5. Early detection, prevention – Oropharyngeal and Hypopharyngeal Carcinoma

The Standing Committee on Vaccination (STIKO) recommends vaccination against HPV for boys aged 9 to 14 years. The recommendation was published together with the scientific justification for this decision in Epidemiological Bulletin 26/2018. The STIKO has recommended HPV vaccination for girls since 2007. The aim of HPV vaccination for girls and boys is to reduce the burden of disease caused by HPV-associated tumours. The results of the systematic review on the efficacy and safety of HPV vaccination in boys and men are presented in tabular form in the appendix (detailed scientific justification: [62][63]).

According to the fact sheets of the STIKO and the current vaccination recommendations from the RKI, the following applies: HPV infects both women and men, often during the first sexual contact. HPV-related cervical cancer mainly affects younger women between the ages of 35 and 59. In men, HPV mainly causes tumours in the throat, genital and anal areas. Complete vaccination protection can only be achieved if there has been no persistent infection with the HPV types contained in the vaccine prior to vaccination. For this reason, the vaccination should ideally be carried out before the first sexual contact. In Germany, 6% of girls and 3% of boys stated that they were 14 years old or younger at the time of their first sexual intercourse, while 82% of 18-year-old girls and 69% of 18-year-old boys are sexually active. Even after their first sexual experience or first intercourse, unvaccinated girls or boys can and should still be vaccinated against HPV. Even if a possible persistent HPV infection has already occurred, the vaccination can still provide protection against the other HPV types contained in the vaccine. The earlier the vaccination is given, the better. Various studies from a number of countries have shown that the HPV vaccination has no influence on the sexual behaviour of vaccinated people. Compared to unvaccinated people, vaccinated girls or women in these studies did not have sexual intercourse with a greater number of partners earlier as a result of knowing about their HPV vaccination, nor did they consciously refrain from using condoms.

Since the vaccination was approved, more than 270 million doses have been administered worldwide. Both before and after approval, the safety of the HPV vaccination was investigated in various extensive studies. No serious side effects, i.e. side effects that have a lasting negative impact on health, were found in causal connection with the HPV vaccination. In particular, the studies showed no connection with autoimmune diseases or neurological complications. Side effects such as headaches, dizziness or fatigue are common and can also occur in a severe form. However, these are temporary and completely reversible. As with other vaccinations, anaphylaxis can occur in very rare cases (approximately 1.7 cases per 1 million vaccinations). The Paul Ehrlich Institute, which is responsible for the safety of vaccines in Germany, has published further information on its website (www.pei.de).

Based on the current vaccination rate (44.6%), model calculations show that HPV vaccination of girls could reduce the incidence of cervical cancer in Germany by more than half over the next 100 years

(163,000 fewer cases). If a comparable vaccination level is achieved for boys, more than 76,000 additional cases of HPV-related cancer in women and men can be prevented. By vaccinating both sexes against HPV, women and men can also protect their respective partners against HPV-related cancers.

Two inactivated HPV vaccines are currently licensed in Germany: the bivalent HPV vaccine Cervarix® and the nine-valent vaccine Gardasil®9. Gardasil®9 offers additional protection against HPV types that are responsible for around 90% of genital warts. Both vaccines are recommended for vaccination against HPV.

Vaccination schedule

• 9 to 14 years: 2 doses at least 5 months apart (3 doses are required if the interval is shorter)
• 15 years and older: Cervarix^®: 0 - 1 - 6 months, Gardasil^®9: 0 - 2 - 6 months

According to the current information for healthcare professionals, there are contraindications: Cervarix® and Gardasil®9 should not be used in case of hypersensitivity to the active substances contained in the respective vaccine or other vaccine components mentioned in the information for healthcare professionals. In addition, persons with hypersensitivity should not receive another dose of Gardasil®9 after previous administration of Gardasil®9 or Gardasil®(quadrivalent). In the case of an existing pregnancy, vaccination against HPV should be postponed.

No booster vaccination is currently recommended (RKI, HPV vaccination). In a systematic review conducted by the RKI in collaboration with the STIKO HPV working group in 2014 on the evidence for the duration of the protective effect of the HPV vaccination against types 16 and 18 in girls and women, there was no evidence of a decrease in vaccination protection over time. The data in the systematic review referred to 1 or 2 RCTs with a follow-up period of ≥ 5 years after basic immunization and the investigated outcomes including the incidence of HPV infections, persistent HPV infections and CIN II+ lesions. According to the GRADE methodology, the quality of the evidence was assessed as "very low". Furthermore, one study showed that HPV 16 and HPV 18 antibody responses are higher after vaccination with the two- or four-valent vaccine over several years than after an immune response following natural infection. In addition, the HPV 16 and HPV 18 antibody responses increase again significantly if a booster vaccination is administered several years after completion of the basic immunization. It can be assumed that HPV vaccination in boys and men has a duration of protection comparable to that in girls and women [63].

In general, the HPV vaccination rate in Germany is too low. In Germany, the nationwide rate for a complete HPV vaccination series with two vaccine doses among 15-year-old girls at the end of 2019 was 47.2% and among 15-year-old boys 5.1% (RKI 2022). Intensive and effective vaccination programs are necessary.

Therapeutic benefit of vaccination after the occurrence of HPV-associated oropharyngeal cancer:

Countrywide, some physicians vaccinate with inactivated vaccine after the occurrence of HPV-associated oropharyngeal carcinoma with reference to the individualized recommendations of this vaccination in cervical carcinoma. However, this vaccination for cervical carcinoma is also controversial and is sometimes only recommended to prevent recurrences of precursor lesions.

