Treatment de‐escalation in HPV‐positive oropharyngeal carcinoma: Ongoing trials,critical issues and perspectives

Due to the generally poor prognosis of head and neck squamous cell carcinoma (HNSCC), treatment has been intensified, these last decades, leading to an increase of serious side effects. High‐risk human papillomavirus (HR‐HPV) infection has been recently etiologically linked to a subset of oropharyngeal squamous cell carcinoma (OPSCC), which is on the increase. These tumors are different, at the clinical and molecular level, when compared to tumors caused by traditional risk factors. Additionally, their prognosis is much more favorable which has led the medical community to consider new treatment strategies. Indeed, it is possible that less intensive treatment regimens could achieve similar efficacy with less toxicity and improved quality of life. Several clinical trials, investigating different ways to de‐escalate treatment, are currently ongoing. In this article, we review these main approaches, discuss the rationale behind them and the issues raised by treatment de‐escalation in HPV‐positive OPSCC.     

The potential impact of prophylactic human papillomavirus vaccination on oropharyngeal cancer

The incidence of oropharyngeal cancer (OPC) is significantly increasing in the United States. Given that these epidemiologic trends are driven by human papillomavirus (HPV), the potential impact of prophylactic HPV vaccines on the prevention of OPC is of interest. The primary evidence supporting the approval of current prophylactic HPV vaccines is from large phase 3 clinical trials focused on the prevention of genital disease (cervical and anal cancer, as well as genital warts). These trials reported vaccine efficacy rates of 89% to 98% for the prevention of both premalignant lesions and persistent genital infections. However, these trials were designed before the etiologic relationship between HPV and OPC was established. There are differences in the epidemiology of oral and genital HPV infection, such as differences in age and sex distributions, which suggest that the vaccine efficacy observed in genital cancers may not be directly translatable to the cancers of the oropharynx. Evaluation of vaccine efficacy is challenging in the oropharynx because no premalignant lesion analogous to cervical intraepithelial neoplasia in cervical cancer has yet been identified. To truly investigate the efficacy of these vaccines in the oropharynx, additional clinical trials with feasible endpoints are needed. Cancer 2016;122:2313–2323 . © 2016 American Cancer Society.     

Circulating tumor-tissue modified HPV DNA analysis for molecular disease monitoring after chemoradiation for anal squamous cell carcinoma: a case report

Squamous cell carcinoma (SCC) of the anus typically arises after human papillomavirus (HPV) infection. We report on the use of molecular disease monitoring using a novel blood test measuring circulating tumor-tissue -modified HPV DNA in two patients with anal cancer. Two patients with anal SCC received concurrent chemotherapy and radiation therapy (chemoRT) with curative intent, one with a T2N0 anal margin squamous cell carcinoma with a history of AIDS, and one with a T3N0 anal squamous cell carcinoma and a history of concurrent prostate cancer. HPV genotyping at diagnosis confirmed the presence of HPV16 DNA in both cases. Circulating, tumor-tissue-modified HPV DNA (TTMV-HPV DNA) was measured in the peripheral blood utilizing digital PCR at baseline and in follow-up. Disease burden was assessed post-treatment with standard anoscopy, biopsy, and PET/CT. Plasma TTMV-HPV DNA levels were elevated at diagnosis, and decreased during and after chemoRT completion in both cases. During post treatment surveillance, TTMV-HPV DNA levels correlated with disease status including one case with progressive local recurrence within 2 months, and one case with 12 months of local control both confirmed by biopsy. These case studies present the first use of circulating tumor-tissue-modified HPV DNA as a biomarker for anal cancer. Further study of this blood test an adjunct to standard treatment and monitoring is warranted in HPV-positive anal cancer.     

Identification of human papillomavirus (HPV) 16 DNA integration and the ensuing patterns of methylation in HPV‐associated head and neck squamous cell carcinoma cell lines

Recent studies showed that human papillomavirus (HPV) integration contributes to the genomic instability seen in HPV‐associated head and neck squamous cell carcinoma (HPV‐HNSCC). However, the epigenetic alterations induced after HPV integration remains unclear. To identify the molecular details of HPV16 DNA integration and the ensuing patterns of methylation in HNSCC, we performed next‐generation sequencing using a target‐enrichment method for the effective identification of HPV16 integration breakpoints as well as the characterization of genomic sequences adjacent to HPV16 integration breakpoints with three HPV16‐related HNSCC cell lines. The DNA methylation levels of the integrated HPV16 genome and that of the adjacent human genome were also analyzed by bisulfite pyrosequencing. We found various integration loci, including novel integration sites. Integration loci were located predominantly in the intergenic region, with a significant enrichment of the microhomologous sequences between the human and HPV16 genomes at the integration breakpoints. Furthermore, various levels of methylation within both the human genome and the integrated HPV genome at the integration breakpoints in each integrant were observed. Allele‐specific methylation analysis suggested that the HPV16 integrants remained hypomethylated when the flanking host genome was hypomethylated. After integration into highly methylated human genome regions, however, the HPV16 DNA became methylated. In conclusion, we found novel integration sites and methylation patterns in HPV‐HNSCC using our unique method. These findings may provide insights into understanding of viral integration mechanism and virus‐associated carcinogenesis of HPV‐HNSCC.     

Health‐related quality‐of‐life in patients with head‐and‐neck cancer in Sri Lanka: psychometric properties of the ‘Sinhala’ version of the EORTC QLQ‐H&N35

Objective: To translate and validate the ‘Sinhala’ language version of the European Organization for Research and Treatment of Cancer head‐and‐neck cancer‐specific health‐related quality‐of‐life questionnaire module, the QLQ‐H&N35, for use in Sri Lanka. Methods: Psychometric testing assessed the hypothesized scale structure, scale reliability, construct validity and acceptability of the translated version of the QLQ‐H&N35 in a consecutive series of 196 newly diagnosed head‐and‐neck cancer patients, recruited from tertiary‐care oncology treatment centres in Sri Lanka. Results: Compliance was high (97.5%), although nearly 40% of patients required assistance with completion of the questionnaire. Twenty‐four sexually inactive patients declined to answer one or both items of the sexuality scale. Multi‐trait scaling confirmed the overall scale structure, with good item‐convergent (100%) and ‐discriminant (93.8%) validity, and scaling success (86.8%) rates. Cronbach's alpha coefficients exceeded 0.70 for all scales, except problems with sexuality (0.60) and problems with senses (0.61), which also evidenced a lower scaling success rate (50%). Confirmation of construct validity included satisfactory results for inter‐scale correlations and known‐groups comparisons for most scales; most correlations were statistically significant (p<0.01), with conceptually related scales showing relatively higher correlation. Most scale scores were able to discriminate clearly between pre‐ and current treatment patients. Conclusions: Results of the study provide strong support for the psychometric robustness of the ‘Sinhala’ version of the QLQ‐H&N35. It may be advisable to interpret the two items assessing sensory problems separately, and to elicit information on sexuality from only those who are sexually active. Copyright © 2009 John Wiley & Sons, Ltd.