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The Changing Aetiology of Head and Neck Cancer: the Role of Human Papillomavirus
Clinical Oncology 22 (2010) 538e546 Contents lists available at ScienceDirect
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Overview
The Changing Aetiology of Head and Neck Cancer: the Role of Human Papillomavirus M. Evans *, N.G. Powell y * Velindre y
Cancer Centre, Cardiff, UK HPV Research Group, Obstetrics and Gynaecology, School of Medicine, Cardiff University, Cardiff, UK
Received 25 March 2010; received in revised form 22 April 2010; accepted 26 April 2010
Abstract Human papillomavirus (HPV) is associated with the development of a subset of head and neck cancers arising in the oropharynx, which includes the tonsils, base of tongue and soft palate. HPV-associated oropharyngeal cancer (OPC) seems to be rapidly increasing in incidence in many countries, including the USA, Sweden and Greece, and is known to affect younger patients who are less likely to have been exposed to the carcinogenic effects of tobacco and alcohol than their HPV-negative counterparts. There is accumulating evidence from prospective studies that HPV-positive OPC responds better to treatment, including chemotherapy and radiotherapy, than HPV-negative OPC, and that patients with HPV-positive disease have excellent long-term survival rates. To date, patients with HPV-positive and HPV-negative OPC are managed according to common treatment protocols; this may no longer be appropriate in an age when the delivery of targeted treatment, tailored to individual tumour and patient characteristics, is becoming a reality. This review summarises our current understanding of HPV-positive OPC, drawing parallels from the role of HPV in the development of cervical cancer. We also consider how knowledge of tumour HPV status may affect the future management and prevention of OPC and discuss the need for future collaborative trials in this important group of patients. Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Head and neck; human papillomavirus; oropharyngeal
Statement of Search Strategies Used and Sources of Information This overview is based on published peer-reviewed reports identified via PubMed using search terms including HPV, oropharyngeal cancer, OPSCC and HNSCC. Other relevant sources are also referred to.
Introduction Head and neck cancers, most of which are squamous cell carcinomas (HNSCC), are traditionally associated with smoking tobacco and drinking alcohol. However, a subset of HNSCC originating in the oropharynx (OPC), including cancers of the tonsil (Figs. 1 and 2), base of the tongue, soft palate and pharyngeal wall, are increasingly associated with human papillomavirus (HPV) infection. HPV is already well Author for correspondence: M. Evans, Velindre Cancer Centre, Whitchurch, Cardiff CF14 2TL, UK. Tel: þ44-2920196160; Fax: þ44-2920316267. E-mail address: [email protected] (M. Evans).
known as the agent responsible for the development of virtually all (99.7%) cervical cancers [1] as well as rarer anogenital cancers, including cancers of the vulva, vagina, anus and penis [2,3].
Incidence of Human Papillomavirusassociated Oropharyngeal Cancer The incidence of most HNSCC, including cancers of the larynx, is stable or decreasing in the UK, whereas the incidence of OPC, and tonsillar cancer in particular, is increasing. In England there were 281 tonsillar cancers diagnosed in 1997; this had increased to 703 diagnoses in 2007 [4]. Similar trends have been reported for the USA, Sweden and Greece, and this increase in incidence seems to be associated with HPV infection [5e8]. For example, in Sweden the incidence of tonsillar cancer almost doubled between 1970 and 2006 and the proportion of HPV-positive cases increased from 23% (1970e1979) to 79% (2000e2007) in the same time period. In 2006e2007, 93% of tonsillar cancers in Sweden were HPV-positive, ‘suggesting an
0936-6555/$36.00 Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.clon.2010.05.024
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rates reported by different studies. The contribution of HPV to the development of OPC in the UK is unclear [11]. A large HPV prevalence study is currently underway in South Wales and a UK-wide study is planned to study regional variations in the incidence of HPV-associated OPC. Most cases (90e95%) of HPV-positive OPC are associated with HPV subtype 16 infection [9]. In contrast, although virtually all cases of cervical cancer are HPV-positive, HPV16 infection accounts for a lower proportion (52e58%) of the overall caseload and other subtypes, including HPV18, -31, -33, -45 and -53, are also important aetiological agents [12,13].
Pathogenesis
Fig. 1. Squamous cell carcinoma of the right tonsil (picture courtesy of Mr Richard Shaw).
epidemic of a virus-induced carcinoma, with soon practically all tonsillar SCC being HPV-positive, as in cervical cancer’ [7]. The prevalence of HPV infection in OPC does, however, vary widely between studies from 18% in a multinational study by the International Agency for Research on Cancer [9] to 82% in a study from the USA [10]. This may in part be due to true geographical variations, but different HPV detection methods may also have influenced the prevalence
HPV is dependent on the host cell replication machinery to copy its own DNA, but the necessary proteins are only produced in actively dividing cells. To induce the production of these proteins, HPV encodes factors that deregulate cell cycle control and cause inappropriate cell division. The HPV proteins chiefly responsible for these effects are the transforming oncoproteins E6 and E7, whose main functions are the inactivation of the cellular p53 and Rb tumour suppressor proteins. Expression of the E6 protein results in proteosomal degradation of p53 leading to loss of cell cycle arrest and apoptosis in response to DNA damage [14]. The E6 protein also mediates activation of telomerase and thereby avoids cellular senescence in response to telomere erosion in proliferating cells [15,16]. The E7 protein causes degradation of Rb, resulting in unrestricted progression through the G1/S cell cycle checkpoint (reviewed in [17]). Expression of the E6 and E7 genes is usually very tightly regulated and correlates with the differentiation state of the host cell. However, loss of this regulation results in neoplasia and prevents completion of the viral lifecycle [18]. The molecular pathways affected by the expression of E6 and E7 are reviewed in [19]. Deregulation of the pattern of gene expression is commonly a consequence of integration of the HPV DNA into the host cell genome [20] and the resulting population of proliferating cells is prone to accumulation of genetic damage, which can ultimately lead to malignant transformation.
Parallels with Cervical Carcinogenesis
Fig. 2. Axial computed tomography scan through the oropharynx showing a carcinoma of the left tonsil (outlined).
Since the isolation of HPV16 from a cervical carcinoma in 1983, considerable effort has been devoted to determining the biology of HPV infection in the cervix. This investment has led to improved screening and prevention of cervical cancer, most recently by prophylactic vaccination. A model of the cellular events and other factors involved in cervical carcinogenesis is shown in Fig. 3. HPV-associated carcinogenesis in the oropharynx probably shares many features with cervical carcinogenesis; however, there are a number of aspects in which carcinogenesis at the two sites differs, including involvement of the cervical transformation zone, the fraction of disease attributable to a viral cause, and the degree of predominance of HPV16.
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Fig. 3. The cellular events associated with progression in cervical carcinogenesis and the genetic, environmental and behavioural factors that may influence progression.
The transformation zone is the region in which the simple columnar epithelia of the endocervix meets the squamous epithelium of the ectocervix, and is the site from which nearly all cervical squamous cell carcinoma arise. Several hypotheses have been advanced to explain the specific vulnerability of the transformation zone: the thinner epithelium present at the transformation zone may allow easier access to the basal epithelium, which is the initial target of HPV infection, and thin epithelia may be more vulnerable to the small wounds and abrasions that facilitate HPV infection; alternatively, it has been suggested that virus-induced cancers often arise at sites where productive viral infection (resulting in the release of infectious virus) cannot be properly supported [21]. It is possible that because cells in the transformation zone do not conform to the normal pattern of epithelial differentiation, they cannot support the full HPV lifecycle, and will allow expression of the viral early genes, including oncogenic E6 and E7, but not of the late genes. It is clear that there is no direct equivalent of the transformation zone in the oropharynx. There is, however, evidence that HPV is found predominantly in the reticulated epithelial crypts in the tonsils [10], which are composed of specialised epithelia with immune and secretory functions, not stratified epithelia [22]. Hence, a mix of epithelial types is present and it is unlikely that HPV is able to complete its lifecycle in such an environment. Therefore, as this appears to be the site from which cancers arise, allowing infection but not completion of the viral lifecycle, it may constitute an equivalent area to the transformation zone in the oropharynx. Whereas virtually all cervical cancers are attributed to HPV infection [1], the proportion of OPC caused by HPV infection seems to be smaller [6,23]. It is reasonable to hypothesise that this simply reflects the greater degree of chemical insult (by tobacco and alcohol) inflicted on the
oral epithelium relative to the cervix. This may also partly explain the predominance of HPV16 in OPC. HPV16 is the most virulent and aggressive of the HPVs, as evidenced by its high population prevalence [24] and the earlier onset of HPV16-associated cervical cancers [25]. It is possible that with greater exposure to potentially carcinogenic DNA damage, the epithelium of the oral cavity has evolved so that its microenvironment presents a challenge, particularly in terms of immunological exposure, which only the most virulent and aggressive HPVs can overcome.
Natural History of Human Papillomavirus Infection in the Oral Cavity The natural history of HPV infection in the oral cavity is currently poorly defined [26]. Oral HPV infection is believed to be sexually acquired, as prevalence is significantly associated with sexual behaviour [5,27]. However, questions relating to the duration of infection, degree of oral transmission, and whether productive viral infections are established in the oropharynx, remain largely unanswered.
