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Head and neck squamous cell carcinoma embraces a wide range of malignancies associated with numerous mucosal sites including, the oral cavity, nasopharynx and oropharynx.1,2 From the 1980's the role of oncogenic human papillomavirus (HPV) as a potent risk factor in HNSCC carcinogenesis has come under greater attention, with many epidemiological studies evidencing a link between HPV and cancer.3,4 Furthermore, HPV related HNSCC's have been shown to display a different molecular profile compared to that of non-HPV related cancer.5 Significantly the HPV status has been suggested as an important consideration in the selection of treatment strategies, with differences seen in prognostic outcomes between HPV positive and negative HNSCCs.4 Compared to HPV negative HNSCCs, HPV positive forms are associated with lower morbidities, increased patient survival and an overall improved prognosis despite also being diagnosed at a late stage.4,5 With a global rise in HPV related oropharyngeal small cell carcinoma (OSCC) being seen, the importance of HPV's role in HNSCC is a pertinent clinical issue that cannot be ignored. This review will aim to discuss and summarize the role of HPV in HNSCC, focusing on the molecular mechanisms of carcinogenesis and their effects on prospective treatment with radiotherapy (RT). This piece will also specifically appraise possible explanations for the prognostic differences seen between HPV positive and negative HNSCC with reference to treatment with RT and potential explanations of the relative radiosensitivity of HPV positive HNSCC. Finally, current and potential future treatment strategies will be reviewed with a focus on the possible role of p53 targeted adenoviral therapy as a future treatment modality.
1.2 Epidemiology of HNSCC
HNSCC is the 6th most prevalent malignancy in the world with approximately 650,000 new cases are identified per annum.1 In the United Kingdom HNSCC accounts for close to 16,000 diagnosed cases, with data from 2007 showing HNSCC accounted for 3.2% of new cancer cases in the United Stated.6,7 Higher incidence rates of HNSCC are generally seen in in regions of high tobacco and alcohol consumption with significant prevalence reported in India, Brazil, Europe and Hong Kong (30 per 100,000).8 Long-term observation studies have revealed that both incidence and mortality rates are changing. Currently 5 year survival rates in HNSCC are seen to vary drastically between 20% and 90% depending on the primary tumour subsites and localisation.2 In general, incidence rates for all HNSCC's when age corrected are seen to decrease.2,3 This decrease is also being reflected in morbidity and mortality rates. Evidence from the Robert-Koch-Institut have identified a 40% decrease on laryngeal carcinoma related morbidity since the 1990's, these changes have been largely attributed to lifestyle changes such as an overall fall in the number of smokers.2
1.1.3 HPV in HNSCC
Despite there being an apparent decrease in the total number of new cases of HNSCC, looking at subsite specific incidence paints a different picture, with significant increases seen in OSCC incidence rates.9,10 This finding substantiates the problem of HPV positive HNSCC, with up to 90% of OSCC cases found to be HPV positive, particularly in the palatine and lingual tonsils or tongue base. Of course HPV infection also plays a role in other sites of HNSCC malignancy with a spectrum of different HPV types seen to be involved. In total HPV infection was seen in 23% to 35% of all HNSCC's worldwide (data combined for HPV 16 and 18 infection), with HPV 16 accounting for a vast majority of HPV positive cases.11,12 Table 1 summarises the prevalence of the various HPV strains in HPV positive HNSCC and different subsites.
