Abstract Background and purpose HPV is found in head and neck cancer from all sites with a higher prevalence in oropharynx cancer (OPC) compared to non-OPC. HPV/p16-status has a significant impact on ...radiotherapy (RT) outcome in advanced OPC, but less is known about the influence in non-OPC. We analyzed HPV-associated p16-expression in a cohort of patients with stage III–IV pharynx and larynx cancer treated with primary, curatively intended (chemo-)RT, aiming to test the hypothesis that the impact of HPV/p16 also extends to tumors of non-oropharyngeal origin. Material and methods 1294 patients enrolled in previously conducted DAHANCA-trials between 1992 and 2012 were identified. Tumors were evaluated by p16-immunohistochemistry and classified as positive in case of staining in >70% of tumors cells. Results Thirty-eight percent (490/1294) of the tumors were p16-positive with a significantly higher frequency in OPC (425/815) than in non-OPC (65/479), p < .0001. In OPC p16-positivity significantly improved loco-regional control (LRC) (adjusted HR 95% CI: 0.43 0.32–0.57), event-free survival (EFS) (HR 0.44 0.35–0.56), and overall survival (OS) (HR: 0.38 0.29–0.49), respectively, compared with p16-negativity. In non-OPC no prognostic impact of p16-status was found for either endpoint: LRC (HR: 1.13 0.75–1.70), EFS (HR: 1.06 0.76–1.47), and OS (HR: 0.82 0.59–1.16). Conclusions The independent influence of HPV-associated p16-expression in advanced OPC treated with primary RT was confirmed. However, RT-outcome in the group of non-OPC did not differ by tumor p16-status, indicating that the prognostic impact may be restricted to OPC only.
The aim was to explore the overall survival (OS) for palatine tonsillar squamous cell carcinoma (TSCC), subdivided, according to certainty of tonsillar tumour origin, into specified tonsillar ...squamous cell carcinomas (STSCCs) and nonspecified tonsillar squamous cell carcinomas (NSTSCCs), and base of tongue squamous cell carcinoma (BSCC) when stratifying for HPV DNA status, p16 expression and combined HPV/p16 status. We included all patients (n = 797) diagnosed with TSCCs and BSCCs in Eastern Denmark as registered in the Danish Head and Neck Cancer Group (DAHANCA) database and the Danish Pathology Databank, 2000–2010. Patients were treated according to national guidelines (radiotherapy +/− concomitant cisplatin). All specimens were analysed using HPV DNA PCR and p16 immunohistochemistry. Clinical information was retrieved from the DAHANCA database and the Danish National Patient Registry. Information on vital status was obtained from the Danish Civil Registration System. We observed improved OS for HPV+/p16+ BSCCs compared to HPV−/p16− (hazard ratio for death HR, 0.15; 95% CI, 0.09–0.24). Among STSCCs, HPV+/p16+ showed the lowest HR (0.19, 95% CI, 0.13–0.29); whereas, HPV−/p16+ showed an intermediate HR (0.39; 95% CI, 0.22–0.70). For NSTSCCs, HPV+/p16+ and HPV−/p16+ showed similar OS (HRs, 0.39; 95% CI, 0.26–0.59; and 0.48; 95% CI, 0.24–0.95, respectively). Combined HPV+/p16+ was a significantly better prognostic marker in BSCCs and STSCCs than HPV DNA and p16, alone (all p‐values < 0.05). Whereas, combined testing in NSTSCC was not better than p16 (p = 0.53), alone. In conclusion, double positivity for HPV/p16 in conjunction with the certainty of tumour site improved prognosis.
What's new?
The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is on the rise in Western countries, and in Denmark increasing numbers of OPSCC patients are positive for human papillomavirus (HPV). In the present study, the impact of HPV positivity on survival was examined among OPSCC patients in Eastern Denmark who were diagnosed with either tonsillar squamous cell carcinoma (TSCC) or base‐of‐the‐tongue squamous cell carcinoma (BSCC) between 2000 and 2010. The results show that positivity for both HPV DNA and the immunohistochemical marker p16, together with certainty of anatomic tumour site (i.e., TSCC or BSCC), is strongly associated with improved prognosis.
