [Indexed: 01/01/2023]
Abstract
High-risk human papillomavirus (HR-HPV), particularly type 16, is now recognised as a causative agent in a subset of oropharyngeal squamous cell carcinomas (OPSCCs). These tumours are on the increase and generally have a better prognosis than their HPV negative counterparts. This raises the question of de escalation therapy to reduce long term consequences in a younger cohort of patients with a long life expectancy. Several clinical trials with anti-epidermal growth factor receptor (EGFR) therapies, particularly cetuximab, are ongoing. Few data exist on the relationship between EGFR and HPV induced oropharyngeal cancers. We summarise the main studies in relation to EGFR alterations (gene copy number, protein expression and mutations) and the impact on prognosis of HPV positive tumours that express high levels of EGFR. We also discuss the opportunity of targeting this pathway in light of recent studies.
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Affiliation(s)
- H Mirghani
- Department of Head and Neck Surgery, Institut de Cancérologie Gustave Roussy, Villejuif, France.
| | - F Amen
- Department of Head and Neck Surgery, Institut de Cancérologie Gustave Roussy, Villejuif, France.
| | - F Moreau
- Department of Virology, Faculty of Medicine University Pierre et Marie Curie Paris VI and Hospital Tenon Assistance Publique Hôpitaux de Paris, France.
| | - J Guigay
- Department of Medical Oncology, Institut de Cancérologie Gustave Roussy, Villejuif, France.
| | - D M Hartl
- Department of Head and Neck Surgery, Institut de Cancérologie Gustave Roussy, Villejuif, France.
| | - J Lacau St Guily
- Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine University Pierre et Marie Curie Paris VI and Hospital Tenon Assistance Publique Hôpitaux de Paris, France.
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22
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Stelow EB. Human papillomavirus-related head and neck squamous cell carcinoma. Cancer Cytopathol 2013; 121:599-600. [PMID: 24115573 DOI: 10.1002/cncy.21323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2013] [Revised: 05/17/2013] [Accepted: 05/20/2013] [Indexed: 11/12/2022]
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Kostareli E, Holzinger D, Bogatyrova O, Hielscher T, Wichmann G, Keck M, Lahrmann B, Grabe N, Flechtenmacher C, Schmidt CR, Seiwert T, Dyckhoff G, Dietz A, Höfler D, Pawlita M, Benner A, Bosch FX, Plinkert P, Plass C, Weichenhan D, Hess J. HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas. J Clin Invest 2013; 123:2488-501. [PMID: 23635773 DOI: 10.1172/jci67010] [Citation(s) in RCA: 100] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2012] [Accepted: 02/22/2013] [Indexed: 01/30/2023] Open
Abstract
High-risk types of human papilloma virus (HPV) are increasingly associated with oropharyngeal squamous cell carcinoma (OPSCC). Strikingly, patients with HPV-positive OPSCC are highly curable with ionizing radiation and have better survival compared with HPV-negative patients, but the underlying molecular mechanisms remain poorly understood. We applied an array-based approach to monitor global changes in CpG island hypermethylation between HPV-negative and HPV-positive OPSCCs and identified a specific pattern of differentially methylated regions that critically depends on the presence of viral transcripts. HPV-related alterations were confirmed for the majority of candidate gene promoters by mass spectrometric, quantitative methylation analysis. There was a significant inverse correlation between promoter hypermethylation of ALDH1A2, OSR2, GATA4, GRIA4, and IRX4 and transcript levels. Interestingly, Kaplan-Meier analysis revealed that a combined promoter methylation pattern of low methylation levels in ALDH1A2 and OSR2 promoters and high methylation levels in GATA4, GRIA4, and IRX4 promoters was significantly correlated with improved survival in 3 independent patient cohorts. ALDH1A2 protein levels, determined by immunohistochemistry on tissue microarrays, confirmed the association with clinical outcome. In summary, our study highlights specific alterations in global gene promoter methylation in HPV-driven OPSCCs and identifies a signature that predicts the clinical outcome in OPSCCs.