Risk Factors for Human Papillomaviruspositive Oropharyngeal Cancer Case-control studies have shown an association between HPV-positive OPC and certain sexual behaviours, including a high lifetime number of oral sex or vaginal sex partners, early age at first intercourse and infrequent use of condoms [5]. These risk factors mirror those for cervical cancer and result in increased transmission of HPV between sexual partners. Women with a past history of HPV-associated carcinoma in situ or cervical cancer and partners of women with carcinoma in situ/cervical cancer are also at increased
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risk of HPV-positive OPC [28]. Furthermore, HPV-positive OPC is associated with the presence of oral HPV infection (odds ratio 14.6; 95% confidence interval 6.3e36.6) [29,30] and seropositivity for the HPV16 L1 capsid protein, which reflects lifetime exposure to HPV16 (odds ratio 32.2; 95% confidence interval 14.6e71.3) [5]. Exposure to tobacco or alcohol does not seem to act synergistically with HPV to further increase the risk of OPC in HPV-exposed individuals [5,31]. It therefore seems probable that there are two distinct pathways for the development of OPC; one driven predominantly by the carcinogenic effects of tobacco or alcohol and another by HPV-induced genomic instability.
Making the Diagnosis of Human Papillomavirus-positive Oropharyngeal Cancer A number of methods are available for detecting HPV DNA in tumour tissue, each with different strengths and weaknesses. They can be applied to formalin-fixed and paraffin-embedded tissues with a turnaround time of a few days in experienced hands. In situ hybridisation (ISH) using HPV type-specific probes has frequently been applied in studies of OPC because it can localise HPV DNA to the tumour cell nucleus, and may discriminate between integrated (punctuate staining) and episomal infections (diffuse staining) [32]; however, its use is limited to a few specialist centres. In contrast, polymerase chain reaction (PCR)-based assays are more widely available and although unable to localise HPV DNA within a tissue or cell, they are highly sensitive and able to detect HPV DNA present at one copy per cell. Because of its high sensitivity, PCR is prone to crosscontamination and stringent quality assurance procedures are necessary in laboratories that rely on PCR for HPV detection. HPV DNA detection in tumours per se does not indicate causal association, particularly if patients have other risk factors for OPC, including smoking and drinking, and markers of viral oncogene expression are required to establish that HPV is indeed ‘driving’ oncogenesis [33,34]. One surrogate marker that has been widely validated is p16 immunohistochemistry (p16 IHC). Down-regulation of Rb by HPV16 E7 results in up-regulation of p16, which can be seen as diffuse nuclear and cytoplasmic staining by IHC [35]. Most tumours (96%) that are positive for HPV by ISH are also positive by p16 IHC [36]; interestingly, however, a significant proportion (16%) of p16-positive tumours are HPVnegative by ISH, suggesting that p16 can be up-regulated by means other than HPV-induced transformation; this may be related to the observation that p16 positivity by IHC has been noted as a feature of normal tonsillar reticulated crypt epithelium, while the surface epithelium remains p16negative [10]. P16 immunostaining alone is thus not a sufficient diagnostic test and should be used in conjunction with ISH or PCR to establish a diagnosis of HPV-associated OPC.
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Clinical Characteristics of Patients with Human Papillomavirus-positive Oropharyngeal Cancer Patients with HPV-positive OPC tend to be younger by 5e10 years than their HPV-negative counterparts, are more likely to be non-smokers and non-drinkers and, unlike most head and neck cancers, men and women seem to be at equal risk [37]. There is some evidence that HPV-positive cancers present with more advanced TNM stage, and cystic lymph node metastases are a characteristic finding [38]. A magnetic resonance imaging scan showing an enlarged lymph node associated with a HPV-positive OPC is shown in Fig. 4. Histologically, HPV-positive tumours tend to have a poorly differentiated, basaloid histology [26].
Prognosis of Human Papillomaviruspositive Oropharyngeal Cancer There is increasing evidence that tumour HPV status is an important prognostic factor associated with a favourable survival for HNSCC. Retrospective studies have shown a 50e80% reduction in the risk of cancer-related death for HPV-positive OPC compared with HPV-negative OPC [34,39e41]. These findings are supported by the results of a large retrospective study correlating HPV status with outcome in 317 patients enrolled into Radiation Therapy Oncology Group (RTOG) 0129, a phase III clinical trial
Fig. 4. T2-weighted axial magnetic resonance imaging scan of the neck showing a malignant left level II lymph node in a man with human papillomavirus-positive squamous cell carcinoma of the left tonsil.
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comparing two radical chemoradiotherapy schedules for stage III/IV OPC [36]; 60.6% of patients were HPV16-positive (by both ISH and p16). Survival in HPV-positive and -negative patients was compared after adjustment for treatment group, age, race, tumour stage, nodal stage and smoking history. Patients with HPV-positive OPC had a 59% reduction in risk of death and a 46% reduction in risk of progression compared with HPVnegative patients and had a significant improvement in 2-year overall survival (87.5% versus 67.2%, P < 0.0001) and 2-year progression-free survival (71.9% versus 51.2%, P < 0.0001). These improvements in survival were due to reduced locoregional failure, rates of distant metastases being similar for HPV-positive and -negative patients. Similar improvements in survival have been shown in a number of prospective phase II clinical trials of multimodality therapy for head and neck cancer [42e44]. The largest of these studies, carried out by the Eastern Cooperative Oncology Group (ECOG 2399), included an analysis of HPV status on survival outcomes in 96 patients with locally advanced (stage III/IV) cancers of the oropharynx and larynx who were treated with chemoradiotherapy [42]. Sixty-three per cent of OPCs were HPV-positive compared with 0% of laryngeal cancers. After adjustment for age, tumour stage and performance status, patients with HPV-positive tumours had a 73% (hazard ratio 0.27; confidence interval 0.10e0.75) reduction in risk of progression and a 64% (hazard ratio 0.36; confidence interval 0.15e0.85) reduction in risk of death compared with HPV-negative patients. Overall survival at 2 years was 95% for HPV-positive patients compared with 62% for HPV-negative patients (P ¼ 0.005). HPV-positive tumours with high p16 expression have a better prognosis (overall survival, disease-free survival and lower recurrence rates) than HPV-positive tumours with low p16 expression [34], presumably because p16 is indicative of a biologically relevant (i.e. transcriptionally active or ‘causative’) HPV infection.
Treatment Response of Human Papillomavirus-positive Oropharyngeal Cancer HPV-positive OPC seems to have a better response to treatment with induction chemotherapy [42,46,47], chemoradiotherapy [42,47] and radiotherapy alone [48e50] than HPV-negative OPC. In ECOG 2399 [42], response rates (complete and partial) to induction chemotherapy (two cycles of carboplatin and paclitaxel) were significantly higher in HPV-positive patients compared with HPV-negative patients (82% versus 55%, P ¼ 0.01) as were responses to concurrent chemoradiotherapy (with weekly paclitaxel) (84% versus 57%, P ¼ 0.07). Similar results have been shown with cisplatin-based chemotherapy/chemoradiotherapy regimens that would be considered more standard in the UK [47]. Retrospective studies have shown complete response rates of up to 94% with radiotherapy alone in HPV-positive OPC [49,50]. Furthermore, analysis of OPC patients treated with conventional radiotherapy in the DAHANCA 5 trial showed improved 5-year local control rates (58% versus 28%, P ¼ 0.0005), disease-specific survival (72% versus 34%, P ¼ 0.0006) and overall survival (62% versus 26%, P ¼ 0.0003) in HPV-positive patients compared with HPVnegative patients [48]. A radiotherapy dose distribution plan for treating a right tonsillar cancer is shown in Fig. 5. Patients with HPV-positive OPC who are treated with surgery with or without adjuvant radiation also seem to
Effect of Smoking on Prognosis Smoking seems to negatively affect the survival of patients with HPV-positive OPC. In the RTOG 0129 study population, overall survival was significantly better in HPVpositive non-smokers than in HPV-positive smokers (95% versus 80% at 2 years); similarly, HPV-negative nonsmokers had better overall survival than HPV-negative smokers (71% versus 63% at 2 years) [36]. Furthermore, past smoking, as well as current smoking, seems to affect survival. In another study of stage III/IV OPC treated with chemoradiotherapy, disease-free survival rates were 88% in HPV-positive never-smokers compared with 80% in HPVpositive former smokers (who stopped smoking a year or more before diagnosis) compared with 68% in HPV-positive current smokers; disease-free survival in HPV-negative current smokers was 47%. Current smokers with HPVpositive OPC were seven times more likely to develop disease recurrence compared with HPV-positive patients who had never smoked and HPV-positive former smokers were 3.6 times more likely to develop recurrence compared with patients who had never smoked [45].
Fig. 5. Radical intensity-modulated radiotherapy dose plan for a right tonsillar cancer (purple ¼ PTV1, 66 Gy; blue ¼ PTV2, 54 Gy; orange ¼ left parotid gland). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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have a better outcome than patients with HPV-negative OPC [41,51].