1.3 Risk Factors
The development of HNSCC has been widely reputed to be related to a myriad of exogenic factors of which the most commonly attributed include, smoking/tobacco use, poor diet and alcohol (see table 2 for common sites of HNSCC malignancies and associated risk factors).2,13 Smokers are reported to be 10 times more likely to develop HNSCC when compared to non-smokers, with 80% of all reported HNSCC cases attributed to tobacco use.14,15 Although identified as individual risk factors, combination of long term smoking and frequent alcohol consumption can further increase HNSCC risk.16 Alcohol itself has been found to potentiate carcinogenesis via interference of DNA synthesis and repair pathways via its metabolites.17
1.3.1 HPV as a risk factor
In 1983, Syrjanen et al first proposed that HPV also had an aetiological role in HNSCC following the detection of HPV related structural proteins in OSCC and consequently identified HPV positive HNSCCs as an independent subgroups.18 Subsequent research has deduced that infection by oncogenic HPV is a substantial risk factor, with HPV 16 identified as the dominant subtype in identified in HPV positive HNSCC.3 Further supportive evidence comes from a case control study by Furniss et al (2007), the study looked at individual serology and presence of HPV positive tumour DNA in 1000 individuals. It was found that HPV seropositivity coupled with HPV 16 tumour DNA presence was associated with HNSCC risk.19
2. HPV Mediated Oncogenesis
2.1 HPV profile and virology
HPV's include a myriad of non-enveloped double stranded DNA (dsDNA) viruses (there are more than 120 known strains), which largely infect the cutaneous epithelium and oral/anogenital region, divided into β and α groups respectively.20 The genome is circular and made up of approximately 8000 nucleotide base pairs; these encode several early and late structural genes, (E1-8 and L1-2 respectively). Functionally, the late coding genes code for the production of structural proteins, whilst the early coding regions have been identified in oncogenesis.17,21 HVP strains can be subdivided based on their oncogenic capacity into low or high risk, these are summarised in table 3. Low risk strains account mostly for more benign lesions such as genital warts of the anogenital region and cervical squamous intraepithelial lesions. High risk strains have greater oncogenic
potential than low risk HPVs. HPV 16 is the most dominant 'high risk' strain identified in HNSCC. It is also worthy to note that HPV 18, 33, 35, 45, 51, 52, 56, 58, 59 and 68 have been identified in HPV positive HNSCC, further HPV strains identified are listed in table 1 which includes both high and low risk strains.21 It should be noted that the presence of HPV DNA alone is not strictly indicative of HPV induced carcinogenesis as it also has to be transcriptionally active.2
Currently, little is known the transmission of oral HPV infection, with little knowledge of the latency period between infection and carcinogenesis.2 Risk of HPV infection has been found to comply with an individual's sexual activity, the increase in OSCC incidence may be considered in line with a populations sexual practices.2,19 Indeed as HPV is considered a causal risk factor for HNSCC, an individual's sexual habits presents a potential risk of HPV transmission and infection, and thus possibly an increased risk of HPV positive HNSCC development. This is supported by Furniss et al (2007), who found that HPV 16 seropositivity corresponded to patients' sexual history, with higher odds ratios (odds ratio=12.8) seen in patients with more than 10 oral sexual partners, compared to those with less.19 It should be stated that little is currently known of oral HPV transmission whilst, HPV's role in HNSCC still remains an on-going area of research.2
2.3 HPV mediated carcinogenesis
Although the mechanisms are still not fully understood, numerous epidemiological and molecular studies have documented and confirmed HPV as a causal oncogenic factor in HNSCC, with an identified carcinogenic model similar to cervical cancer.2,22 The most prominent signalling cascades that generally drive proliferation in HPV negative HNSCC are, epidermal growth factor receptor (EGFR), phosphatidylinositol-3-kinase-AKT-mammilian target of rapamycin (PI3K-AKT-mTOR) and Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. These proliferative pathways however may become active secondary to HPV infection.23