Defining margins around the Gross Tumour Volume (GTV) to create a Clinical Target Volume (CTV) for head and neck cancer radiotherapy has traditionally been based on presumed knowledge of anatomical ...routes of spread. However, using a concentric geometric expansion around the GTV may be more reproducible. The purpose of this study was to analyse the inter-observer consistency of geometric CTV delineation with adaptation for anatomical boundaries versus anatomically defined CTVs.
Radiation oncologists at four Danish cancer centres delineated high, intermediate and elective dose CTVs (CTV1, CTV2 and CTV3, respectively) in a patient-case template (stage IV squamous cell carcinoma of the oropharynx), first using mainly anatomical margins (original standard) and then using concentric geometric expansion (new standard). Each centre made a dummy-run radiotherapy plan based on the delineated CTVs. The difference between the CTV contours and the radiotherapy plans was evaluated across the centres.
Anatomy-based contours were significantly more heterogenous and showed larger volume differences between centres than geometric margins. Dice similarity coefficient increased by 0.29 and mean surface distance decreased by 4mm for CTV1. Use of consistent CTV volumes resulted in more consistent irradiated volumes between centres.
Introduction of geometric margins resulted in more uniform CTV1 and CTV2 delineation. Geometric CTV expansion was easier, left less room for misinterpretation, and resulted in more uniform treatment plans with similar irradiated high and intermediate dose volumes across all centres.
Abstract Background Comorbidity is common in head and neck squamous cell carcinoma (HNSCC) patients due to the etiology of the disease being primarily smoking. The aim of this study was to ...investigate the impact of comorbidity on survival in a national population-based cohort study on 9388 HNSCC-patients treated with radiotherapy (RT), to re-evaluate the prognostic impact of individual diseases within the Charlson Comorbidity Index (CCI), and to develop a revised head and neck comorbidity index (HN-CCI). Material and methods A national cohort of 9388 HNSCC-patients treated with curative intended RT diagnosed from 1992 to 2008 was identified from the DAHANCA-database. Data on comorbidity prior to HNSCC-diagnosis was obtained from the National Patient Registry and adapted to the CCI. Results By dividing the patients into two groups, we tested and validated which type of comorbidities within the CCI affected overall survival (OS) and cancer specific death (CSD). In total, 36% of patients had comorbidity. Six comorbid conditions within the CCI significantly reduced five-year OS probability: congestive heart failure, cerebrovascular disease, chronic pulmonary disease, peptic ulcer disease, liver disease, and diabetes, and based on these conditions the new head and neck specific comorbidity index was developed, the HN-CCI. Comorbidity according to HN-CCI had a highly significant impact on OS, whereas it was not associated with CSD. Chronological age was not associated with increased risk of CSD after controlling for comorbidity. Conclusions Comorbidity is frequent in HNSCC patients and negatively impacts OS. Therefore assessment of comorbidity will be of great importance, both in order to treat/optimize patient’s health before radiotherapy, but also in order to be able to stratify/control for comorbidity in randomized trials to avoid bias. Re-evaluation of the CCI revealed that only six conditions had an impact on survival, and a new modified index to assess comorbidity for HNSCC-patients was developed. The performance of HN-CCI to stratify patients on survival was good and HN-CCI is highly recommended for future assessment of comorbidity and prognostic staging of radiotherapy-treated HNSCC-patients.
Salivary gland hypofunction and xerostomia are major complications to head and neck radiotherapy. This trial assessed the safety and efficacy of adipose tissue-derived mesenchymal stem cell (ASC) ...therapy for radiation-induced xerostomia.
This randomized, placebo-controlled phase 1/2 trial included 30 patients, randomized in a 1:1 ratio to receive ultrasound-guided transplantation of ASCs or placebo to the submandibular glands. Patients had previously received radiotherapy for a T1-2, N0-2A, human papillomavirus-positive, oropharyngeal squamous cell carcinoma. The primary outcome was the change in unstimulated whole salivary flow rate, measured before and after the intervention. All assessments were performed one month prior (baseline) and one and four months following ASC or placebo administration.