Reasons for Improved Outcome of Human Papillomavirus-positive Oropharyngeal Cancer The biological explanations for the improved outcome of patients with HPV-positive OPC are not yet fully understood. It is clear that HPV-positive tumours have a significantly improved response to chemotherapy and radiotherapy compared with HPV-negative tumours. This may be due to the presence (and even overexpression [46]) of wild-type p53 and Rb tumour suppressor genes in HPVtransformed cells, which in turn means that the tumoursuppressing pathways in these cells are intact, but dormant due to continued expression of viral E6 and E7; these pathways (including apoptosis) may be partially reactivated in response to chemotherapy and radiation-induced damage, unlike in carcinogen-transformed cells containing mutant p53 and/or Rb. Other factors, including the presence of immune surveillance to viral antigens, may augment treatment responses in HPV-positive patients and indeed, HPV16 E7-specific T-cells have been found at higher frequencies in HPV-positive OPC patients compared with HPV-negative patients and healthy controls [52,53]. Other factors that may contribute to the improved outcome of HPV-positive OPC include the absence of field cancerisation, which may result in a reduced rate of second primary cancers [51]. Furthermore, HPV-positive tumours tend to express low levels of other biomarkers that correlate with poor prognosis in locally advanced HNSCC, including the epidermal growth factor receptor (EGFR). HPV-positive tumours with low EGFR expression have been shown to have a better outcome (overall survival and disease-specific survival) compared with HPV-positive tumours with higher EGFR expression [46]. Smoking may contribute to increased EGFR expression, possibly through increased hypoxia in the tumour tissue of smokers, and this may in part explain the poorer outcome of HPV-positive smokers compared with HPV-positive non-smokers.
Future Directions: Prevalence, Screening, Treatment and Prevention Prevalence Before the introduction of new treatment strategies for HPV-positive OPC, the true prevalence of HPV-induced OPC in different countries, including the UK, needs to be assessed. This cannot be assumed from existing studies because of the geographical variation that exists in HPV prevalence studies from around the world [7,9,10]. A retrospective, UK-wide HPV prevalence study is proposed to look at the association of HPV with OPC in England, Scotland, Wales and Northern Ireland and prospective studies correlating HPV status with outcome will also be required
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to determine the significance of HPV status relative to genetic and environmental factors (e.g. rates of smoking and drinking). Screening Because cervical cancer and HPV-induced OPC share a HPV linked aetiology, it is worth considering whether the paradigms for prevention of cervical cancer may be relevant to OPC. Cervical screening depends on: 1. The existence of a well-characterised premalignant phase [cervical intraepithelial neoplasia (CIN) characterised by cell proliferation and dyskaryosis but not invasion]. 2. A screening test capable of identifying women at increased risk of having the premalignant phase (this is currently cytological testing but will probably change to HPV testing in the near future due to its proven greater sensitivity for CIN [54]). 3. The availability of a treatment to prevent progression to cervical cancer (currently excision of the neoplastic cells). It is reasonable to hypothesise that the development of OPC is broadly similar to the development of cervical squamous cell carcinoma, where persistent viral infection leads to cellular neoplasia and genetic instability followed by the accumulation of mutations that may lead to invasion and metastasis (as shown in Fig. 3) [55]. Intraepithelial neoplasias are precursors of HPV-associated malignancy at other anatomical sites, including the penis, anus, vagina and vulva. Hence, there may be a premalignant phase preceding OPC that could be targeted for screening. The most likely candidate for a screening test for oropharyngeal intraepithelial neoplasia (if it exists) is currently HPV testing. However, the odds ratios demonstrated for oral HPV16 infection and OPC (63 [30];14.6 [5]) are substantially smaller than have been reported for HPV16 in exfoliated cervical cells and cervical cancer (434.5 [12]). This may represent a limitation of the sampling technique, as poor correlations between HPV DNA in tumours and in the corresponding oral exfoliated sample have been reported. Regarding interventions that could be used in patients with a premalignant lesion, certainly for tonsillar lesions (the subsite with the strongest association with HPV infection) it would be possible to remove the lesion with a simple tonsillectomy. Treatment Testing tumour samples for HPV status is not part of routine clinical practice and currently patients with HPVpositive and -negative OPC are managed according to common treatment protocols, which may include surgery, radiotherapy (primary or postoperative) and chemoradiotherapy according to disease stage, patient fitness and local expertise. Chemoradiotherapy and surgery-based treatment strategies are both associated with significant
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acute and long-term toxicities and lifelong impairment of quality of life in survivors [51,56e58]. Given the high survival rates seen with both these approaches in HPVpositive OPC, a worthwhile goal would be to achieve these outcomes with the minimum treatment intervention. There is growing support for the view that treatment protocols for OPC should be modified according to HPV status and that de-escalation of treatment intensity may be a real possibility for patients with HPV-positive OPC. If equivalent survival rates could be achieved with less toxic treatment protocols, e.g. radiation therapy alone [48] or radiation therapy with an EGFR inhibitor [59], this could significantly improve long-term quality of life in surviving HPV-positive patients. Randomised, prospective studies, stratified for variables including smoking behaviour, are therefore urgently needed to determine the optimum management of affected patients in the future. Such studies are currently being supported by the National Cancer Research Institute Head and Neck Cancer Site Group and by the wider international community. Furthermore, patients with OPC should be stratified by HPV status in future clinical trials and the RTOG have already adopted this policy [60]. Highly accurate HPV testing methods will be required before treatment de-escalation can be safely adopted for HPV-positive patients, to minimise the risk of undertreating HPV-negative patients who may be falsely diagnosed as HPV-positive. Detection of HPV DNA by ISH and/or PCR should be combined with p16 IHC to confirm the presence of biologically relevant (i.e. transcriptionally active or ‘causative’) HPV infection. Immunological strategies directed against HPV have been widely tested in cervical cancer and similar therapeutic studies are proposed in HPV-positive OPC. A phase I study (REALISTIC) to investigate the tolerability and immunogenicity of a modified Listeria monocytogenes vaccine expressing HPV16 E7, given as an adjuvant after radical treatment of HPV-positive OPC, will start recruiting at selected UK sites in the next year. Prevention Once a viral cause of cervical cancer was established, prophylactic vaccination became a possible intervention. The pioneering work of Ian Frazer and others [61] led to the production of HPV virus-like particle vaccines, which are now in use across the developed world. These vaccines are highly effective in preventing both persistent infection and CIN in women who have not previously been exposed to HPV [62e64]. Both of the commercially available vaccines target HPV types 16 and 18, and in the UK vaccination of 12e13-year-old girls began in September 2008. Up to 95% of HPV-positive OPC are associated with HPV16 infection and so, if the vaccination programme is successful in reducing the prevalence of HPV16, it would be expected to significantly reduce the number of HPV-attributable OPC in the future, at least in females. This is, however, a very long-term prospect, and because the mean age at presentation for HPV-associated OPC is 50e55 years, it will probably be 30e40 years before the benefits of vaccination become
apparent. Furthermore, if vaccination can reduce the incidence of HPV16-related OPC, this may be used as an argument to extend the vaccination programme to include boys as well as girls in the future.
Conclusion HPV-positive OPC represents a new and emerging disease, with a different natural history and prognosis to HPV-negative OPC and other HNSCC. Patients with HPVpositive OPC are younger and are less likely to smoke and drink. They respond well to current treatment strategies but at the cost of significant long-term side-effects. Individualising patient management according to the presence of tumour-specific biomarkers is a goal for many tumour subsites and is a real possibility for patients with OPC. The results of ongoing UK clinical trials will help inform treatment decisions for this patient group in the future.
References [1] Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12e19. [2] De Vuyst H, Clifford GM, Nascimento MC, Madeleine MM, Franceschi S. Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis. Int J Cancer 2009;124:1626e1636. [3] Miralles-Guri C, Bruni L, Cubilla AL, Castellsague X, Bosch FX, de Sanjose S. Human papillomavirus prevalence and type distribution in penile carcinoma. J Clin Pathol 2009;62: 870e878. [4] Anon. Cancer Statistics: registrations series MB1. Available from: http://www.statistics.gov.uk/statbase/Product.asp?vlnk¼ 8843; 2009. Accessed 2 April 2010. [5] D’Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007;356:1944e1956. [6] Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 2005;14:467e475. [7] Nasman A, Attner P, Hammarstedt L, et al. Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma? Int J Cancer 2009;125:362e366. [8] Romanitan M, Nasman A, Ramqvist T, et al. Human papillomavirus frequency in oral and oropharyngeal cancer in Greece. Anticancer Res 2008;28:2077e2080. [9] Herrero R, Castellsague X, Pawlita M, et al. Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study. J Natl Cancer Inst 2003;95:1772e1783. [10] Begum S, Cao D, Gillison M, Zahurak M, Westra WH. Tissue distribution of human papillomavirus 16 DNA integration in patients with tonsillar carcinoma. Clin Cancer Res 2005;11: 5694e5699. [11] Anderson CE, McLaren KM, Rae F, Sanderson RJ, Cuschieri KS. Human papilloma virus in squamous carcinoma of the head and neck: a study of cases in south east Scotland. J Clin Pathol 2007;60:439e441.