HPVs are able to produce a selection of oncoproteins which disrupts host cell DNA synthesis and cellular proliferation mechanisms, ultimately leading to malignant transformation and a malignant phenotype. Of the oncoproteins produced, the most significant ones identified in HNSCC carcinogenesis are E5, E6 and E7 (encoded for by E5, 6 and 7 genes respectively). The development of a malignant phenotype is preceded by viral integration of the pathogen DNA specifically involving the insertion of early genes, including E5, 6 and 7 into the host genome. Integration into the host DNA consequently inactivates the viral E2 gene.23-25 This leads to a loss of transcriptional control of oncoproteins E5, 6 and 7.2,24 The expression of E6 and 7 are also involved in creating a more suitable environment for viral replication by moving the cell into the S-phase of the cell cycle.2
E5 is involved in modulating the expression of EGFR, resulting in the inhibition of EGFR degradation, this raises EGFR mediated proliferation.25 EGFRs are transmembrane receptor tyrosine kinases and part of the ErbB family, they are activated via ligand binding of transforming growth factor α and β-cellulin. Ligand binding is followed by tyrosine kinase activation and subsequent auto-phosphorylation. This is followed by a downstream signalling cascade regulating cellular proliferation including PI3K-AKT-mTOR and Jak-STAT.23 EGFR can also function as a transcription factor by translocation to the nucleus and activating signal transducer and activator of transcription (STAT). STAT3 can also be activated by the janus kinase pathway.23,25 Another nuclear target is CCND1 gene which codes cyclin D1 a prominent factor in cell cycle progression. The EGFR pathway is an established pathway in HPV negative HNSCC carcinogenesis, however, it does appear that HPV positive HNSCC can also influence the upregulation of EGFR mediated cellular proliferation via oncoprotein E5. The resultant elevated levels of EGFR would further induce proliferative signalling cascades. It should be noted that although E5 inhibits degradation of EGFR, there is an inverse relationship between HPV and EGFR in HPV positive HNSCC.22
Oncoprotein E6 is involved in p53 degradation by directly binding the ubiquitin ligase E6AP and p53. p53 is a tumour suppressor protein encoded by the TP53 gene, and is involved in regulation of cell cycle and apoptotic pathways to prevent gene mutation following DNA damage. E6-E6AP-p53 binding results in the proteolytic degradation of p53.23 This consequently disrupts the p53 mediated pathways for cell cycle arrest and apoptosis.23,25,26 E6 also blocks pro-apoptotic pathways via human telomerase reverse transcriptase (hTERT) activation, as a result of E6/E6AP mediated NFXI degradation.2,26 Finally, E6 plays a prominent role in enhancing Ras oncogenic signalling pathways; this is due to the proteolytic degradation of PTPNI3 tumour suppressor by E6-E6AP-p53 complex.22,26
Oncoprotein E7 inhibits the tumour suppressive retinoblastoma protein (pRb), the binding of E7 with pRb induces the release of the transcription factor E2F which, activates genes that push the cell through the G1 phase of the cell cycle.27 Normally in vivo pRb inhibits the transcription of the p16 gene, subsequently E7-pRb binding will result in the upregulation of the p16 tumour suppressor protein p16INK4A in HPV positive HNSCC.22,27,28 Some studies have suggested that p16 expression may provide a powerful diagnostic marker in HPV positive HNSCC and transcriptionally active HPV infection.23,27,28 E7 also has a role in cellular proliferation via the activation of cyclin dependant kinase (CDK), and inhibition of CDK inhibitors, specifically p21 and 27. HPV mediated carcinogenic mechanisms in HNSCC are summarized in figure 1.23,27
The aforementioned mechanisms for HPV positive HNSCC can also become prominent in HPV negative HNSCCs. HPV negative HNSCCs occurring due to exposure to exogenic noxa may become infected with high risk HPV post-malignancy, however the molecular hallmarks of the tumour do not match those of HPV mediated carcinogenesis and it has been considered that the HPV infection is transcriptionally inactive, as such these tumours would be HPV positive but p53 mutated with unelevated p16, with a different prognostic outlook.22
2.4 HPV positive HNSCC and metastasis
Wittekindt et al (2012) looked at the concept of epithelial mesenchymal transition (EMT) in HPV positive HNSCC. It was witnessed that reduced E-cadherin in primary HPV positive OSCC indicating an early initiation of EMT. The results suggest that early EMT initiation in HPV positive HNSCC is a potential metastatic mechanism in HPV positive HNSCC.2,29
2.5 Molecular difference in carcinogenic mechanisms, HPV positive vs HPV negative HNSCC
Molecular carcinogenic process in HPV positive HNSCC are seen to vastly differ to the mechanisms involved in HPV negative HNSCC and even from those tumours that have been infected with HPV post-malignancy, table 2 summarises the key differences in their respective molecular profiles. In HPV positive HNSCC, the constant expression of viral oncoproteins E5, 6 and 7 facilitate the carcinogenic process, which results in the disabling of p53 and pRb.2,23 As such, these pathways are not damaged or mutated and would still retain their function were it not for the constant presence of E6 and 7.23,24 It has been shown that repression of the E6 oncoprotein recovers p53 expression and function.2 In HPV negative HNSCC, carcinogenic processes are underlined by the accumulation of mutations notably to oncogenes or tumour suppressor genes and thus the information coding for their corresponding mechanisms is lost.2,22