The S3-LL "Vaccination prevention of HPV-associated neoplasia" explicitly does not recommend this vaccination. Recommendation 09-10: Consensus-based recommendations state: "HPV vaccination with the aim of therapeutic benefit in the treatment of existing HPV-associated lesions should not be performed", and "In HPV-vaccine-naïve women with cervical intraepithelial neoplasia (CIN), HPV vaccination may be considered before or after treatment of CIN with the aim of reducing the recurrence rate" [64][65]. As there is no evidence to date for the possible effectiveness of vaccination with the same intention in manifest oropharyngeal carcinoma, no vaccination recommendation is made in analogy to the recommendation for cervical carcinoma. [64]

Any biomarker used for the early detection of OPSCC, especially HPV16-driven OPSCCs in the normal population, would therefore have to have a specificity of approximately 100% in order not to generate many more false-positive than true-positive test results, the ratio of which can be expressed as the positive predictive value (PPV). Even with a sensitivity of 100% (all patients are identified as such), a test with 99% specificity generates one (n=1) false-positive test result in 100 individuals tested. If 100,000 tests were carried out, this would result in 1,000 positive test results, of which, however, a maximum of 10 can be true-positive due to the rarity of the disease (approximately 10/100,000), i.e. there would be approximately 100 times more false-positive than true-positive test results, or a PPV of 1%. Such a test is unacceptable due to the associated psychological stress for those tested false-positive, and not cost-effective due to the diagnostic follow-up costs of all those tested positive. These correlations and fundamental implications for the screening of OPSCC were presented and discussed in detail at [66].

In contrast to cervical carcinoma, the location of the primary HPV infection in the head and neck area is unknown and therefore cannot be specifically sampled. There are no described precursor lesions for HPV-OPSCC that would be clinically detectable and thus represent an endpoint for a screening procedure. The early detection of small tumours in asymptomatic patients with the aid of various HPV biomarkers therefore appears feasible at best, with the aim of improving treatment morbidity and thus post-therapeutic quality of life.

Brush cytologies of the palatine tonsils and the base of the tongue are poorly tolerated in awake individuals [67]and are not very sensitive due to poor access to the tonsillar crypts where the tumours often arise [68]. Mouth and throat rinse samples have been used in various studies for the detection of oral HPV infections [D'Souza, G et al. 2007] [69] [56], but even in incident HPV-positive OPSCC patients they only show a sensitivity of approximately 50% [70] or have proven to be insufficiently sensitive for use outside of studies [71]. In addition, there is little data to suggest that the development of HPV-positive OPSCC can be predicted by measuring oral HPV DNA [D'Souza, G et al. 2007].

Antibodies against early HPV16 proteins, in particular oncoprotein E6 (and to a lesser extent E2), on the other hand, are very sensitive (approximately 90%) and specific (approximately 99%) markers for HPV16-positive OPC at the time of diagnosis [72], and can be measured years to decades before diagnosis [73][3][Kreimer, AR et al. 2019]. They are being actively investigated in various studies as early detection markers [Robbins, HA et al. 2022][76]. It is important to differentiate between antibodies against viral proteins that are expressed early ("early", E) or late ("late", L) during the viral replication cycle, as the latter, in particular antibodies against the main capsid protein L1, also occur in natural HPV infection and HPV vaccination, and are therefore completely unsuitable for HPV-OPSCC prediction [77].

A "liquid biopsy", i.e. the detection of cell-free or circulating HPV DNA (cfDNA, ctDNA) from peripheral blood or plasma using droplet digital PCR (ddPCR) or next generation sequencing (NGS), is very sensitive [78], but the prognostic value cannot yet be estimated well due to the currently insufficient data available [79].

Post-therapeutic follow-up represents a completely different area of application for HPV biomarkers. The prediction of treatment success or failure with the help of early HPV antibodies does not appear promising, as the kinetics of the antibody response are greatly delayed, i.e. even successful tumour treatment does not lead to complete seroreversion [80]. In contrast, HPV DNA detection in liquid biopsies appears to be very suitable as a tumour marker in tumour aftercare [81] [82]. However, the detection of HPV DNA in mouthwashes proved to be unsuitable for routine use due to its low sensitivity in a German feasibility study [71].

The prediction of HPV-positive OPSCC with the aid of antibodies against early HPV proteins therefore appears promising, although the feasibility has not been conclusively clarified due to the difficulties associated with screening for rare diseases described above. Robbins et al. [Robbins, HA et al. 2022] estimate that an HPV16 E6 seropositive 50-year-old man has a risk of 7.3% and 17.4% of developing HPV-positive OPSCC in the next 5 and 10 years respectively (age 60: 14.4% and 27.1%). The maximum risk for women is 5.5% for a 60-year-old woman over the next 10 years. However, these calculations are based on figures from the USA, where both the OPSCC incidence rate and the proportion of HPV-driven OPSCCs among all OPSCCs are significantly higher than in Germany. Outside of international clinical studies [83], HPV serology for the detection of antibodies against "early" viral proteins is not routinely available. Effective screening would also require a defined risk profile to narrow down risk groups. Brenner et al., D'Souza et al. and Giuliano et al. [55] [D'Souza, G et al. 2007] [56] describe risk factors for the occurrence of early HPV antibodies as essentially risky sexual behaviour in the USA, although this was not observed in cohorts from Germany (as described in more detail above) [84] [85]. The use of this information, which probably applies to the USA and Canada but may not be readily transferable to Germany, for an organized screening procedure therefore appears to be feasible/useful only to a limited extent, also in view of the rarity of the disease, so that general screening of both the population and special risk groups is not currently recommended.