M. Evans, N.G. Powell / Clinical Oncology 22 (2010) 538e546 [12] Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518e527. [13] Smith JS, Lindsay L, Hoots B, et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer 2007;121:621e632. [14] Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 1990;63:1129e1136. [15] Veldman T, Horikawa I, Barrett JC, Schlegel R. Transcriptional activation of the telomerase hTERT gene by human papillomavirus type 16 E6 oncoprotein. J Virol 2001;75:4467e4472. [16] Veldman T, Liu X, Yuan H, Schlegel R. Human papillomavirus E6 and Myc proteins associate in vivo and bind to and cooperatively activate the telomerase reverse transcriptase promoter. Proc Natl Acad Sci USA 2003;100:8211e8216. [17] Munger K, Baldwin A, Edwards KM, et al. Mechanisms of human papillomavirus-induced oncogenesis. J Virol 2004;78: 11451e11460. [18] Middleton K, Peh W, Southern S, et al. Organization of human papillomavirus productive cycle during neoplastic progression provides a basis for selection of diagnostic markers. J Virol 2003;77:10186e10201. [19] Chung CH, Gillison ML. Human papillomavirus in head and neck cancer: its role in pathogenesis and clinical implications. Clin Cancer Res 2009;15:6758e6762. [20] Pett M, Coleman N. Integration of high-risk human papillomavirus: a key event in cervical carcinogenesis? J Pathol 2007;212:356e367. [21] Doorbar J. Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci (Lond) 2006;110: 525e541. [22] Perry ME. The specialised structure of crypt epithelium in the human palatine tonsil and its functional significance. J Anat 1994;185(Pt 1):111e127. [23] Herrero R, Castle PE, Schiffman M, et al. Epidemiologic profile of type-specific human papillomavirus infection and cervical neoplasia in Guanacaste, Costa Rica. J Infect Dis 2005;191:1796e1807. [24] Hibbitts S, Jones J, Powell N, et al. Human papillomavirus prevalence in women attending routine cervical screening in South Wales, UK: a cross-sectional study. Br J Cancer 2008;99:1929e1933. [25] Wheeler CM, Hunt WC, Joste NE, Key CR, Quint WG, Castle PE. Human papillomavirus genotype distributions: implications for vaccination and cancer screening in the United States. J Natl Cancer Inst 2009;101:475e487. [26] Adelstein DJ, Ridge JA, Gillison ML, et al. Head and neck squamous cell cancer and the human papillomavirus: summary of a National Cancer Institute State of the Science Meeting, November 9e10, 2008, Washington, D.C. Head Neck 2009;31:1393e1422. [27] Kreimer AR, Alberg AJ, Daniel R, et al. Oral human papillomavirus infection in adults is associated with sexual behavior and HIV serostatus. J Infect Dis 2004;189:686e698. [28] Hemminki K, Dong C, Frisch M. Tonsillar and other upper aerodigestive tract cancers among cervical cancer patients and their husbands. Eur J Cancer Prev 2000;9:433e437. [29] Mork J, Lie AK, Glattre E, et al. Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 2001;344:1125e1131. [30] Hansson BG, Rosenquist K, Antonsson A, et al. Strong association between infection with human papillomavirus and oral
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
545
and oropharyngeal squamous cell carcinoma: a populationbased case-control study in southern Sweden. Acta Otolaryngol 2005;125:1337e1344. Applebaum KM, Furniss CS, Zeka A, et al. Lack of association of alcohol and tobacco with HPV16-associated head and neck cancer. J Natl Cancer Inst 2007;99:1801e1810. Samama B, Plas-Roser S, Schaeffer C, Chateau D, Fabre M, Boehm N. HPV DNA detection by in situ hybridization with catalyzed signal amplification on thin-layer cervical smears. J Histochem Cytochem 2002;50:1417e1420. Jung AC, Briolat J, Millon R, et al. Biological and clinical relevance of transcriptionally active human papillomavirus (HPV) infection in oropharynx squamous cell carcinoma. Int J Cancer 2010;126:1882e1894. Weinberger PM, Yu Z, Haffty BG, et al. Molecular classification identifies a subset of human papillomavirus-associated oropharyngeal cancers with favorable prognosis. J Clin Oncol 2006;24:736e747. Klaes R, Friedrich T, Spitkovsky D, et al. Overexpression of p16 (INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer 2001;92: 276e284. Gillison M, Harris J, Westra C, et al. Survival outcomes by tumor human papillomavirus (HPV) status in stage IIIeIV oropharyngeal cancer (OPC) in RTOG 0129. J Clin Oncol 2009;27:15s. Fakhry C, Gillison ML. Clinical implications of human papillomavirus in head and neck cancers. J Clin Oncol 2006;24: 2606e2611. Goldenberg D, Begum S, Westra WH, et al. Cystic lymph node metastasis in patients with head and neck cancer: an HPVassociated phenomenon. Head Neck 2008;30:898e903. Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000;92:709e720. Mellin H, Friesland S, Lewensohn R, Dalianis T, MunckWikland E. Human papillomavirus (HPV) DNA in tonsillar cancer: clinical correlates, risk of relapse, and survival. Int J Cancer 2000;89:300e304. Ritta M, De Andrea M, Mondini M, et al. Cell cycle and viral and immunologic profiles of head and neck squamous cell carcinoma as predictable variables of tumor progression. Head Neck 2009;31:318e327. Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008;100:261e269. Jo S, Juhasz A, Zhang K, et al. Human papillomavirus infection as a prognostic factor in oropharyngeal squamous cell carcinomas treated in a prospective phase II clinical trial. Anticancer Res 2009;29:1467e1474. Kies MS, Holsinger FC, Lee JJ, et al. Induction chemotherapy and cetuximab for locally advanced squamous cell carcinoma of the head and neck: results from a phase II prospective trial. J Clin Oncol 2010;28:8e14. Worden FP, Hooton J, Lee A, et al. Association of tobacco (T) use with risk of distant metastases (DM), tumor recurrence, and death in patients (pts) with HPV-positive (þ) squamous cell cancer of the oropharynx (SCCOP). J Clin Oncol 2009;27:15s. Kumar B, Cordell KG, Lee JS, et al. EGFR, p16, HPV Titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer. J Clin Oncol 2008;26:3128e3137. Worden FP, Kumar B, Lee JS, et al. Chemoselection as a strategy for organ preservation in advanced oropharynx
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[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
M. Evans, N.G. Powell / Clinical Oncology 22 (2010) 538e546 cancer: response and survival positively associated with HPV16 copy number. J Clin Oncol 2008;26:3138e3146. Lassen P, Eriksen JG, Hamilton-Dutoit S, Tramm T, Alsner J, Overgaard J. Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol 2009;27: 1992e1998. Lindel K, Beer KT, Laissue J, Greiner RH, Aebersold DM. Human papillomavirus positive squamous cell carcinoma of the oropharynx: a radiosensitive subgroup of head and neck carcinoma. Cancer 2001;92:805e813. Mellin Dahlstrand H, Lindquist D, Bjornestal L, et al. P16 (INK4a) correlates to human papillomavirus presence, response to radiotherapy and clinical outcome in tonsillar carcinoma. Anticancer Res 2005;25:4375e4383. Licitra L, Perrone F, Bossi P, et al. High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol 2006;24:5630e5636. Albers A, Abe K, Hunt J, et al. Antitumor activity of human papillomavirus type 16 E7-specific T cells against virally infected squamous cell carcinoma of the head and neck. Cancer Res 2005;65:11146e11155. Hoffmann TK, Arsov C, Schirlau K, et al. T cells specific for HPV16 E7 epitopes in patients with squamous cell carcinoma of the oropharynx. Int J Cancer 2006;118:1984e1991. Naucler P, Ryd W, Tornberg S, et al. Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening. J Natl Cancer Inst 2009;101: 88e99. Snijders PJ, Steenbergen RD, Heideman DA, Meijer CJ. HPVmediated cervical carcinogenesis: concepts and clinical implications. J Pathol 2006;208:152e164.
[56] Bhide SA, Miah AB, Harrington KJ, Newbold KL, Nutting CM. Radiation-induced xerostomia: pathophysiology, prevention and treatment. Clin Oncol (R Coll Radiol) 2009;21:737e744. [57] Machtay M, Moughan J, Trotti A, et al. Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis. J Clin Oncol 2008;26:3582e3589. [58] Rathmell AJ, Ash DV, Howes M, Nicholls J. Assessing quality of life in patients treated for advanced head and neck cancer. Clin Oncol (R Coll Radiol) 1991;3:10e16. [59] Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567e578. [60] Laino C. HPV-positive oropharyngeal tumours associated with better outcomes. Oncol Times 2009;31:26e29. [61] Zhou J, Sun XY, Stenzel DJ, Frazer IH. Expression of vaccinia recombinant HPV 16 L1 and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles. Virology 1991;185:251e257. [62] Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 2006;367:1247e1255. [63] Paavonen J, Jenkins D, Bosch FX, et al. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III doubleblind, randomised controlled trial. Lancet 2007;369: 2161e2170. [64] Future II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915e1927.