Both genome mutation and oncoprotein based disruption ultimately result in a malignant phenotype in HPV negative and positive HNSCC respectively.24 The molecular differences seen between carcinogenic mechanisms may provide an explanation for the superior prognosis of HPV positive HNSCC compared to HPV negative HNSCC.22,23 In HPV positive tumours, tumour suppressive and oncogenic pathways are disrupted via oncoprotein interaction while the oncoproteins are present for a prolonged period, as opposed to being permanently dysfunctional by genome mutation in HPV positive tumours.2,22,24
Epigenetic changes involve functional modifications to the genome outside of the underlying DNA sequence. Epigenetic alterations also play a role in carcinogenesis.2 Patterns of hypomethylation to the viral genome have been seen in many cases on HPV positive HNSCC, which has been found to correlate with oncoprotein expression.2 Such epigenetic changes therefore may be considered another carcinogenic factor which increases the expression of the viral genome, facilitating the development of a malignant phenotype.
2.7 The role of miRNAs in HPV positive HNSSCC
MicroRNA's (miRNAs) have been found to have a role in carcinogenesis of many cancer types including HNSCC, with different malignancies displaying diverse tissue-specific miRNA profiles.30,31 miRNAs are non-coding regulatory RNAs of between 18-25 nucleotides in length involved in mRNA translation and degeneration. Normally they are degraded however, they have a prominent role various cellular differentiation processes and can have both tumour supressing and oncogenic properties.(2) In HNSCC miRNAs have been linked to carcinogenesis, metastasis and treatment resistance, and ultimately play a role in carcinogenic processes when oncogenic miRNAs are overexpressed, accompanied by a loss of tumour suppressor miRNAs.2,30 The different carcinogenic processes of HPV positive and negative HNSCC would indicate that HPV status also has an influence on the pattern of miRNA, with HPV known to elicit widespread changes to gene expression. These cellular gene changes could be deemed partially responsible for the clinical behaviour of HPV positive HNSCC.32,33
The consideration that HPV status of a tumour can alter the miRNA profile of said tumour increases the potential complexity of the pathogenesis involved in oncogenesis. Lajer et al (2012) demonstrated that HPV positive and negative HNSCCs display distinct miRNA profiles although with some expected similarities based on tumour location (figure 2 illustrates the number of miRNAs similarly and differentially expressed in HPV positive and negative HNSCC).34 Generally, HPV DNA in cancer is largely linked to miRNA down regulation in HPV positive HNSCC. It was found that closely related HPV miRNAs are clustered, these are HPV core miRNAs and have distinctive interactions with various HPV related pathways, most notably the E6/p53 and E7/pRb pathways.34,35
Of the HPV core miRNAs, miR-15a, -16, -143, -145 and the -106-363 cluster have been identified to target cellular factors in HPV positive HNSCC oncogenesis. In HPV positive HNSCC, increased levels of miR-15a and -16 have been detected. These miRNAs are considered as tumour suppressors and are involved in the cell cycle, specifically at the G1/S checkpoints.34 It has been found that in HPV positive cancers, non- functioning Rb induces the cells resistance to miR-15a and -16 cycle arrest via an inverse relationship with cyclin D1.34,35 Upregulation of miR-363 in HP positive HNSCC is seen to be induced by HPV 16 viral oncoprotein E6, whilst the miR-106-363 cluster has been seen to induce growth of specific cancer cells.34 miR-143 and -145 have also been seen to be down regulated in HPV positive HNSCC possibly due to the HPV oncoprotein E6, and have previously been shown to repress cell growth in cervical small cell carcinoma.36 Figure 3 displays the possible relationships of HPV related miRNAs and malignant processes as described by Lajer et al (2012).34
Although unclear, it is apparent that the upregulation of oncogenic miRNAs and down regulation of tumour suppressor miRNA play a vital and highly specific role in HPV positive HNSCC. It has been widely considered in research that miRNAs present a potential therapeutic target as well as molecular marker for HPV positive HNSCCs.34 It should be noted however that current evidence of miRNAs role in HPV positive HNSCC is very limited.
