Human papillomavirus-related oropharyngeal carcinoma Free

Abstract

Human papillomavirus-related oropharyngeal carcinoma (HPV-OPSCC)

Kiyabu et al.’s study published in 1989 was the earliest paper among the PubMed hits for human papillomavirus (HPV)-related oropharyngeal carcinoma (OPSCC) (1), which reported that HPV DNA was detected in 9 (36%) of 25 paraffin-embedded oropharyngeal carcinoma tissue sections. In 2001, Mork et al. reported a 2.2-fold increase in the risk of oropharyngeal carcinogenesis in a cohort with positive HPV-16 antibody titer (2), and HPV-induced oropharyngeal carcinogenesis became widely known. HPV-positive cancers were reported to be more common in the oropharyngeal subsite, with less history of alcohol consumption and smoking and less frequent TP53 gene mutation but higher recurrence-free survival (RFS) rate compared with HPV-negative cancers (3). In a case-control study of HPV-OPSCC, the lifetime numbers of sexual partners and oral sex partners were identified as risk factors (4). In addition to these patient background factors, differential treatment response has received considerable attention, and the clinical importance of HPV-OPSCC has been established with the publication of Ang et al.’s secondary analysis of RTOG0129 reporting that HPV positivity and smoking history can be used to stratify patient prognosis (5). Since this report, several papers on HPV-OPSCC have been published, and as of August 2021, the standard treatment for HPV-OPSCC is concurrent chemoradiotherapy (CRT) with high-dose cisplatin (CDDP).

Molecular mechanisms underlying HPV-related head and neck carcinoma

The HPV carcinogenicity model for head and neck cancer was developed based on earlier studies on cervical cancers, demonstrating that persistent high-risk HPV infection increased the likelihood of viral integration into the host chromosome (6,7). HPV DNA integration into the human genome is also speculated as an important step in oropharyngeal carcinogenesis (8). In cervical cancer (9), the linearization of the circular HPV genome before integration usually occurs with disruption of viral E2 sequence, resulting in a defective virus. Importantly, the loss of E2 expression prevents promoter repression for the expression of E6 and E7 oncogenes, resulting in their induction. In head and neck cancer, the relationship between physical state and HPV integration may be more complex, and tumors with episomal HPV, regardless of the presence or absence of integration sites, overexpress HPV E2, E4 and E5 genes (10–12).

The E6 protein interacts with different host proteins responsible for cell proliferation, with their interactions inducing the degradation of critical cellular partners that inhibit cell growth. A particularly critical target of E6 in head and neck cancer is the tumor suppressor protein p53 (13). E6 interactions inhibit p53-mediated apoptosis, G1/S checkpoints and DNA damage repair, eventually resulting in chromosomal instability.

The high-risk HPV E7 protein also interacts with several host cellular proteins and separately contributes to cellular proliferation. Most importantly, the interaction of E7 protein with the tumor suppressor protein pRb results in its hyperphosphorylation and ubiquitin-mediated degradation (14). This leads to the release of E2F from pRb/E2F complexes, thereby promoting the transactivation of S-phase gene expression. The inactivation of pRb leads to histone acetylation and p16/CDKN2A upregulation, which is vital for cell cycle progression and is a common surrogate biomarker for HPV carcinogenesis (15).

HPV-OPSCC evaluation in clinical practice

HPV detection is performed in the laboratory via PCR or in situ hybridization (ISH) using tissue DNA or RNA. As mentioned previously, E7-induced overexpression of p16 protein in HPV-OPSCC is known, and the sensitivity and specificity of p16 positivity have been reported to be 90 and 70%, respectively (16). In 2017, the tumor–node–metastasis (TNM) classification for HPV-OPSCC was revised as a patient with at least 75% p16- or ISH-HPV-positive tumors, as a substitute for HPV nucleic acid testing in patient populations with an increased prevalence of HPV-OPSCC (17).