Clinical Oncology journal homepage: www.elsevier.com/locate/clon
Overview
The Changing Aetiology of Head and Neck Cancer: the Role of Human Papillomavirus M. Evans *, N.G. Powell y * Velindre y
Cancer Centre, Cardiff, UK HPV Research Group, Obstetrics and Gynaecology, School of Medicine, Cardiff University, Cardiff, UK
Received 25 March 2010; received in revised form 22 April 2010; accepted 26 April 2010
Abstract Human papillomavirus (HPV) is associated with the development of a subset of head and neck cancers arising in the oropharynx, which includes the tonsils, base of tongue and soft palate. HPV-associated oropharyngeal cancer (OPC) seems to be rapidly increasing in incidence in many countries, including the USA, Sweden and Greece, and is known to affect younger patients who are less likely to have been exposed to the carcinogenic effects of tobacco and alcohol than their HPV-negative counterparts. There is accumulating evidence from prospective studies that HPV-positive OPC responds better to treatment, including chemotherapy and radiotherapy, than HPV-negative OPC, and that patients with HPV-positive disease have excellent long-term survival rates. To date, patients with HPV-positive and HPV-negative OPC are managed according to common treatment protocols; this may no longer be appropriate in an age when the delivery of targeted treatment, tailored to individual tumour and patient characteristics, is becoming a reality. This review summarises our current understanding of HPV-positive OPC, drawing parallels from the role of HPV in the development of cervical cancer. We also consider how knowledge of tumour HPV status may affect the future management and prevention of OPC and discuss the need for future collaborative trials in this important group of patients. Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Head and neck; human papillomavirus; oropharyngeal
Statement of Search Strategies Used and Sources of Information This overview is based on published peer-reviewed reports identified via PubMed using search terms including HPV, oropharyngeal cancer, OPSCC and HNSCC. Other relevant sources are also referred to.
Introduction Head and neck cancers, most of which are squamous cell carcinomas (HNSCC), are traditionally associated with smoking tobacco and drinking alcohol. However, a subset of HNSCC originating in the oropharynx (OPC), including cancers of the tonsil (Figs. 1 and 2), base of the tongue, soft palate and pharyngeal wall, are increasingly associated with human papillomavirus (HPV) infection. HPV is already well Author for correspondence: M. Evans, Velindre Cancer Centre, Whitchurch, Cardiff CF14 2TL, UK. Tel: þ44-2920196160; Fax: þ44-2920316267. E-mail address: [email protected] (M. Evans).
known as the agent responsible for the development of virtually all (99.7%) cervical cancers [1] as well as rarer anogenital cancers, including cancers of the vulva, vagina, anus and penis [2,3].
Incidence of Human Papillomavirusassociated Oropharyngeal Cancer The incidence of most HNSCC, including cancers of the larynx, is stable or decreasing in the UK, whereas the incidence of OPC, and tonsillar cancer in particular, is increasing. In England there were 281 tonsillar cancers diagnosed in 1997; this had increased to 703 diagnoses in 2007 [4]. Similar trends have been reported for the USA, Sweden and Greece, and this increase in incidence seems to be associated with HPV infection [5e8]. For example, in Sweden the incidence of tonsillar cancer almost doubled between 1970 and 2006 and the proportion of HPV-positive cases increased from 23% (1970e1979) to 79% (2000e2007) in the same time period. In 2006e2007, 93% of tonsillar cancers in Sweden were HPV-positive, ‘suggesting an
0936-6555/$36.00 Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.clon.2010.05.024
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rates reported by different studies. The contribution of HPV to the development of OPC in the UK is unclear [11]. A large HPV prevalence study is currently underway in South Wales and a UK-wide study is planned to study regional variations in the incidence of HPV-associated OPC. Most cases (90e95%) of HPV-positive OPC are associated with HPV subtype 16 infection [9]. In contrast, although virtually all cases of cervical cancer are HPV-positive, HPV16 infection accounts for a lower proportion (52e58%) of the overall caseload and other subtypes, including HPV18, -31, -33, -45 and -53, are also important aetiological agents [12,13].
Pathogenesis
Fig. 1. Squamous cell carcinoma of the right tonsil (picture courtesy of Mr Richard Shaw).
epidemic of a virus-induced carcinoma, with soon practically all tonsillar SCC being HPV-positive, as in cervical cancer’ [7]. The prevalence of HPV infection in OPC does, however, vary widely between studies from 18% in a multinational study by the International Agency for Research on Cancer [9] to 82% in a study from the USA [10]. This may in part be due to true geographical variations, but different HPV detection methods may also have influenced the prevalence
HPV is dependent on the host cell replication machinery to copy its own DNA, but the necessary proteins are only produced in actively dividing cells. To induce the production of these proteins, HPV encodes factors that deregulate cell cycle control and cause inappropriate cell division. The HPV proteins chiefly responsible for these effects are the transforming oncoproteins E6 and E7, whose main functions are the inactivation of the cellular p53 and Rb tumour suppressor proteins. Expression of the E6 protein results in proteosomal degradation of p53 leading to loss of cell cycle arrest and apoptosis in response to DNA damage [14]. The E6 protein also mediates activation of telomerase and thereby avoids cellular senescence in response to telomere erosion in proliferating cells [15,16]. The E7 protein causes degradation of Rb, resulting in unrestricted progression through the G1/S cell cycle checkpoint (reviewed in [17]). Expression of the E6 and E7 genes is usually very tightly regulated and correlates with the differentiation state of the host cell. However, loss of this regulation results in neoplasia and prevents completion of the viral lifecycle [18]. The molecular pathways affected by the expression of E6 and E7 are reviewed in [19]. Deregulation of the pattern of gene expression is commonly a consequence of integration of the HPV DNA into the host cell genome [20] and the resulting population of proliferating cells is prone to accumulation of genetic damage, which can ultimately lead to malignant transformation.
Parallels with Cervical Carcinogenesis
Fig. 2. Axial computed tomography scan through the oropharynx showing a carcinoma of the left tonsil (outlined).
Since the isolation of HPV16 from a cervical carcinoma in 1983, considerable effort has been devoted to determining the biology of HPV infection in the cervix. This investment has led to improved screening and prevention of cervical cancer, most recently by prophylactic vaccination. A model of the cellular events and other factors involved in cervical carcinogenesis is shown in Fig. 3. HPV-associated carcinogenesis in the oropharynx probably shares many features with cervical carcinogenesis; however, there are a number of aspects in which carcinogenesis at the two sites differs, including involvement of the cervical transformation zone, the fraction of disease attributable to a viral cause, and the degree of predominance of HPV16.
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Fig. 3. The cellular events associated with progression in cervical carcinogenesis and the genetic, environmental and behavioural factors that may influence progression.
The transformation zone is the region in which the simple columnar epithelia of the endocervix meets the squamous epithelium of the ectocervix, and is the site from which nearly all cervical squamous cell carcinoma arise. Several hypotheses have been advanced to explain the specific vulnerability of the transformation zone: the thinner epithelium present at the transformation zone may allow easier access to the basal epithelium, which is the initial target of HPV infection, and thin epithelia may be more vulnerable to the small wounds and abrasions that facilitate HPV infection; alternatively, it has been suggested that virus-induced cancers often arise at sites where productive viral infection (resulting in the release of infectious virus) cannot be properly supported [21]. It is possible that because cells in the transformation zone do not conform to the normal pattern of epithelial differentiation, they cannot support the full HPV lifecycle, and will allow expression of the viral early genes, including oncogenic E6 and E7, but not of the late genes. It is clear that there is no direct equivalent of the transformation zone in the oropharynx. There is, however, evidence that HPV is found predominantly in the reticulated epithelial crypts in the tonsils [10], which are composed of specialised epithelia with immune and secretory functions, not stratified epithelia [22]. Hence, a mix of epithelial types is present and it is unlikely that HPV is able to complete its lifecycle in such an environment. Therefore, as this appears to be the site from which cancers arise, allowing infection but not completion of the viral lifecycle, it may constitute an equivalent area to the transformation zone in the oropharynx. Whereas virtually all cervical cancers are attributed to HPV infection [1], the proportion of OPC caused by HPV infection seems to be smaller [6,23]. It is reasonable to hypothesise that this simply reflects the greater degree of chemical insult (by tobacco and alcohol) inflicted on the
oral epithelium relative to the cervix. This may also partly explain the predominance of HPV16 in OPC. HPV16 is the most virulent and aggressive of the HPVs, as evidenced by its high population prevalence [24] and the earlier onset of HPV16-associated cervical cancers [25]. It is possible that with greater exposure to potentially carcinogenic DNA damage, the epithelium of the oral cavity has evolved so that its microenvironment presents a challenge, particularly in terms of immunological exposure, which only the most virulent and aggressive HPVs can overcome.
Natural History of Human Papillomavirus Infection in the Oral Cavity The natural history of HPV infection in the oral cavity is currently poorly defined [26]. Oral HPV infection is believed to be sexually acquired, as prevalence is significantly associated with sexual behaviour [5,27]. However, questions relating to the duration of infection, degree of oral transmission, and whether productive viral infections are established in the oropharynx, remain largely unanswered.