3.1 Prognosis of HPV positive vs HPV negative HNSCC
With an inherent rise in HPV positive HNSCC being seen, the determination of suitable treatment strategies is vital to better improve patient survival. It is interesting to note that HPV positive HNSCC's have been found to have better prognostic values, with a more positive response to treatments than HPV negative cancers; this is despite late stage diagnosis. One study deduced an overall 5 year survival rate of 62% compared to 26% in HPV negative HNSCCs following treatment with RT.2,4,37 This prognostic pattern is seen to be independent of the treatment modality used, Fishcer et al found post-surgical 5 year survival rates of 57% and 26% for HPV positive and negative HNSCC tumours respectively.38,39 HPV positive HNSCCs are found to also have a better prognostic outcome to post-malignancy HPV positive tumours.40
The prognosis of HPV positive HNSCC can also be affected by other exogenic factors including smoking and cancer stage, thus allowing sub division of HPV positive HNSCCs. Evidence of this can be found in the RTOG 0129 study, HPV positive OSCC cases could be divided into low, intermediate and high risk. Low risk group had a smoking history of less than 10 pack years or a smoking history of greater than 10 pack years with stage N0-2a disease. The intermediate group that a pack year history greater than 10 years with higher disease progression N2b-3. Finally high risk group has a pack year history greater than 10 years and disease progression greater than N3. When comparing survival of the groups, the low risk group had the best 5 year survival when compared to the higher risk groups.41 With the knowledge of the prognostic differences seen between HPV positive and negative malignancies, it can be deemed that HPV status is a significantly important factor in HNSCC prognosis, with HPV positive HNSCCs appearing to be more receptive to treatments including RT. Additionally, HPV positive HNSCC is further effected by exogenic factors.41
4. Radiotherapy in HPV positive HNSCC
4.1 Radiosensitivity in HPV positive HNSCC
Studies have demonstrated that HPV positive HNSCC is more receptive to RT than the HPV negative variant. Lassen et al (2009) showed that HPV positive OSCC responded significantly better to RT than HPV negative OSCC, with the patients that were HPV positive displaying a better 5 year survival.37 It is therefore interesting to note that in vitro HPV positive cell lines display radioresistance to ionising radiation. Banath et al (2004) illustrated that following radiation at 2 Gy, all HPV-positive cell lines have a survival fraction greater than the analysed HPV negative line.42 Analysis of γ-H2AX foci, a marker for double strand DNA breaks showed that the HPV negative cell line with mutated p53 gene displayed the lowest level of foci when compared to the HPV positive cell lines.42 This pattern parallels to other findings looking at γ-H2AX foci in keratinocytes, where HPV oncoprotein E7 expression was concomitant with increased foci levels.42,43 In HPV positive HNSCC, oncoprotein E6 effectively binds and inactivates the tumour suppressor p53. p53 is able to modulate genes involved in cellular apoptosis, and cells with higher levels of double strand breaks will undergo apoptosis however in HPV positive cancers, blockage of p53 dependant pathways would prevent the initiation of such pro-apoptotic pathways, and the DNA strand breaks do not induce cellular apoptosis.42,44 All of this indicates that the better prognosis of HPV positive HNSCC following RT is not down to intrinsic radiosensitivity or DNA lesion formation and p53 function.