Due to the high sensitivity of p16 positivity, a 3-class model was suggested based on HPV-DNA/RNA and p16 status: Class I (HPV-negative/p16-negative), Class II (HPV-negative/p16-positive) and Class III (HPV-positive/p16-positive). Class III is associated with the most favorable survival outcome compared with Class I. HPV-negative/p16-positive patients, according to the TCGA dataset, have survival characteristics similar to HPV-positive/p16-positive patients and significantly better survival outcomes than HPV-negative/p16-negative patients (18). Even in clinical trials, HPV-OPSCC is mostly defined as p16-positive carcinoma, except in some trials with HPV-specific therapeutic agents.

Prognostic factors of HPV-OPSCC

A previous report on the subgroup analysis of RTOG1015 determined that HPV-OPSCC has a good prognosis (5). Ang et al. reported that patients with HPV-OPSCC who were smokers of ≥10 pack-years and had N2b or higher grade were at intermediate-risk. Since this report was published, smoking has been widely recognized as an important prognostic factor in HPV-OPSCC. Vainstein et al. (19) reported that among patients with HPV-OPSCC, T4 grade was the predominant risk factor for local recurrence. Huang et al. (20) reported that N2c is also a risk factor for distant metastasis, and Spector et al. (21) reported that fused metastatic nodes (matted nodes) are a risk factor. The ICON-S study reported a consolidated analysis from major centers in 2016 (22). A total of 1907 patients were analyzed, a new stage classification was proposed, and the stage classification in this report is almost the same as that in the revised TNM 8^th edition published in 2017. The treatment intensity should not be adjusted according to stages as most of the patients enrolled in this report were treated with CRT. In 2018, in a retrospective study of patients treated with curative CRT, Deschuymer et al. (23) proposed a new risk group classification for patients with HPV-OPSCC based on TNM 8^th edition, i.e. comorbidity and smoking pack-years. The authors found no differences in the overall survival (OS) between those with N2 and N3 classification nor between those with T3 and T4 classification. They identified a low-risk group of patients, defined as Stage I, comprising never smokers or smokers with <10 pack-years and few comorbidities, showing excellent prognosis. The current literature suggests a worse prognosis for p16-positive smokers compared with nonsmokers when treated with nonsurgical therapy.

Transoral surgery for HPV-OPSCC

HPV-OPSCC has a particularly good prognosis and is more common in younger patients than classic head and neck cancers. This has led to the use of minimally invasive surgery based on transoral robotic surgery (TORS) using the da Vinci platform, initially developed at the University of Pennsylvania (24), for the treatment of HPV-OPSCC. In 2009, the Food and Drug Administration approved TORS exclusively for benign and malignant tumors classified as T1 and T2.

Given the ability of minimally invasive tumoral resection, three-dimensional view of the surgical field, intraoperative margin control and future possibility of de-escalated adjuvant therapies, TORS appears to be an optimal treatment option for the treatment of HPV-OPSCC (25). The approaches for minimally invasive head and neck surgery, such as TORS, are based on maximizing exposure while minimizing morbidity. Preoperatively, exposure details must be addressed to select the right candidates for TORS. These factors are referred to as the 8Ts of endoscopic access: teeth, trismus, transverse dimensions (mandibular), tori, tongue, tilt, treatment (prior radiation) and tumor (26). Weinstein et al. (27) identified the contraindications for TORS, and patients with these contraindications are not candidates for this treatment. The contraindications for TORS can be summarized into vascular (closeness to the carotid or both lingual arteries in midline tongue base cancer), functional (resection includes >50% of the deep tongue base musculature, 50% of the posterior pharyngeal wall and up to 50% of the tongue base and the entire epiglottis), oncological (trismus, unresectable neck disease and multiple distant metastases) and non-oncological (medical comorbidities, non-cancer–related trismus, unacceptable morbidity and cervical spine diseases that interfere with patient positioning). Despite these contraindications, a multicenter study of 410 patients who underwent TORS (28) reported an excellent 2-year local control rate of 91.8%, a disease-specific survival (DSS) rate of 94.5%, and a crude survival rate of 91%. In this report, 47.3% (160/338) of patients did not receive any postoperative treatment, 31.4% (106/338) received postoperative RT and 21.3% (72/338) received postoperative CRT. In a recent study, published in 2020 by Roden et al. (29), smoking did not appear to affect the RFS, OS and DSS in 258 patients treated with TORS, followed by adjuvant therapy. Ryan et al. (30) reported on 344 patients with HPV-OPSCC treated via surgery alone from 12 centers and concluded that those diagnosed with HPV-OPSCC according to AJCC 7^th edition pT0-T2N0-N2b with pathological metastatic lymph node grades of 0–3, no perineural invasion, no extranodal lymph node extension and negative margins could be treated with surgery alone.