Risk Factors for Human Papillomaviruspositive Oropharyngeal Cancer Case-control studies have shown an association between HPV-positive OPC and certain sexual behaviours, including a high lifetime number of oral sex or vaginal sex partners, early age at first intercourse and infrequent use of condoms [5]. These risk factors mirror those for cervical cancer and result in increased transmission of HPV between sexual partners. Women with a past history of HPV-associated carcinoma in situ or cervical cancer and partners of women with carcinoma in situ/cervical cancer are also at increased
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risk of HPV-positive OPC [28]. Furthermore, HPV-positive OPC is associated with the presence of oral HPV infection (odds ratio 14.6; 95% confidence interval 6.3e36.6) [29,30] and seropositivity for the HPV16 L1 capsid protein, which reflects lifetime exposure to HPV16 (odds ratio 32.2; 95% confidence interval 14.6e71.3) [5]. Exposure to tobacco or alcohol does not seem to act synergistically with HPV to further increase the risk of OPC in HPV-exposed individuals [5,31]. It therefore seems probable that there are two distinct pathways for the development of OPC; one driven predominantly by the carcinogenic effects of tobacco or alcohol and another by HPV-induced genomic instability.
Making the Diagnosis of Human Papillomavirus-positive Oropharyngeal Cancer A number of methods are available for detecting HPV DNA in tumour tissue, each with different strengths and weaknesses. They can be applied to formalin-fixed and paraffin-embedded tissues with a turnaround time of a few days in experienced hands. In situ hybridisation (ISH) using HPV type-specific probes has frequently been applied in studies of OPC because it can localise HPV DNA to the tumour cell nucleus, and may discriminate between integrated (punctuate staining) and episomal infections (diffuse staining) [32]; however, its use is limited to a few specialist centres. In contrast, polymerase chain reaction (PCR)-based assays are more widely available and although unable to localise HPV DNA within a tissue or cell, they are highly sensitive and able to detect HPV DNA present at one copy per cell. Because of its high sensitivity, PCR is prone to crosscontamination and stringent quality assurance procedures are necessary in laboratories that rely on PCR for HPV detection. HPV DNA detection in tumours per se does not indicate causal association, particularly if patients have other risk factors for OPC, including smoking and drinking, and markers of viral oncogene expression are required to establish that HPV is indeed ‘driving’ oncogenesis [33,34]. One surrogate marker that has been widely validated is p16 immunohistochemistry (p16 IHC). Down-regulation of Rb by HPV16 E7 results in up-regulation of p16, which can be seen as diffuse nuclear and cytoplasmic staining by IHC [35]. Most tumours (96%) that are positive for HPV by ISH are also positive by p16 IHC [36]; interestingly, however, a significant proportion (16%) of p16-positive tumours are HPVnegative by ISH, suggesting that p16 can be up-regulated by means other than HPV-induced transformation; this may be related to the observation that p16 positivity by IHC has been noted as a feature of normal tonsillar reticulated crypt epithelium, while the surface epithelium remains p16negative [10]. P16 immunostaining alone is thus not a sufficient diagnostic test and should be used in conjunction with ISH or PCR to establish a diagnosis of HPV-associated OPC.
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Clinical Characteristics of Patients with Human Papillomavirus-positive Oropharyngeal Cancer Patients with HPV-positive OPC tend to be younger by 5e10 years than their HPV-negative counterparts, are more likely to be non-smokers and non-drinkers and, unlike most head and neck cancers, men and women seem to be at equal risk [37]. There is some evidence that HPV-positive cancers present with more advanced TNM stage, and cystic lymph node metastases are a characteristic finding [38]. A magnetic resonance imaging scan showing an enlarged lymph node associated with a HPV-positive OPC is shown in Fig. 4. Histologically, HPV-positive tumours tend to have a poorly differentiated, basaloid histology [26].
Prognosis of Human Papillomaviruspositive Oropharyngeal Cancer There is increasing evidence that tumour HPV status is an important prognostic factor associated with a favourable survival for HNSCC. Retrospective studies have shown a 50e80% reduction in the risk of cancer-related death for HPV-positive OPC compared with HPV-negative OPC [34,39e41]. These findings are supported by the results of a large retrospective study correlating HPV status with outcome in 317 patients enrolled into Radiation Therapy Oncology Group (RTOG) 0129, a phase III clinical trial
Fig. 4. T2-weighted axial magnetic resonance imaging scan of the neck showing a malignant left level II lymph node in a man with human papillomavirus-positive squamous cell carcinoma of the left tonsil.
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comparing two radical chemoradiotherapy schedules for stage III/IV OPC [36]; 60.6% of patients were HPV16-positive (by both ISH and p16). Survival in HPV-positive and -negative patients was compared after adjustment for treatment group, age, race, tumour stage, nodal stage and smoking history. Patients with HPV-positive OPC had a 59% reduction in risk of death and a 46% reduction in risk of progression compared with HPVnegative patients and had a significant improvement in 2-year overall survival (87.5% versus 67.2%, P < 0.0001) and 2-year progression-free survival (71.9% versus 51.2%, P < 0.0001). These improvements in survival were due to reduced locoregional failure, rates of distant metastases being similar for HPV-positive and -negative patients. Similar improvements in survival have been shown in a number of prospective phase II clinical trials of multimodality therapy for head and neck cancer [42e44]. The largest of these studies, carried out by the Eastern Cooperative Oncology Group (ECOG 2399), included an analysis of HPV status on survival outcomes in 96 patients with locally advanced (stage III/IV) cancers of the oropharynx and larynx who were treated with chemoradiotherapy [42]. Sixty-three per cent of OPCs were HPV-positive compared with 0% of laryngeal cancers. After adjustment for age, tumour stage and performance status, patients with HPV-positive tumours had a 73% (hazard ratio 0.27; confidence interval 0.10e0.75) reduction in risk of progression and a 64% (hazard ratio 0.36; confidence interval 0.15e0.85) reduction in risk of death compared with HPV-negative patients. Overall survival at 2 years was 95% for HPV-positive patients compared with 62% for HPV-negative patients (P ¼ 0.005). HPV-positive tumours with high p16 expression have a better prognosis (overall survival, disease-free survival and lower recurrence rates) than HPV-positive tumours with low p16 expression [34], presumably because p16 is indicative of a biologically relevant (i.e. transcriptionally active or ‘causative’) HPV infection.
Treatment Response of Human Papillomavirus-positive Oropharyngeal Cancer HPV-positive OPC seems to have a better response to treatment with induction chemotherapy [42,46,47], chemoradiotherapy [42,47] and radiotherapy alone [48e50] than HPV-negative OPC. In ECOG 2399 [42], response rates (complete and partial) to induction chemotherapy (two cycles of carboplatin and paclitaxel) were significantly higher in HPV-positive patients compared with HPV-negative patients (82% versus 55%, P ¼ 0.01) as were responses to concurrent chemoradiotherapy (with weekly paclitaxel) (84% versus 57%, P ¼ 0.07). Similar results have been shown with cisplatin-based chemotherapy/chemoradiotherapy regimens that would be considered more standard in the UK [47]. Retrospective studies have shown complete response rates of up to 94% with radiotherapy alone in HPV-positive OPC [49,50]. Furthermore, analysis of OPC patients treated with conventional radiotherapy in the DAHANCA 5 trial showed improved 5-year local control rates (58% versus 28%, P ¼ 0.0005), disease-specific survival (72% versus 34%, P ¼ 0.0006) and overall survival (62% versus 26%, P ¼ 0.0003) in HPV-positive patients compared with HPVnegative patients [48]. A radiotherapy dose distribution plan for treating a right tonsillar cancer is shown in Fig. 5. Patients with HPV-positive OPC who are treated with surgery with or without adjuvant radiation also seem to
Effect of Smoking on Prognosis Smoking seems to negatively affect the survival of patients with HPV-positive OPC. In the RTOG 0129 study population, overall survival was significantly better in HPVpositive non-smokers than in HPV-positive smokers (95% versus 80% at 2 years); similarly, HPV-negative nonsmokers had better overall survival than HPV-negative smokers (71% versus 63% at 2 years) [36]. Furthermore, past smoking, as well as current smoking, seems to affect survival. In another study of stage III/IV OPC treated with chemoradiotherapy, disease-free survival rates were 88% in HPV-positive never-smokers compared with 80% in HPVpositive former smokers (who stopped smoking a year or more before diagnosis) compared with 68% in HPV-positive current smokers; disease-free survival in HPV-negative current smokers was 47%. Current smokers with HPVpositive OPC were seven times more likely to develop disease recurrence compared with HPV-positive patients who had never smoked and HPV-positive former smokers were 3.6 times more likely to develop recurrence compared with patients who had never smoked [45].
Fig. 5. Radical intensity-modulated radiotherapy dose plan for a right tonsillar cancer (purple ¼ PTV1, 66 Gy; blue ¼ PTV2, 54 Gy; orange ¼ left parotid gland). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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have a better outcome than patients with HPV-negative OPC [41,51].