4.2 Radiotherapy and the immune system
The immune system has been implicated in HPV positive HNSCCs radiosensitivity and irradiation, playing a positive role in HPV positive HNSCC prognosis. There has been evidence that RT can modulate the immune response which in turn can enhance the common mechanism involved in HPV positive HNSCCs better prognosis.23 Spanos et al (2009) deduced that radiation and chemotherapeutic agents (cisplatin) are able to induce an immune response. The study showed that in vivo HPV positive HNSCC cell lines were more radiosensitive than the HPV negative counterparts however; RT was unable to eradicate cancer cells in immune-incompetent mice. It was found that by transferring wild-type immune cells into the immune-incompetent rats, HPV positive tumours were able to respond well to RT and cisplatin.45
The presence of viral proteins in HPV positive tumours may trigger and HPV specific immune response. It has been suggested that radiation induced damage by RT may enhance antigen presentation and HPV specific immune response.45 It is interesting to note that the heightened immune response may even confer an immunity to future HPV positive HNSCC development. The same study by Spanos et al (2009) found that it was not possible to reinstate HPV positive tumours in mice that had been cleared of a previous HPV positive tumour.45 This finding provides a possible explanation of why patients in remission from HPV positive HNSCC do not suffer a recurrence of the tumour.2,45 It must be noted however, that this hypothesis does not explain the better post-surgical prognosis seen HPV positive HNSCC.
4.2.1 Implications for treatment with radiotherapy
The notion that an immune response plays a pivotal role in increasing radiosensitivity could suggests a need for novel treatment modalities to better tackle the growing problem of HPV positive HNSCC. Indeed this notion also transfers to other HPV positive cancers. Evidence that RT was found to clear a large bulk of HPV positive tumours in mice models45, may suggest that RT could be a mainstay treatment modality however further study needs to be carried out on this. The prospective enhancing role of the immune system also suggests that immunosuppressed patients may have a poorer response to RT for treatment of HPV positive HNSCC. It is also vital to consider whether adjunct therapy with a chemotherapeutic agent may have a limiting effect on RT efficacy, due to subsequent immune suppression.45 Enhancing immune response via blood transfusion prior to and during RT may be considered a viable method of further increasing treatment efficacy and survival outcomes for patients with HPV positive HNSCC however, studies reviewing this have seen little improvement. Thw DAHAHCA trials by Hof et al (2011) found that transfusion may even have a negative impact on patient survival.46 Other potential methods to enhance the immune system may prove more successful however, this is currently only a potential area of research.
Most cases of HNSCC are treated with combination chemo-radiotherapy however; both chemotherapeutic agents and radiation are noxious with high levels of toxicity seen in patients. As patients with HPV positive HNSCC respond better to RT than those patients with HPV negative HNSCC, there is a reason to suggest that RT could be used independently to treat 'low risk' HPV positive HNSCC cases as categorised by Ang et al (2010). Furthermore, treatment could be de-intensified to lower toxicity in 'high risk' HPV positive HNSCCs without effecting treatment efficacy and patient survival outcomes.41,47 In relation to this, it has been found that at least for stage IV HPV positive HNSCC, treatment with standalone RT resulted in a fall in patient survival but control rates of the tumours were comparable with combined chemo-radiotherapy.47
4. Current and prospective clinical therapies
4.1 Current therapies
As it stands treatment for HNSCC is standard for both HPV positive and negative HNSCCs including surgery followed by combination chemo-radiotherapy (usually cisplatin with RT at 2Gy doses). Numerous molecular targeting therapies are under research for HPV negative HNSCC, and in many cases due to differences in carcinogenic mechanisms these therapies are largely inapplicable to treatment of HPV positive tumours.2,23,47 One possible exception is the use of Cetuximab (Erbitux®) with is an antagonist of EGFR.48 Based on current knowledge of the carcinogenic mechanisms involved in HPV positive HNSCC, it is possible that Cetuximab may have a potential action in nullifying the action of the oncoprotein E5 thereby blocking EGFR mediated proliferative pathways.48 Of course this does not account for the actions of E6 and 7 and thus any potential therapeutic effects may be limited.
