In head and neck cancer and other cancer sites, studies suggest that patients highly value survival and are willing to accept added toxicities to maximize their chances to survive. Understanding the patient´s perspective in the context of a de-intensification study is critical in planning a multi-institutional trial, because patients with HPV-positive oropharyngeal SCC must potentially risk reduction of their higher survival probability with standard CRT in favor of reduced toxicity potentially achieved with the experimental arm. Brotherston et al. (2013) conducted an investigation to answer this specific question for patient´s preference regarding acceptable expense for de-escalating cancer treatment. Fifty-one patients with oropharyngeal SCC (post-CRT) underwent semi-structured interviews contrasting toxicities of radiotherapy (RT) alone and CRT. Patients were asked what potential difference in cancer survival was acceptable to prefer RT over CRT. Initially, survival rate was the same for both treatments, then the RT rate was reduced until the preference switched. Ninety percent of patients initially selected RT, but 69 % switched to CRT after 0 to 5 % reduction in survival. Patients that rated their treatment experience as mild would accept lower survival versus severe treatment (p. 0.02). Eighty-one percent of patients (33 of 40) indicated they preferred reduced chemotherapy in CRT. The study shows that the primary concern of patients is survival, with 35 % of patients surveyed unwilling to risk any drop in survival probability to switch to RT over CRT, and a further 34 % willing to accept a 5 % or less reduction in probability of survival. In conclusion, with the limited data available currently, the majority of patients with oropharyngeal SCC are willing to take little or no risk of a survival decrease to receive RT alone as a de-intensification strategy.

Nevertheless, head and neck cancers are categorized by HPV16 status, because the presence of the virus tends to correlate with better survival. But the presence of HPV16 DNA in the tumor may not influence the disease characteristics if that DNA is not expressed. The detection of E6/E7 mRNA is considered as the definitive proof of viral involvement; but, it is often not feasible on a routine daily praxis. Therefore, p16-staining was established as easy to detect surrogate parameter in many centers worldwide. Indeed, several authors have reported that approximately 15–20 % of p16-positive OPSCCs are HPV16-negative by polymerase chain reaction and in situ hybridization (Robinson et al. 2012; Smeets et al. 2007; Lewis 2012; Rischin et al. 2010; Wasylyk et al. 2013; Adelstein et al. 2009). Stratification of head and neck squamous cell carcinomas (HNSCC) based on HPV16 DNA and RNA status, gene expression patterns, and mutated candidate genes may facilitate patient treatment decision. Recently our group could in concordance with other consortial research groups show that DNA-positive and RNA-positive OHNSCC have to be distinguished precisely regarding real HPV16 involvement and correlating typical biological tumor behavior (Wichmann et al. 2015). We characterized OHNSCC with different HPV16 DNA and RNA (E6*I) status from 290 consecutively recruited patients by gene expression profiling and targeted sequencing of 50 genes. We showed that tumors with transcriptionally inactive HPV16 (DNA+ RNA-) are similar to HPV-negative (DNA-) tumors regarding gene expression and frequency of TP53 mutations (47 %, 8/17 and 43 %, 72/167, respectively). We also found that an immune response-related gene expression cluster is associated with lymph node metastasis, independent of HPV16 status.

In line with our observations, Holzinger et al. (2013) pointed out that at present, detection of HPV16-specific viral RNA patterns in snap-frozen biopsies is best suited to identify OHNSCC patients with biologically active HPV in their tumors and improved prognosis. Tumor samples of 188 OHNSCC patients with known HPV16 DNA and RNA status were included. High p16^INK4a, but also low pRb, low Cyclin D1 and normal p53 protein levels were strongly associated with OHNSCCs harboring biologically active HPV. However, p16^INK4a alone had only limited prognostic value and unsatisfactory power to predict RNA+ tumors in this patient cohort. It conferred significantly longer survival in univariate Kaplan–Meier analysis, but lost significant survival advantage after adjusting for gender, age, clinical stage, therapy status and alcohol and tobacco consumption. Kostareli et al. (2013) additional could describe a HPV16-specific methylation signatures which correlated in three independent well-characterized patient cohorts (Chicago, Heidelberg, Leipzig) with significant better overall survival, but interestingly also correlated with better survival if HPV16 was negative. In this study, the CpG island methylome of 15 OHNSCC tumors (5 HPV DNA-, 5 DNA+ RNA-, 5 DNA+ RNA+) revealed specific methylation signatures (5-gene [ALDH1A2, OSR2, GATA4, GRIA4, IRX4] promoter-methylation signature score) screened in 220 OHNSCC. It could be demonstrated that, in addition to genetic aberrations, epigenetic alterations critically contribute to histopathological and clinical differences between HPV-driven and non-HPV-driven tumors.