Reasons for Improved Outcome of Human Papillomavirus-positive Oropharyngeal Cancer The biological explanations for the improved outcome of patients with HPV-positive OPC are not yet fully understood. It is clear that HPV-positive tumours have a significantly improved response to chemotherapy and radiotherapy compared with HPV-negative tumours. This may be due to the presence (and even overexpression [46]) of wild-type p53 and Rb tumour suppressor genes in HPVtransformed cells, which in turn means that the tumoursuppressing pathways in these cells are intact, but dormant due to continued expression of viral E6 and E7; these pathways (including apoptosis) may be partially reactivated in response to chemotherapy and radiation-induced damage, unlike in carcinogen-transformed cells containing mutant p53 and/or Rb. Other factors, including the presence of immune surveillance to viral antigens, may augment treatment responses in HPV-positive patients and indeed, HPV16 E7-specific T-cells have been found at higher frequencies in HPV-positive OPC patients compared with HPV-negative patients and healthy controls [52,53]. Other factors that may contribute to the improved outcome of HPV-positive OPC include the absence of field cancerisation, which may result in a reduced rate of second primary cancers [51]. Furthermore, HPV-positive tumours tend to express low levels of other biomarkers that correlate with poor prognosis in locally advanced HNSCC, including the epidermal growth factor receptor (EGFR). HPV-positive tumours with low EGFR expression have been shown to have a better outcome (overall survival and disease-specific survival) compared with HPV-positive tumours with higher EGFR expression [46]. Smoking may contribute to increased EGFR expression, possibly through increased hypoxia in the tumour tissue of smokers, and this may in part explain the poorer outcome of HPV-positive smokers compared with HPV-positive non-smokers.
Future Directions: Prevalence, Screening, Treatment and Prevention Prevalence Before the introduction of new treatment strategies for HPV-positive OPC, the true prevalence of HPV-induced OPC in different countries, including the UK, needs to be assessed. This cannot be assumed from existing studies because of the geographical variation that exists in HPV prevalence studies from around the world [7,9,10]. A retrospective, UK-wide HPV prevalence study is proposed to look at the association of HPV with OPC in England, Scotland, Wales and Northern Ireland and prospective studies correlating HPV status with outcome will also be required
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to determine the significance of HPV status relative to genetic and environmental factors (e.g. rates of smoking and drinking). Screening Because cervical cancer and HPV-induced OPC share a HPV linked aetiology, it is worth considering whether the paradigms for prevention of cervical cancer may be relevant to OPC. Cervical screening depends on: 1. The existence of a well-characterised premalignant phase [cervical intraepithelial neoplasia (CIN) characterised by cell proliferation and dyskaryosis but not invasion]. 2. A screening test capable of identifying women at increased risk of having the premalignant phase (this is currently cytological testing but will probably change to HPV testing in the near future due to its proven greater sensitivity for CIN [54]). 3. The availability of a treatment to prevent progression to cervical cancer (currently excision of the neoplastic cells). It is reasonable to hypothesise that the development of OPC is broadly similar to the development of cervical squamous cell carcinoma, where persistent viral infection leads to cellular neoplasia and genetic instability followed by the accumulation of mutations that may lead to invasion and metastasis (as shown in Fig. 3) [55]. Intraepithelial neoplasias are precursors of HPV-associated malignancy at other anatomical sites, including the penis, anus, vagina and vulva. Hence, there may be a premalignant phase preceding OPC that could be targeted for screening. The most likely candidate for a screening test for oropharyngeal intraepithelial neoplasia (if it exists) is currently HPV testing. However, the odds ratios demonstrated for oral HPV16 infection and OPC (63 [30];14.6 [5]) are substantially smaller than have been reported for HPV16 in exfoliated cervical cells and cervical cancer (434.5 [12]). This may represent a limitation of the sampling technique, as poor correlations between HPV DNA in tumours and in the corresponding oral exfoliated sample have been reported. Regarding interventions that could be used in patients with a premalignant lesion, certainly for tonsillar lesions (the subsite with the strongest association with HPV infection) it would be possible to remove the lesion with a simple tonsillectomy. Treatment Testing tumour samples for HPV status is not part of routine clinical practice and currently patients with HPVpositive and -negative OPC are managed according to common treatment protocols, which may include surgery, radiotherapy (primary or postoperative) and chemoradiotherapy according to disease stage, patient fitness and local expertise. Chemoradiotherapy and surgery-based treatment strategies are both associated with significant
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acute and long-term toxicities and lifelong impairment of quality of life in survivors [51,56e58]. Given the high survival rates seen with both these approaches in HPVpositive OPC, a worthwhile goal would be to achieve these outcomes with the minimum treatment intervention. There is growing support for the view that treatment protocols for OPC should be modified according to HPV status and that de-escalation of treatment intensity may be a real possibility for patients with HPV-positive OPC. If equivalent survival rates could be achieved with less toxic treatment protocols, e.g. radiation therapy alone [48] or radiation therapy with an EGFR inhibitor [59], this could significantly improve long-term quality of life in surviving HPV-positive patients. Randomised, prospective studies, stratified for variables including smoking behaviour, are therefore urgently needed to determine the optimum management of affected patients in the future. Such studies are currently being supported by the National Cancer Research Institute Head and Neck Cancer Site Group and by the wider international community. Furthermore, patients with OPC should be stratified by HPV status in future clinical trials and the RTOG have already adopted this policy [60]. Highly accurate HPV testing methods will be required before treatment de-escalation can be safely adopted for HPV-positive patients, to minimise the risk of undertreating HPV-negative patients who may be falsely diagnosed as HPV-positive. Detection of HPV DNA by ISH and/or PCR should be combined with p16 IHC to confirm the presence of biologically relevant (i.e. transcriptionally active or ‘causative’) HPV infection. Immunological strategies directed against HPV have been widely tested in cervical cancer and similar therapeutic studies are proposed in HPV-positive OPC. A phase I study (REALISTIC) to investigate the tolerability and immunogenicity of a modified Listeria monocytogenes vaccine expressing HPV16 E7, given as an adjuvant after radical treatment of HPV-positive OPC, will start recruiting at selected UK sites in the next year. Prevention Once a viral cause of cervical cancer was established, prophylactic vaccination became a possible intervention. The pioneering work of Ian Frazer and others [61] led to the production of HPV virus-like particle vaccines, which are now in use across the developed world. These vaccines are highly effective in preventing both persistent infection and CIN in women who have not previously been exposed to HPV [62e64]. Both of the commercially available vaccines target HPV types 16 and 18, and in the UK vaccination of 12e13-year-old girls began in September 2008. Up to 95% of HPV-positive OPC are associated with HPV16 infection and so, if the vaccination programme is successful in reducing the prevalence of HPV16, it would be expected to significantly reduce the number of HPV-attributable OPC in the future, at least in females. This is, however, a very long-term prospect, and because the mean age at presentation for HPV-associated OPC is 50e55 years, it will probably be 30e40 years before the benefits of vaccination become
apparent. Furthermore, if vaccination can reduce the incidence of HPV16-related OPC, this may be used as an argument to extend the vaccination programme to include boys as well as girls in the future.
Conclusion HPV-positive OPC represents a new and emerging disease, with a different natural history and prognosis to HPV-negative OPC and other HNSCC. Patients with HPVpositive OPC are younger and are less likely to smoke and drink. They respond well to current treatment strategies but at the cost of significant long-term side-effects. Individualising patient management according to the presence of tumour-specific biomarkers is a goal for many tumour subsites and is a real possibility for patients with OPC. The results of ongoing UK clinical trials will help inform treatment decisions for this patient group in the future.
References [1] Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12e19. [2] De Vuyst H, Clifford GM, Nascimento MC, Madeleine MM, Franceschi S. Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis. Int J Cancer 2009;124:1626e1636. [3] Miralles-Guri C, Bruni L, Cubilla AL, Castellsague X, Bosch FX, de Sanjose S. Human papillomavirus prevalence and type distribution in penile carcinoma. J Clin Pathol 2009;62: 870e878. [4] Anon. Cancer Statistics: registrations series MB1. Available from: http://www.statistics.gov.uk/statbase/Product.asp?vlnk¼ 8843; 2009. Accessed 2 April 2010. [5] D’Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007;356:1944e1956. [6] Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 2005;14:467e475. [7] Nasman A, Attner P, Hammarstedt L, et al. Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma? Int J Cancer 2009;125:362e366. [8] Romanitan M, Nasman A, Ramqvist T, et al. Human papillomavirus frequency in oral and oropharyngeal cancer in Greece. Anticancer Res 2008;28:2077e2080. [9] Herrero R, Castellsague X, Pawlita M, et al. Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study. J Natl Cancer Inst 2003;95:1772e1783. [10] Begum S, Cao D, Gillison M, Zahurak M, Westra WH. Tissue distribution of human papillomavirus 16 DNA integration in patients with tonsillar carcinoma. Clin Cancer Res 2005;11: 5694e5699. [11] Anderson CE, McLaren KM, Rae F, Sanderson RJ, Cuschieri KS. Human papilloma virus in squamous carcinoma of the head and neck: a study of cases in south east Scotland. J Clin Pathol 2007;60:439e441.