No adverse events were detected. Unstimulated whole salivary flow rates significantly increased in the ASC-arm at one (33%; P = .048) and four months (50%; P = .003), but not in the placebo-arm (P = .6 and P = .8), compared to baseline. The ASC-arm symptom scores significantly decreased on the xerostomia and VAS questionnaires, in the domains of thirst (-22%, P = .035) and difficulties in eating solid foods (-2%, P = .008) after four months compared to baseline. The ASC-arm showed significantly improved salivary gland functions of inorganic element secretion and absorption, at baseline and four months, compared to the placebo-arm. Core-needle biopsies showed increases in serous gland tissue and decreases in adipose and connective tissues in the ASC-arm compared to the placebo-arm (P = .04 and P = .02, respectively). MRIs showed no significant differences between groups in gland size or intensity (P < .05).
ASC therapy for radiation-induced hypofunction and xerostomia was safe and significantly improved salivary gland functions and patient-reported outcomes. These results should encourage further exploratory and confirmatory trials.
We compare outcomes in two large‐scale contemporaneously treated HPV‐positive (HPV+) oropharynx cancer (OPC) cohorts treated with definitive radiotherapy/chemoradiotherapy (RT/CRT). p16‐confirmed ...HPV+ OPC treated between 2007 and 2015 at PMH and DAHANCA were identified. Locoregional failure (LRF), distant metastasis (DM), and overall survival (OS) were compared. Multivariable analysis (MVA) calculated adjusted‐hazard‐ratio (aHR) with 95% confidence interval (95% CI), adjusting for cohort, age, gender, performance status, smoking pack‐years, T‐category and N‐category and chemotherapy. Compared to PMH (n = 701), DAHANCA (n = 1174) contained lower TNM‐8T‐categories (T1‐T2: 77% vs 56%), N‐categories (N0‐N1: 77% vs 67%) and stages (stage I: 63% vs 44% (all P < .001). PMH used standard‐fractionation CRT in 69% (481) while 31% (220) received hypofractionated or moderately accelerated RT‐alone. All DAHANCA patients were treated with moderately accelerated RT; 96% (1129) received nimorazole (NIM) and 73% (856) concurrent weekly cisplatin. DAHANCA had shorter overall‐treatment‐time (P < .001), lower gross tumor (66‐68 vs 70 Gy) and elective neck (50 vs 56 Gy) doses. Median follow‐up was 4.8 years. DAHANCA had higher 5‐year LRF (13% vs 7%, aHR = 0.47 0.34‐0.67), comparable DM (7% vs 12%, aHR = 1.32 0.95‐1.82), but better OS (85% vs 80%, aHR = 1.30 1.01‐1.68). CRT patients had a lower risk of LRF (aHR 0.56 0.39‐0.82), DM (aHR 0.70 0.50‐1.00) and death (aHR 0.39 0.29‐0.52) vs RT‐alone. We observed exemplary outcomes for two large‐scale trans‐Atlantic HPV+ OPC cohorts treated in a similar manner. Concurrent chemotherapy was a strong, independent prognostic factor for all endpoints. Our findings underscore the need for a very careful approach to de‐intensification of treatment for this disease.
What's new?
HPV‐positive oropharyngeal cancer (OPC) represents a unique subgroup which has very different epidemiology, molecular biology, and response to radiotherapy/chemo‐radiotherapy (RT/CRT) than HPV‐negative squamous cell carcinoma of the head and neck (HNSCC). In this study, the authors compared two large cohorts of HPV‐positive OPC, and found significantly better outcomes in patients that routinely received concurrent chemoradiotherapy with cisplatin compared with radiotherapy alone. The authors conclude that these findings underscore the need for a cautious approach to efforts aimed at de‐intensifying treatment for this disease.
