Treatment de-escalation in HPV-positive oropharyngeal carcinoma: Ongoing trials, critical issues and perspectives
TL;DR: These main approaches to de‐escalate treatment in HPV‐positive OPSCC are reviewed, the rationale behind them are discussed, and the issues raised by treatment de-escalation are discussed.
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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Vanderbilt University Medical Center1, Stanford University2, Johns Hopkins University3, Washington University in St. Louis4, College of American Pathologists5, American Society of Clinical Oncology6, Walter Reed National Military Medical Center7, Ohio State University8, Houston Methodist Hospital9, University of Pittsburgh10, Harvard University11
TL;DR: High-risk HPV testing is recommended for all new oropharyngeal squamous cell carcinoma patients, but not routinely recommended for other head and neck carcinomas.
Abstract: Context Human papillomavirus (HPV) is a major cause of oropharyngeal squamous cell carcinomas, and HPV (and/or surrogate marker p16) status has emerged as a prognostic marker that significantly impacts clinical management. There is no current consensus on when to test oropharyngeal squamous cell carcinomas for HPV/p16 or on which tests to choose. Objective To develop evidence-based recommendations for the testing, application, interpretation, and reporting of HPV and surrogate marker tests in head and neck carcinomas. Design The College of American Pathologists convened a panel of experts in head and neck and molecular pathology, as well as surgical, medical, and radiation oncology, to develop recommendations. A systematic review of the literature was conducted to address 6 key questions. Final recommendations were derived from strength of evidence, open comment period feedback, and expert panel consensus. Results The major recommendations include (1) testing newly diagnosed oropharyngeal squamous cell ca...
351 citations
Cites background from "Treatment de-escalation in HPV-posi..."
...Determining that an OPSCC is positive for HR-HPV (by strictly defined testing in the correct clinical and pathologic contexts) has significant implications for patient prognosis, and it is now integrated into the recently updated American Joint Committee on Cancer (AJCC) staging manual(14); furthermore, HPV status determines patient eligibility for clinical trials investigating new treatment regimens and modalities.(15,16) In addition, determining that a metastatic SCC of unknown primary to a cervical lymph node is HPV positive strongly points to the oropharynx as the site of origin, with consequences for subsequent clinical management and treatment decisions....
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Journal Article•
TL;DR: The results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms and suggest the development of targeted therapies for head and neck cancer may be hindered by complex mutational profiles.
Abstract: Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), our analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (for example, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.
264 citations
TL;DR: In this article, the authors conducted a systematic review and meta-analysis to determine the diagnostic accuracy of p16INK4a immunohistochemistry (IHC) to identify human papillomavirus (HPV) causality in oropharyngeal squamous cell carcinomas (OPSCC).
Abstract: The accurate diagnosis of human papillomavirus (HPV) causality in oropharyngeal squamous cell carcinomas (OPSCC) is likely to influence therapeutic decisions in affected patients in the near future. We conducted a systematic review and meta-analysis to determine the diagnostic accuracy of p16INK4a immunohistochemistry (IHC) to identify HPV-induced OPSCC. We identified all studies that performed p16INK4a IHC (index test) and HPV E6/E7 mRNA detection using an amplification-based method (gold standard to indicate a transforming relevance of HPV) in OPSCC. Testing with one or more comparator tests (HPV DNA PCR, HPV DNA in situ hybridization (ISH) and p16INK4a IHC/HPV DNA PCR combined testing) was an optional criterion for inclusion. Among 1,636 retrieved studies 24 fulfilled the inclusion criteria. The pooled sensitivity of p16INK4a IHC, HPV DNA PCR, HPV DNA ISH and p16INK4a IHC/HPV DNA PCR combined testing was 94% (95%-confidence interval (CI) 91-97%), 98% (CI 94-100%), 85% (CI 76-92%) and 93% (CI 87-97%), respectively. The pooled specificity was 83% (CI 78-88%), 84% (CI 74-92%), 88% (CI 78-96%) and 96% (CI 89-100%), respectively. p16INK4a IHC/HPV DNA PCR combined testing was as sensitive as either p16INK4a IHC or HPV DNA PCR alone but significantly more specific than either separate test. In conclusion, p16INK4a IHC is highly sensitive but moderately specific to diagnose HPV-transformed OPSCC when used as a single test. Combined p16INK4a IHC and HPV DNA PCR testing significantly enhances specificity while maintaining high sensitivity. This diagnostic test combination thus represents an attractive testing strategy for the reliable diagnosis of HPV-induced OPSCC in the clinical setting and may constitute an inclusion criterion for future therapeutic trials.