Clinical trials for HPV-OPSCC

Various clinical trials have been conducted to develop therapies to reduce the intensity of HPV-OPSCC treatment, particularly for the low-risk group (Table 1).

The approach of replacing cisplatin with cetuximab in CRT for HPV-OPSCC was initially attempted. However, the results of the RTOG1016 (31) and DeESCaLaTE (32) trials were reported in 2019, revealing that cetuximab showed no benefits in terms of reduced toxicity and resulted in inferior OS and progression-free survival (PFS) compared with standard cisplatin. Recently, the results of the TROG12.01 trial (33) in Australia revealed that cetuximab is inferior to weekly cisplatin for treating low-risk HPV-OPSCC.

Several clinical trials reported on reducing treatment intensity. ECOG-ACRIN 3311 is one of the most recent clinical trials. This study included 515 patients who underwent transoral resection and were divided into three groups: low-, intermediate- and high-risk. The low-risk group (≤1 metastasis and pT1-2) received no adjuvant treatment, the intermediate-risk group was randomly administered 50 Gy/25 fr and 60 Gy/30 fr and the high-risk group (positive margins, extranodal extension and >5 nodes) received postoperative CRT (34). Although the final analysis has not yet been reported, the 3-year survival results presented at American Society of clinical oncology in 2021 were equivalent for treatment with 50 Gy/25 fr and 60 Gy/30 fr (94.9 and 93.5%, respectively). Hence, the development of treatments with reduced radiation dose for additional postoperative therapy in the intermediate-risk group is expected in the future. The PATHOS trial, a Phase II/III trial that aimed to involve 1100 patients, was a randomized trial for treatment with 50 Gy/25 fr and 60 Gy/30 fr in the intermediate-risk group after transoral resection and 60 Gy CRT and with 60 Gy RT alone in the high-risk group (35). The benefits of lowering the treatment intensity are expected to improve the functional outcomes, and both of the abovementioned trials have evidenced this. However, the ORATOR trial, a small Phase II trial, reported contradictory results (36). This randomized trial on 68 patients compared the quality of life (QOL) between those who had undergone CRT and those who had undergone TORS (plus postoperative treatment). The study used the MDADI QOL score as an endpoint, and although it is necessary to consider that 24 of 34 patients received postoperative treatment, the CRT group significantly outperformed the surgical group, showing MDADI score of 86.9 and 80.1 in the CRT and surgical groups, respectively.

Clinical trials on radiation dose reduction have also been performed. A Phase II study on CDDP-RT 60 Gy with weekly CDDP of 30 mg/m² in 114 patients with HPV-OPSCC having low smoking history was reported by Chera et al. (37). This study reported a 2-year PFS and local control rate of 86 and 95%, respectively (37). Similarly, the results of the NRG HN-002 trial, a Phase II randomized trial on 308 patients with low-risk HPV-OPSCC treated with 60 Gy RT alone or 60 Gy CDDP-RT with weekly CDDP 40 mg/m², were recently reported (38). This trial reported 2-year PFS of 90.5 and 87.6% in the CRT and RT groups. Based on these findings, the NRG-HN005 trial has been planned, which is a Phase III study investigating a combination of reduced radiation dose and immune checkpoint inhibitors (NCT03952585). Furthermore, the Sloan Kettering Cancer Center reported on the 30 ROC trial (39), in which FMISO-PET was used to estimate the hypoxic status of the tumor and treatment was performed with a dose as low as 30 Gy. In this trial, 15 out of 19 patients could be treated with 30 Gy, resulting in a 2-year survival rate of 94.7%. Patients with HPV-OPSCC who responded to de-escalated chemoradiotherapy were found to have enrichment in deletions with microhomology. Thus, the response of patients with HPV-OPSCC to chemoradiotherapy may depend on the type of genetic instability and/or DNA-repair defects in the tumor.