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Affiliation(s)
- Efterpi Kostareli
- Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
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BOSCOLO-RIZZO P, DEL MISTRO A, BUSSU F, LUPATO V, BABOCI L, ALMADORI G, DA MOSTO M, PALUDETTI G. New insights into human papillomavirus-associated head and neck squamous cell carcinoma. ACTA OTORHINOLARYNGOLOGICA ITALICA : ORGANO UFFICIALE DELLA SOCIETA ITALIANA DI OTORINOLARINGOLOGIA E CHIRURGIA CERVICO-FACCIALE 2013; 33:77-87. [PMID: 23853396 PMCID: PMC3665382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/01/2012] [Accepted: 01/07/2013] [Indexed: 11/05/2022]
Abstract
Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is an entity with peculiar clinical and molecular characteristics, which mainly arises from the reticulated epithelium lining the crypts of the palatine tonsils and the base of the tongue. The only head and neck site with a definite etiological association between persistent high-risk (HR) HPV infection and development of SCC is the oropharynx. HPV-positive malignancies represent 5-20% of all HNSCCs and 40-90% of those arising from the oropharynx, with widely variable rates depending on the geographic area, population, relative prevalence of environment-related SCC and detection assay. HPV-16 is by far the most common HR HPV genotype detected in oropharyngeal SCC (OPSCC), and the only definitely carcinogenic genotype for the head and neck region. Patients with HPV-induced OPSCC are more likely to be middle-aged white men, non-smokers, non-drinkers or mild to moderate drinkers, with higher socioeconomic status and better performance status than subjects with HPV-unrelated SCC. HPV-induced HNSCCs are often described as non-keratinizing, poorly differentiated or basaloid carcinomas, and are diagnosed in earlier T-category with a trend for a more advanced N-category, with cystic degeneration, than the HPV-unrelated carcinomas. HPV positivity is associated with better response to treatment and modality-independent survival benefit. Treatment selection in HPV-related oropharyngeal carcinoma is becoming a critical issue, and although there is no evidence from randomized, controlled trials to support a treatment de-escalation in HPV-positive SCC, some investigators argue that intensive combined modality strategies may represent an overtreatment.
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Affiliation(s)
- P. BOSCOLO-RIZZO
- Department of Neurosciences, ENT Clinic and Regional Center for Head and Neck Cancer, University of Padua, Treviso Regional Hospital, Treviso, Italy
| | - A. DEL MISTRO
- Immunology and Diagnostic Molecular Oncology Unit, Istituto Oncologico Veneto IRCCS, Padua, Italy
| | - F. BUSSU
- Department of Head and Neck Surgery - Otorhinolaryngology, Catholic University of the Sacred Heart, Rome, Italy
| | - V. LUPATO
- Department of Neurosciences, ENT Clinic and Regional Center for Head and Neck Cancer, University of Padua, Treviso Regional Hospital, Treviso, Italy
| | - L. BABOCI
- Immunology and Diagnostic Molecular Oncology Unit, Istituto Oncologico Veneto IRCCS, Padua, Italy
| | - G. ALMADORI
- Department of Head and Neck Surgery - Otorhinolaryngology, Catholic University of the Sacred Heart, Rome, Italy
| | - M.C. DA MOSTO
- Department of Neurosciences, ENT Clinic and Regional Center for Head and Neck Cancer, University of Padua, Treviso Regional Hospital, Treviso, Italy
| | - G. PALUDETTI
- Department of Head and Neck Surgery - Otorhinolaryngology, Catholic University of the Sacred Heart, Rome, Italy
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Spiotto MT, Pytynia M, Liu GFF, Ranck MC, Widau R. Animal models to study the mutational landscape for oral cavity and oropharyngeal cancers. EJOURNAL OF ORAL MAXILLOFACIAL RESEARCH 2013; 4:e1. [PMID: 24422024 PMCID: PMC3886108 DOI: 10.5037/jomr.2013.4101] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Accepted: 01/23/2013] [Indexed: 12/19/2022]
Abstract
OBJECTIVES Cancer is likely caused by alterations in gene structure or expression. Recently, next generation sequencing has documented mutations in 106 head and neck squamous cell cancer genomes, suggesting several new candidate genes. However, it remains difficult to determine which mutations directly contributed to cancer. Here, summarize the animal models which have already validated and may test cancer causing mutations identified by next generation sequencing approaches. MATERIAL AND METHODS We reviewed the existing literature on genetically engineered mouse models and next generation sequencing (NGS), as it relates to animal models of squamous cell cancers of the head and neck (HNSCC) in PubMed. RESULTS NSG has identified an average of 19 to 130 distinct mutations per HNSCC specimen. While many mutations likely had biological significance, it remains unclear which mutations were essential to, or "drive," carcinogenesis. In contrast, "passenger" mutations also exist that provide no selection advantage. The genes identified by NGS included p53, RAS, Human Papillomavirus oncogenes, as well as novel genes such as NOTCH1, DICER and SYNE1,2. Animal models of HNSCC have already validated some of these common gene mutations identified by NGS. CONCLUSIONS The advent of next generation sequencing will provide new leads to the genetic changes occurring in squamous cell cancers of the head and neck. Animal models will enable us to validate these new leads in order to better elucidate the biology of squamous cell cancers of the head and neck.