176 citations
Cites background from "Treatment de-escalation in HPV-posi..."
...with HPV-associated OPSCC is currently discussed and has given rise to the implementation of new clinical trials.(11) Furthermore, HPV-specific therapeutics may become available in the near future....
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...Consequently, therapy de-escalation for HPV-associated oropharyngeal cancer patients has moved into the clinical focus and has recently been implemented in phase I-III clinical trials.(11) Furthermore, HPV-specific cancer treatment such as therapeutic vaccines may become available in the near future....
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...…staining Quabius et al. (2014) Strong nuclear as well as cytoplasmic staining in >25% of the cells Masterson et al. (2015) >70% tumor cell staining Mirghani et al. (2015) Strong and diffuse nuclear and cytoplasmic staining in >70% of the tumor Vojtechova et al. (2016) More than 50% of…...
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TL;DR: These genetically-defined experimental HNSCC cellular systems, together with the identification of novel actionable molecular targets, may now facilitate the pre-clinical evaluation of emerging therapeutic agents in tumors exhibiting each precise genomic alteration.
Abstract: // Daniel Martin 1 , Martin C. Abba 2 , Alfredo A. Molinolo 1 , Lynn Vitale-Cross 1 , Zhiyong Wang 1 , Moraima Zaida 1 , Naomi C. Delic 4, 5 , Yardena Samuels 3 , J. Guy Lyons 4, 5 , J. Silvio Gutkind 1 1 Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, USA 2 CINIBA, Facultad de Ciencias Medicas, Universidad Nacional de La Plata, La Plata, Argentina 3 Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel 4 Dermatology, University of Sydney, Camperdown, Australia 5 Cancer Services, Royal Prince Alfred Hospital, Camperdown, Australia Correspondence to: Silvio Gutkind, e-mail: sg39v@nih.gov Keywords: HNSCC, Sequencing, Exome, RNAseq, Cancer Received: July 11, 2014 Accepted: August 28, 2014 Published: November 04, 2014 ABSTRACT The recent elucidation of the genomic landscape of head and neck squamous cell carcinoma (HNSCC) has provided a unique opportunity to develop selective cancer treatment options. These efforts will require the establishment of relevant HNSCC models for preclinical testing. Here, we performed full exome and transcriptome sequencing of a large panel of HNSCC-derived cells from different anatomical locations and human papillomavirus (HPV) infection status. These cells exhibit typical mutations in TP53 , FAT1 , CDK2NA , CASP8 , and NOTCH1 , and copy number variations (CNVs) and mutations in PIK3CA , HRAS , and PTEN that reflect the widespread activation of the PI3K-mTOR pathway. SMAD4 alterations were observed that may explain the decreased tumor suppressive effect of TGF-β in HNSCC. Surprisingly, we identified HPV + HNSCC cells harboring TP53 mutations, and documented aberrant TP53 expression in a subset of HPV + HNSCC cases. This analysis also revealed that most HNSCC cells harbor multiple mutations and CNVs in epigenetic modifiers (e.g., EP300, CREBP, MLL1, MLL2, MLL3, KDM6A, and KDM6B) that may contribute to HNSCC initiation and progression. These genetically-defined experimental HNSCC cellular systems, together with the identification of novel actionable molecular targets, may now facilitate the pre-clinical evaluation of emerging therapeutic agents in tumors exhibiting each precise genomic alteration.
167 citations
Cites background from "Treatment de-escalation in HPV-posi..."
...These findings may have direct clinical implications, as HPV+ HNSCCs respond better to chemoradiation, leading to a current trend towards dose de-escalation in HPV+ HNSCC cases [50]....