A review by Mehannna et al. (40) is very informative in terms of administering a new treatment for HPV-OPSCC. They argued that a 5% survival difference in treatment outcome is generally unacceptable for patients with carcinomas. As for patient selection, de-escalation is not desirable in patients with high-risk T4, N3 and heavy smoking history. Moreover, reflecting the favorable prognosis of the disease, the RTOG1016 trial showed the dissociation of PFS after 6 months and OS after >1 year. They concluded that a study with a very large sample size is warranted and that a randomized Phase II study should be conducted before proceeding to a Phase III study. In conclusion, it is challenging to plan a clinical trial with reduced treatment intensity for a disease with a good prognosis.

HPV-OPSCC prevention

HPV is the cause of carcinogenesis associated with HPV-OPSCC. Therefore, HPV-OPSCC can be considered preventable cancer. In public health, cancer prevention strategies are often divided into primary, secondary and tertiary.

HPV is assumed to be transmitted through sexual contact via saliva. A report that examined the sexual behavior of patients with HPV-OPSCC (41) found that the risk factors for the occurrence of HPV-OPSCC included oral sex and the age when it began, the number of sexual partners, having an extramarital partner and being with a partner older than 10 years. The incidence of HPV-OPSCC has been increasing in Caucasian males born in 1930 and is expected to increase over the next decade, particularly in those aged 60–70 years (42). The increased incidence of HPV-OPSCC is more pronounced than that of other carcinomas in the USA, which is projected to surpass that of lung and prostate carcinomas by 2045 in Caucasian men aged 55–69 years (43). This highlights the importance of primary prevention strategies to eliminate cancer-causing factors, such as HPV, by preventing infection through vaccination.

At present, bivalent, quadrivalent and nine-valent HPV vaccines have been developed, all of which confer immunity against HPV-16, the cause of 90% of cases of HPV-OPSCC. However, no reports have revealed that the HPV vaccine reduces the mortality or morbidity associated with HPV-OPSCC. Nevertheless, in recent years, HPV vaccination has been reported to reduce the rate of oral HPV infection. In Berenson et al.’s study (44) that examined the effects of vaccines on oral HPV infection, the oral HPV infection rate decreased from 7.2 to 4.2% in the vaccinated group. The oral HPV infection rate was higher in men, and the vaccine was not effective in preventing infection with the indicated HPV types. Therefore, they concluded that vaccination for men before the onset of sexual activity is desirable. Furthermore, current HPV vaccines aim to prevent infection and HPV-OPSCC, which typically manifests several decades after HPV infection (45). Hence, vaccination should be performed before engaging in sexual practices. However, at present, primary prevention in adult men is considered difficult. HPV vaccines are extremely effective and indispensable for preventing HPV-related carcinomas and HPV-OPSCC in the next generation.

From a different perspective, tonsillectomy has been reported to prevent HPV-OPSCC. A Danish registry study (46) proposed an association between the decreased incidence of tonsillectomy and increased incidence of oropharyngeal carcinoma. This interesting report showed that prior tonsillectomy correlated with OPSCC prognosis. However, prior tonsillectomy was not correlated with the occurrence or prognosis of base of tongue carcinoma.

As for the secondary prevention of HPV-OPSCC, early diagnosis and treatment in individuals with HPV infection detected in the saliva or blood are recommended; however, considering the current morbidity of HPV-OPSCC and the sensitivity and specificity of HPV detection tests, achieving efficient secondary prevention is challenging. In a cohort study in the USA (47), 6 of 533 patients were HPV antibody-positive and 41 were HPV-16-positive. These 47 patients were followed up: 1 patient was found to have HPV-OPSCC and 2 had HPV-related anal lesions. In a cohort study in Australia (48), among 665 patients, 12 (1.8%) were found to have oral HPV-16 infection, 9 were followed up and 3 who remained HPV-positive for >30 months were closely examined. In one of the patients, a small HPV-OPSCC of 2 mm was detected after tonsillectomy.