4.2 HPV vaccination as a prophylactic measure in HNSCC
HPV vaccination is not a recent concept and is already a used prophylactic for cervical cancer. Due to the known role of HPV in certain types of HNSCC, it is highly viable to suggest vaccination as a prophylaxis for HPV positive HNSCC although little is still known about the progression from pre-cancerous to post cancerous stage. With HPV vaccination still in its infancy and largely restricted to women, it will take time before data can be gathered on the efficacy of HPV positive HNSCC prevention due to the time taken to potentially develop HNSCC following HPC exposure. Studies will also need to be carried to access the potential role for HPV in men.49
4.3 p53 adenoviral therapy
Within HPV positive HNSCC, p53 is degenerated via oncoprotein E6 binding, consequently corresponding mechanisms of apoptosis are disrupted. This presents a potential target for adenoviral therapy to reinstate p53 function and improve treatment outcomes especially when combined with either chemotherapy of radiotherapy.50 The process involves the use of a viral vector to insert a wild-type p53 gene into tumours with inactive p53 or mutated TP53 gene, where transcription of the gene can re-establish p53 function supressing tumour growth via p53 mediated apoptotic pathways.51
Many preclinical models have shown p53 adenoviral therapy to be efficacious against a wide range of malignancies with non-functional p53.50-52 As a result p53 adenoviral therapy has been moved into Phase I/II trial, with overall safety and p53 adenovirus tolerance seen. Studies have looked at this further and factored in combination of p53 with chemotherapy or radiotherapy, findings have proved largely positive. One such study by Gurnani et al (1999) found that combined p53 adenoviral therapy and chemotherapeutic agent (cisplatin, doxorubicin, 5-fluorouracil, methotrexate or etoposide) were more effective in preventing cellular proliferation in many cancer types including HNSCC, than chemotherapy or p53 alone.50
Adenoviral p53 therapy has also been study in the context of and adjuvant in surgery of HNSCCs. A phase I clinical trial by Clayman et al (1999), provided preliminary support for adenoviral p53 use as an adjuvant in surgery with minimal to no adenoviral related complications.53 The apparent success of p53 adenoviral therapy in cancer therapeutics, validates its potential in the treatment of all HNSCC types as a novel intervention strategy.
HPV positive HNSCC is a highly complex and multifactorial clinical issue. Through this review it can be recognised that many aspects regarding carcinogenesis have been identified, however there is still much to understand and explain. With respect to the carcinogenic processes, oncoprotein expression is seen to mediate many tumour suppressive and proliferative pathways however, it is still poorly defined whether different strains of HPV will have different molecular markers or carcinogenic profiles.
The biggest implications of our growing understanding of HPV positive HNSCC will be with respect to classification and therapy. Currently HNSCCs are all treated similarly, however studies have implied that subdivisions and classifications need to be made based on HPV status as carcinogenic profiles have an effect on treatment efficacy and overall disease prognosis, such as with respect RT. Another area of treatment that is increasingly clinically relevant is p53 adenoviral therapy which has proved successful in vitro. With combination p53 and chemo/radiotherapy in clinical trials this is very likely to have a prolific role in HNSCC treatment of both HPV positive and negative strains. The knowledge currently available does open the door to further therapeutic developments in HNSCC screening processes, prophylaxis and targeted molecular therapies. It is interesting to consider that HPV positive HNSCC due to its distinct pathogenicity and prognostic properties has the potential to be eradicated as a clinical issue in the future.