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TL;DR: This Commentary seeks to summarize the state of the art of the understanding of HPV-associated head and neck cancers that has emerged since the publication of seminal findings by Fakhry et al.
Abstract: Over the last two decades, it has been recognized that head and neck cancers, primarily in the oropharynx, can be a distinct entity that is causally related to human papilloma virus (HPV). Fakhry et al. established in 2008 that such tumors have a strikingly better prognosis with improved responsiveness to chemotherapy as well as chemoradiotherapy and favorable survival rates. Since then, new studies have contributed to our increased understanding of this new entity, ranging from a detailed understanding of the genetic fingerprint and risk modifiers such as smoking to successful early attempts to personalize therapy with de-escalation in the definitive intent treatment setting and specific evaluation of targeted therapies in this patient population. This Commentary seeks to summarize the state of the art of our understanding of HPV-associated head and neck cancers that has emerged since the publication of seminal findings by Fakhry et al.
151 citations
References
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TL;DR: Small-molecule therapeutics that block PI3K signalling might deal a severe blow to cancer cells by blocking many aspects of the tumour-cell phenotype.
Abstract: One signal that is overactivated in a wide range of tumour types is the production of a phospholipid, phosphatidylinositol (3,4,5) trisphosphate, by phosphatidylinositol 3-kinase (PI3K) This lipid and the protein kinase that is activated by it — AKT — trigger a cascade of responses, from cell growth and proliferation to survival and motility, that drive tumour progression Small-molecule therapeutics that block PI3K signalling might deal a severe blow to cancer cells by blocking many aspects of the tumour-cell phenotype
5,654 citations
University of Texas MD Anderson Cancer Center1, University of Utah2, Université de Montréal3, Johns Hopkins University4, Vanderbilt University5, University of California, San Francisco6, Wayne State University7, Thomas Jefferson University8, University of Louisville9, University of Cincinnati10, Ohio State University11
TL;DR: Tumor HPV status is a strong and independent prognostic factor for survival among patients with oropharyngeal cancer and the risk of death significantly increased with each additional pack-year of tobacco smoking.
Abstract: Background Oropharyngeal squamous-cell carcinomas caused by human papillomavirus (HPV) are associated with favorable survival, but the independent prognostic significance of tumor HPV status remains unknown. Methods We performed a retrospective analysis of the association between tumor HPV status and survival among patients with stage III or IV oropharyngeal squamous-cell carcinoma who were enrolled in a randomized trial comparing accelerated-fractionation radiotherapy (with acceleration by means of concomitant boost radiotherapy) with standard-fractionation radiotherapy, each combined with cisplatin therapy, in patients with squamous-cell carcinoma of the head and neck. Proportional-hazards models were used to compare the risk of death among patients with HPV-positive cancer and those with HPV-negative cancer. Results The median follow-up period was 4.8 years. The 3-year rate of overall survival was similar in the group receiving accelerated-fractionation radiotherapy and the group receiving standard-fractionation radiotherapy (70.3% vs. 64.3%; P = 0.18; hazard ratio for death with accelerated-fractionation radiotherapy, 0.90; 95% confidence interval [CI], 0.72 to 1.13), as were the rates of high-grade acute and late toxic events. A total of 63.8% of patients with oropharyngeal cancer (206 of 323) had HPV-positive tumors; these patients had better 3-year rates of overall survival (82.4%, vs. 57.1% among patients with HPV-negative tumors; P<0.001 by the log-rank test) and, after adjustment for age, race, tumor and nodal stage, tobacco exposure, and treatment assignment, had a 58% reduction in the risk of death (hazard ratio, 0.42; 95% CI, 0.27 to 0.66). The risk of death significantly increased with each additional packyear of tobacco smoking. Using recursive-partitioning analysis, we classified our patients as having a low, intermediate, or high risk of death on the basis of four factors: HPV status, pack-years of tobacco smoking, tumor stage, and nodal stage. Conclusions Tumor HPV status is a strong and independent prognostic factor for survival among patients with oropharyngeal cancer. (ClinicalTrials.gov number, NCT00047008.)