M. Evans, N.G. Powell / Clinical Oncology 22 (2010) 538e546 [12] Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348:518e527. [13] Smith JS, Lindsay L, Hoots B, et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer 2007;121:621e632. [14] Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 1990;63:1129e1136. [15] Veldman T, Horikawa I, Barrett JC, Schlegel R. Transcriptional activation of the telomerase hTERT gene by human papillomavirus type 16 E6 oncoprotein. J Virol 2001;75:4467e4472. [16] Veldman T, Liu X, Yuan H, Schlegel R. Human papillomavirus E6 and Myc proteins associate in vivo and bind to and cooperatively activate the telomerase reverse transcriptase promoter. Proc Natl Acad Sci USA 2003;100:8211e8216. [17] Munger K, Baldwin A, Edwards KM, et al. Mechanisms of human papillomavirus-induced oncogenesis. J Virol 2004;78: 11451e11460. [18] Middleton K, Peh W, Southern S, et al. Organization of human papillomavirus productive cycle during neoplastic progression provides a basis for selection of diagnostic markers. J Virol 2003;77:10186e10201. [19] Chung CH, Gillison ML. Human papillomavirus in head and neck cancer: its role in pathogenesis and clinical implications. Clin Cancer Res 2009;15:6758e6762. [20] Pett M, Coleman N. Integration of high-risk human papillomavirus: a key event in cervical carcinogenesis? J Pathol 2007;212:356e367. [21] Doorbar J. Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci (Lond) 2006;110: 525e541. [22] Perry ME. The specialised structure of crypt epithelium in the human palatine tonsil and its functional significance. J Anat 1994;185(Pt 1):111e127. [23] Herrero R, Castle PE, Schiffman M, et al. Epidemiologic profile of type-specific human papillomavirus infection and cervical neoplasia in Guanacaste, Costa Rica. J Infect Dis 2005;191:1796e1807. [24] Hibbitts S, Jones J, Powell N, et al. Human papillomavirus prevalence in women attending routine cervical screening in South Wales, UK: a cross-sectional study. Br J Cancer 2008;99:1929e1933. [25] Wheeler CM, Hunt WC, Joste NE, Key CR, Quint WG, Castle PE. Human papillomavirus genotype distributions: implications for vaccination and cancer screening in the United States. J Natl Cancer Inst 2009;101:475e487. [26] Adelstein DJ, Ridge JA, Gillison ML, et al. Head and neck squamous cell cancer and the human papillomavirus: summary of a National Cancer Institute State of the Science Meeting, November 9e10, 2008, Washington, D.C. Head Neck 2009;31:1393e1422. [27] Kreimer AR, Alberg AJ, Daniel R, et al. Oral human papillomavirus infection in adults is associated with sexual behavior and HIV serostatus. J Infect Dis 2004;189:686e698. [28] Hemminki K, Dong C, Frisch M. Tonsillar and other upper aerodigestive tract cancers among cervical cancer patients and their husbands. Eur J Cancer Prev 2000;9:433e437. [29] Mork J, Lie AK, Glattre E, et al. Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 2001;344:1125e1131. [30] Hansson BG, Rosenquist K, Antonsson A, et al. Strong association between infection with human papillomavirus and oral
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
545
and oropharyngeal squamous cell carcinoma: a populationbased case-control study in southern Sweden. Acta Otolaryngol 2005;125:1337e1344. Applebaum KM, Furniss CS, Zeka A, et al. Lack of association of alcohol and tobacco with HPV16-associated head and neck cancer. J Natl Cancer Inst 2007;99:1801e1810. Samama B, Plas-Roser S, Schaeffer C, Chateau D, Fabre M, Boehm N. HPV DNA detection by in situ hybridization with catalyzed signal amplification on thin-layer cervical smears. J Histochem Cytochem 2002;50:1417e1420. Jung AC, Briolat J, Millon R, et al. Biological and clinical relevance of transcriptionally active human papillomavirus (HPV) infection in oropharynx squamous cell carcinoma. Int J Cancer 2010;126:1882e1894. Weinberger PM, Yu Z, Haffty BG, et al. Molecular classification identifies a subset of human papillomavirus-associated oropharyngeal cancers with favorable prognosis. J Clin Oncol 2006;24:736e747. Klaes R, Friedrich T, Spitkovsky D, et al. Overexpression of p16 (INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer 2001;92: 276e284. Gillison M, Harris J, Westra C, et al. Survival outcomes by tumor human papillomavirus (HPV) status in stage IIIeIV oropharyngeal cancer (OPC) in RTOG 0129. J Clin Oncol 2009;27:15s. Fakhry C, Gillison ML. Clinical implications of human papillomavirus in head and neck cancers. J Clin Oncol 2006;24: 2606e2611. Goldenberg D, Begum S, Westra WH, et al. Cystic lymph node metastasis in patients with head and neck cancer: an HPVassociated phenomenon. Head Neck 2008;30:898e903. Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000;92:709e720. Mellin H, Friesland S, Lewensohn R, Dalianis T, MunckWikland E. Human papillomavirus (HPV) DNA in tonsillar cancer: clinical correlates, risk of relapse, and survival. Int J Cancer 2000;89:300e304. Ritta M, De Andrea M, Mondini M, et al. Cell cycle and viral and immunologic profiles of head and neck squamous cell carcinoma as predictable variables of tumor progression. Head Neck 2009;31:318e327. Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008;100:261e269. Jo S, Juhasz A, Zhang K, et al. Human papillomavirus infection as a prognostic factor in oropharyngeal squamous cell carcinomas treated in a prospective phase II clinical trial. Anticancer Res 2009;29:1467e1474. Kies MS, Holsinger FC, Lee JJ, et al. Induction chemotherapy and cetuximab for locally advanced squamous cell carcinoma of the head and neck: results from a phase II prospective trial. J Clin Oncol 2010;28:8e14. Worden FP, Hooton J, Lee A, et al. Association of tobacco (T) use with risk of distant metastases (DM), tumor recurrence, and death in patients (pts) with HPV-positive (þ) squamous cell cancer of the oropharynx (SCCOP). J Clin Oncol 2009;27:15s. Kumar B, Cordell KG, Lee JS, et al. EGFR, p16, HPV Titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer. J Clin Oncol 2008;26:3128e3137. Worden FP, Kumar B, Lee JS, et al. Chemoselection as a strategy for organ preservation in advanced oropharynx
546
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
M. Evans, N.G. Powell / Clinical Oncology 22 (2010) 538e546 cancer: response and survival positively associated with HPV16 copy number. J Clin Oncol 2008;26:3138e3146. Lassen P, Eriksen JG, Hamilton-Dutoit S, Tramm T, Alsner J, Overgaard J. Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol 2009;27: 1992e1998. Lindel K, Beer KT, Laissue J, Greiner RH, Aebersold DM. Human papillomavirus positive squamous cell carcinoma of the oropharynx: a radiosensitive subgroup of head and neck carcinoma. Cancer 2001;92:805e813. Mellin Dahlstrand H, Lindquist D, Bjornestal L, et al. P16 (INK4a) correlates to human papillomavirus presence, response to radiotherapy and clinical outcome in tonsillar carcinoma. Anticancer Res 2005;25:4375e4383. Licitra L, Perrone F, Bossi P, et al. High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol 2006;24:5630e5636. Albers A, Abe K, Hunt J, et al. Antitumor activity of human papillomavirus type 16 E7-specific T cells against virally infected squamous cell carcinoma of the head and neck. Cancer Res 2005;65:11146e11155. Hoffmann TK, Arsov C, Schirlau K, et al. T cells specific for HPV16 E7 epitopes in patients with squamous cell carcinoma of the oropharynx. Int J Cancer 2006;118:1984e1991. Naucler P, Ryd W, Tornberg S, et al. Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening. J Natl Cancer Inst 2009;101: 88e99. Snijders PJ, Steenbergen RD, Heideman DA, Meijer CJ. HPVmediated cervical carcinogenesis: concepts and clinical implications. J Pathol 2006;208:152e164.
[56] Bhide SA, Miah AB, Harrington KJ, Newbold KL, Nutting CM. Radiation-induced xerostomia: pathophysiology, prevention and treatment. Clin Oncol (R Coll Radiol) 2009;21:737e744. [57] Machtay M, Moughan J, Trotti A, et al. Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis. J Clin Oncol 2008;26:3582e3589. [58] Rathmell AJ, Ash DV, Howes M, Nicholls J. Assessing quality of life in patients treated for advanced head and neck cancer. Clin Oncol (R Coll Radiol) 1991;3:10e16. [59] Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567e578. [60] Laino C. HPV-positive oropharyngeal tumours associated with better outcomes. Oncol Times 2009;31:26e29. [61] Zhou J, Sun XY, Stenzel DJ, Frazer IH. Expression of vaccinia recombinant HPV 16 L1 and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles. Virology 1991;185:251e257. [62] Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 2006;367:1247e1255. [63] Paavonen J, Jenkins D, Bosch FX, et al. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III doubleblind, randomised controlled trial. Lancet 2007;369: 2161e2170. [64] Future II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915e1927.