No study has combined tumour and clinical covariates for survival to construct an individual risk-profile for overall survival (OS), time to progression (TTP), and survival after progression (SAP) in ...patients with HPV+ and HPV- oropharyngeal squamous cell carcinoma (OPSCC). Based on the largest-to-date, unselected, population-based cohort of patients diagnosed with OPSCC, we performed a comprehensive analysis of long-term OS, TTP, and SAP and constructed novel nomograms to evaluate patients' prognoses.
At a median follow-up of 4.0 years (range: 0.8-15.8 yrs.), 690 deaths were recorded. The 5-year OS, TTP, and SAP for the HPV+/p16+ subgroup were 77%, 82%, and 33, vs. 30%, 66%, and 6% for the HPV-/p16- group (P < 0.01). 376 patients failed to maintain disease control with a median TTP of 13 months in the HPV+/p16+ subgroup vs. 8.5 months in the HPV-/p16- subgroup (P < 0.05). HPV combined with p16 status remained one of the most informative covariates in the final Cox regression model for OS, TTP, and SAP.
We included all patients diagnosed with OPSCC (n = 1,542) between 2000-2014 in Eastern Denmark. Survival rates were estimated by the Kaplan-Meier method. A multivariate Cox regression model was used to construct predictive, internally validated nomograms.
The HPV+/p16+ subgroup had improved OS, TTP, and SAP compared with other combinations of HPV and p16 after adjusting for covariates. Nomograms were constructed for 1-, 5- and 10-year survival probability. Models may aid patients and clinicians in their clinical decision making as well as in counselling, research, and trial design.
Patients with head and neck squamous cell carcinoma (HNSCC) undergoing radiotherapy (RT) or chemoradiation (CRT) may become immunocompromised. In this population-based study, we aimed to investigate ...the risk factors, microbiological aetiologies, prognosis and impact on early non-cancer mortality of bloodstream infections (BSIs) after RT/CRT.
Patients with HNSCC of the pharynx, larynx and oral cavity treated with curative-intent RT/CRT in Denmark between 2010 and 2017 and subsequent BSI episodes occurring within 18 months of RT/CRT initiation were identified in national registries.
We included 5674 patients and observed 238 BSIs. Increasing age, stage and performance status were significantly associated with an elevated BSI risk, while sex, smoking and high-grade mucositis were not. Human papillomavirus-positive oropharyngeal cancer patients had a decreased risk. Staphylococcus aureus accounted for 34% of episodes occurring during the first 3 months. The 30-day post-BSI mortality rate was 26% (95% confidence interval: 19-32) and BSIs were involved in 10% of early non-cancer deaths.
The risk of BSI development is associated with several patient- and disease-related factors and BSIs contribute considerably to early non-cancer mortality. Empiric antibiotic treatment regimens should prioritise coverage for S. aureus when treating suspected systemic infection in this population.
Summary To describe the incidence, site and histology (WHO 2005) of salivary gland carcinomas in Denmark. Nine hundred and eighty-three patients diagnosed from 1990 to 2005 were identified from three ...nation-wide registries. The associated clinical data were retrospectively retrieved from patient medical records. Histological revision was performed in 886 cases (90%). Based on histological revision, 31 patients (3%) were excluded from the study leaving 952 for epidemiological analysis. The mean crude incidence in Denmark was 1.1/100,000/year. The male vs. female ratio was 0.97 and the median age was 62 years. The parotid gland was the most common site (52.5%) followed by the minor salivary glands of the oral cavity (26.3%). The most frequent histological subtypes were adenoid cystic carcinoma (25.2%), mucoepidermoid carcinoma (16.9%), adenocarcinoma NOS (12.2%) and acinic cell carcinoma (10.2%). The revision process changed the histological diagnosis in 121 out of 886 cases (14%). The incidence of salivary gland carcinoma in Denmark is higher than previously reported. More than half of salivary gland carcinomas are located in the parotid gland with adenoid cystic carcinoma being the most frequent subtype. Histological classification of salivary gland carcinomas is difficult and evaluation by dedicated pathology specialists might be essential for optimal diagnosis and treatment.
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