5,263 citations
"Treatment de-escalation in HPV-posi..." refers methods or result in this paper
...The data produced by Ang et al.(7) have shown that HPVpositive patients with a high nodal category (N2b-N3) and more than 10 pack years smoking history have an increased risk of disease progression and death (3-year overall survival rate of 70....
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...Numerous retrospective and prospective studies have demonstrated that patients with HPV-positive OPSCC have markedly improved survival outcomes compared to those with HPV-negative HNSCC.(7,8) These favorable outcomes are independent of treatment choice, as long as this conforms to current standard of care....
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...However, cancer related death will affect up to 20% of HPV-positive OPSCC which is not insignificant when compared to other good prognosis malignancies.(7,8) Additionally, several authors have reported that distant metastases are as frequent among HPV-positive and negative OPSCC and that it seems to be the leading cause of death in HPV-positive patients....
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...Finally, there is no strong biological evidence supporting the role of anti EGFR therapy in HPV-induced tumors, as EGFR alterations (protein over expression, increased gene copy number or activating mutations) are rare in HPVpositive OPSCC.19 Moreover, the Cancer Genome Atlas Group have recently investigated the cumulative effect of various mechanisms of biological alteration in HNSCC.20 The results suggested that EGFR is a relevant oncogenic target in only HPV-negative disease....
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...1).2,3 These tumors mainly affect the oropharynx (particularly tonsil and base of tongue) and their incidence is increasing.4 Considering current trends, and decreasing tobacco and alcohol consumption, it is estimated that HR-HPV will become the dominant etiologic factor for oropharyngeal squamous cell carcinoma (OPSCC) in the coming decades in most Western countries.5,6 Numerous retrospective and prospective studies have demonstrated that patients with HPV-positive OPSCC have markedly improved survival outcomes compared to those with HPV-negative HNSCC.7,8 These favorable outcomes are independent of treatment choice, as long as this conforms to current standard of care.9 Given that these patients are generally young and have a high likelihood of surviving their disease, post-treatment quality of life becomes of paramount importance....
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University of Alabama at Birmingham1, University of Wisconsin-Madison2, Autonomous University of Barcelona3, Eli Lilly and Company4, University of Texas MD Anderson Cancer Center5, University of Virginia6, University of the Witwatersrand7, University of Colorado Boulder8, Gdańsk Medical University9, University of Alabama10, Merck KGaA11, ImClone Systems12
TL;DR: Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoreGional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head andneck.
Abstract: BACKGROUND We conducted a multinational, randomized study to compare radiotherapy alone with radiotherapy plus cetuximab, a monoclonal antibody against the epidermal growth factor receptor, in the treatment of locoregionally advanced squamous-cell carcinoma of the head and neck. METHODS Patients with locoregionally advanced head and neck cancer were randomly assigned to treatment with high-dose radiotherapy alone (213 patients) or high-dose radiotherapy plus weekly cetuximab (211 patients) at an initial dose of 400 mg per square meter of body-surface area, followed by 250 mg per square meter weekly for the duration of radiotherapy. The primary end point was the duration of control of locoregional disease; secondary end points were overall survival, progression-free survival, the response rate, and safety. RESULTS The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone (hazard ratio for locoregional progression or death, 0.68; P = 0.005). With a median follow-up of 54.0 months, the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone (hazard ratio for death, 0.74; P = 0.03). Radiotherapy plus cetuximab significantly prolonged progression-free survival (hazard ratio for disease progression or death, 0.70; P = 0.006). With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or greater toxic effects, including mucositis, did not differ significantly between the two groups. CONCLUSIONS Treatment of locoregionally advanced head and neck cancer with concomitant highdose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck. (ClinicalTrials.gov number, NCT00004227.)
4,705 citations
"Treatment de-escalation in HPV-posi..." refers methods in this paper
...treatment of patients with locally advanced HNSCC on the basis of a phase III trial published in 2006.(12) In this study,(12) Bonner et al....
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TL;DR: In this article, the prevalence of human papillomavirus (HPV) infection in oropharyngeal cancer was determined for all 271 oropharygeal cancers (1984-2004) collected by the three population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Residual Tissue Repositories Program.