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Affiliation(s)
- Michael T Spiotto
- Department of Radiation and Cellular Oncology, The University of Chicago Chicago, Illinois USA
| | - Matthew Pytynia
- Department of Radiation and Cellular Oncology, The University of Chicago Chicago, Illinois USA
| | - Gene-Fu F Liu
- Department of Radiation and Cellular Oncology, The University of Chicago Chicago, Illinois USA
| | - Mark C Ranck
- Department of Radiation and Cellular Oncology, The University of Chicago Chicago, Illinois USA
| | - Ryan Widau
- Department of Radiation and Cellular Oncology, The University of Chicago Chicago, Illinois USA
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Recommendations for the diagnosis of human papilloma virus (HPV) high and low risk in the prevention and treatment of diseases of the oral cavity, pharynx and larynx. Guide of experts PTORL and KIDL. Otolaryngol Pol 2013; 67:113-34. [PMID: 23719268 DOI: 10.1016/j.otpol.2013.01.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Accepted: 01/09/2013] [Indexed: 11/20/2022]
Abstract
The role of human papilloma viruses (HPV) in malignant and nonmalignant ENT diseases and the corresponding epidemiological burden has been widely described. International head and neck oncology community discussed growing evidence that oral HPV infection contributes to the risk of oro-pharyngeal carcinoma (OPC) and recommended HPV testing as a part of the work up for patients with OPC. Polish Society of ENT Head Neck Surgery and National Chamber of Laboratory Diagnosticians have worked together to define the minimum requirements for assigning a diagnosis of HPV-related conditions and testing strategy that include HPV specific tests in our country. This paper briefly frames the literature information concerning low risk (LR) and high risk (HR) HPV, reviews the epidemiology, general guidance on the most appropriate biomarkers for clinical assessment of HPV. The definition of HPV-related cancer was presented. The article is aiming to highlight some of major issues for the clinician dealing with patients with HPV-related morbidities and to introduce the diagnostic algorithm in Poland.
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Atienza JAS, Dasanu CA. Incidence of second primary malignancies in patients with treated head and neck cancer: a comprehensive review of literature. Curr Med Res Opin 2012; 28:1899-909. [PMID: 23121148 DOI: 10.1185/03007995.2012.746218] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND Increased incidence of a second primary aero-digestive malignancy after an index head and neck cancer (HNC) is well-documented. Furthermore, a clear set of surveillance strategies for second primary aero-digestive cancers in these patients exists. METHODS The goal of this article is to review the published literature on risk of second primary malignancies (SPMs) (including aero-digestive malignancies) after a treated index HNC as well as its associated predictors, prognosis and surveillance. Most relevant publications were identified through searching the PubMed database for articles published up to July 2012; epidemiologic evidence was synthesized and thoroughly analyzed. FINDINGS Data from randomized controlled trials, meta-analyses, population-based and cohort group studies, prior reviews, and case reports indicate an increased incidence of various SPMs after occurrence of a HNC. These cancers are not limited to upper aero-digestive sites. Common risk factors including environmental, genetic and immune factors may explain the increased incidence of second cancers in this patient population. In addition, site of the index HNC may predict the site of a future SPM. CONCLUSIONS As a general rule, oral cavity and oropharyngeal squamous cell cancers are associated more with head and neck region SPM, while laryngeal and hypopharyngeal cancers - with that of the lung. As these cancers confer dismal prognosis and shorter survival in patients with HNCs, several literature sources recommend close surveillance for and an aggressive therapy of SPM. Notwithstanding, their optimal management and follow-up schedule remains to be established.
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Affiliation(s)
- Jonessa Ann S Atienza
- University of Connecticut, Department of Internal Medicine, Farmington, CT 06030, USA.
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