HPV-OPSCC in Japan

Among studies related to HPV-OPSCC in Japan, a study by Mineta et al. on the detection of HPV-16 and HPV-18 is the earliest article that can be found in PubMed (49). In their report, 23% (23 out of 98) of patients with head and neck carcinomas and 38% (5 out of 13) of those with oropharyngeal carcinomas were PCR-positive for HPV-16. Subsequently, following the publication of the aforementioned reports from Europe and the USA, several reports on oropharyngeal carcinoma and HPV were published in 2011. In a study in Okinawa conducted by Deng et al. (50), the HPV positivity rate was reported to be ~50%. Although there is variation among institutions in the reported HPV positivity rate among those with oropharyngeal carcinoma in Japan, Hama et al. (51) reported an HPV-PCR positivity rate of 50.3% (79/157 patients with OPSCC) in their multicenter study conducted in 2014. Recently, according to the 2018 National Head and Neck Cancer Registry in Japan, the p16 positivity rate was 60% in patients with OPSCC, indicating an increasing trend of HPV-OPSCC in Japan.

The prognostic value of p16 for HPV-OPSCC was reported by Saito et al. in 2013 (52), whereas Mizumachi et al. reported on the prognostic value of HPV-16 positivity (53). In Japan, HPV factors associated with oropharyngeal carcinoma have been investigated previously. As a registry study on HPV-OPSCC in Japan, the results of the AMED-HPV study conducted by Yane, Nibu et al. (54) were recently reported: a multicenter study with a backward analysis of 688 treated patients, which reported that the TNM classification revised in 2018 defines the prognosis—T1-2N0 indicates good prognosis with radiotherapy alone, and lower doses of cisplatin might have efficacy equivalent to the standard dose. However, a prospective comparison should be conducted to investigate and validate this in detail.

The HPV vaccination rate in Japan is poor because the Ministry of Health, Labour and Welfare does not actively recommend vaccination owing to media reports of adverse reactions in 2013. A report also revealed that the vaccination rate is dramatically decreasing among women born in 2000 (55). Unfortunately, due to the declined vaccination rates, cases of HPV-related carcinomas are expected to increase in Japan in the future. Wu et al. predicted the future incidence of HPV-related carcinomas in 45 countries. Although a downward trend is expected in most countries, the incidence of HPV-related carcinomas is expected to increase not only in Japan (56) but also in Uganda, Costa Rica, Italy, the UK and the Netherlands. Cho et al. reported (57) that the HPV positivity rate in the oral gargle of healthy Japanese individuals is 5.7%, a rate comparable with that in American individuals. Considering these results, an increase in the incidence of HPV-OPSCC is predicted in the future.

Primary prevention, vaccination; secondary prevention, the establishment of screening methods; and tertiary prevention, the establishment of minimally invasive treatment, are urgently needed for HPV-OPSCC.

Conclusion

In this review, we described the history, treatment, clinical trials and prevention of HPV-OPSCC. The current standard of care for this disease is RT with CDDP and surgery. We believe that surgical treatment is best indicated for patients eligible for CDDP-RT when postoperative adjuvant therapy can be omitted, i.e. patients with pathological Stage I disease, negative margins and negative extranodal extension of lymph node metastasis. HPV-OPSCC prevention is urgently needed in Japan, where the HPV vaccination rate is low and the possibility of an increase in the incidence of HPV-OPSCC is high. Thus, the development of less-invasive treatment methods for HPV-OPSCC with promising prognosis is warranted.

Acknowledgments

The authors thank the Japan Clinical Oncology Group Head and Neck Cancer Study Group.

Funding

This study was partially supported by a National Cancer Center Research and Development grant (2020-J-3).

Conflict of Interest

The authors declare no conflicts of interest.

References