Abstract: Purpose Recent increases in incidence and survival of oropharyngeal cancers in the United States have been attributed to human papillomavirus (HPV) infection, but empirical evidence is lacking. Patients and Methods HPV status was determined for all 271 oropharyngeal cancers (1984-2004) collected by the three population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Residual Tissue Repositories Program by using polymerase chain reaction and genotyping (Inno-LiPA), HPV16 viral load, and HPV16 mRNA expression. Trends in HPV prevalence across four calendar periods were estimated by using logistic regression. Observed HPV prevalence was reweighted to all oropharyngeal cancers within the cancer registries to account for nonrandom selection and to calculate incidence trends. Survival of HPV-positive and HPV-negative patients was compared by using Kaplan-Meier and multivariable Cox regression analyses. Results HPV prevalence in oropharyngeal cancers significantly increased over ...
2,950 citations
TL;DR: It is suggested that HPV-positive oropharyngeal cancers comprise a distinct molecular, clinical, and pathologic disease entity that is likely causally associated with HPV infection and that has a markedly improved prognosis.
Abstract: Background: High-risk human papillomaviruses (HPVs) are etiologic agents for anogenital tract cancers and have been detected in head and neck squamous cell carcinomas (HNSCCs). We investigated, retrospectively, an etiologic role for HPVs in a large series of patients with HNSCC. Methods: Tumor tissues from 253 patients with newly diagnosed or recurrent HNSCC were tested for the presence of HPV genome by use of polymerase chain reaction (PCR)-based assays, Southern blot hybridization, and in situ hybridization. The viral E6 coding region was sequenced to confirm the presence of tumor-specific viral isolates. Exons 5‐9 of the TP53 gene were sequenced from 166 specimens. The hazard of death from HNSCC in patients with and without HPVpositive tumors was determined by proportional hazards regression analysis. Results: HPV was detected in 62 (25%) of 253 cases (95% confidence interval [CI] = 19%‐30%). Highrisk, tumorigenic type HPV16 was identified in 90% of the HPV-positive tumors. HPV16 was localized specifically by in situ hybridization within the nuclei of cancer cells in preinvasive, invasive, and lymph node disease. Southern blot hybridization patterns were consistent with viral integration. Poor tumor grade (odds ratio [OR] = 2.4; 95% CI = 1.2‐ 4.9) and oropharyngeal site (OR = 6.2; 95% CI = 3.1‐12.1) independently increased the probability of HPV presence. As compared with HPV-negative oropharyngeal cancers, HPVpositive oropharyngeal cancers were less likely to occur among moderate to heavy drinkers (OR = 0.17; 95% CI = 0.05‐0.61) and smokers (OR = 0.16; 95% CI = 0.02‐1.4), had a characteristic basaloid morphology (OR = 18.7; 95% CI = 2.1‐167), were less likely to have TP53 mutations (OR = 0.06; 95% CI = 0.01‐0.36), and had improved disease-specific survival (hazard ratio [HR] = 0.26; 95% CI = 0.07‐0.98). After adjustment for the presence of lymph node disease (HR = 2.3; 95% CI = 1.4‐ 3.8), heavy alcohol consumption (HR = 2.6; 95% CI = 1.4‐4.7), and age greater than 60 years old (HR = 1.4; 95% CI = 0.8‐2.3), all patients with HPV-positive tumors had a 59% reduction in risk of death from cancer when compared with HPV-negative HNSCC patients (HR = 0.41; 95% CI = 0.20‐0.88). Conclusions: These data extend recent molecular and epidemiologic studies and strongly suggest that HPV-positive oropharyngeal cancers comprise a distinct molecular, clinical, and pathologic disease entity that is likely causally associated with HPV infection and that has a markedly improved prognosis. [J Natl Cancer Inst 2000; 92:709‐20]
2,887 citations
"Treatment de-escalation in HPV-posi..." refers background in this paper
...These tumors mainly affect the oropharynx (particularly tonsil and base of tongue) and their incidence is increasing.(4) Considering current trends, and decreasing tobacco and alcohol consumption, it is estimated that HR-HPV will become the dominant etiologic factor for oropharyngeal squamous cell carcinoma (OPSCC) in the coming decades in most Western countries....
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