Statewide trends in oropharyngeal cancer management, p16 status, and patient outcomes in Queensland, 2012–2021

Introduction

The overall incidence of certain head and neck cancers has been declining in high-income countries, linked to a reduction in the traditional risk factors such as smoking and alcohol consumption. However, there has been a rapidly rising incidence of oropharyngeal cancer (OPC) (1,2). This is attributable to a shift in the aetiological risk factors with a rise in the sexually transmitted human papillomavirus (HPV) associated cancers (1). In Australia, the rate of HPV-positive OPCs increased from 20% [1987–1995] to 64% [2006–2010] (3). In the United States, 71% of diagnosed oropharyngeal squamous cell carcinomas are HPV-associated (2). p16 status, as determined by immunohistochemistry, is used in clinical practice and recommended by the American Joint Committee on Cancer (AJCC) 8^th edition (4) as a surrogate for HPV-associated OPC.

The prognosis of HPV-associated OPC is significantly better than HPV-negative OPC (5). The current standard of care for OPC is multifaceted, encompassing surgical resection, radiotherapy (RT) (alone or with concurrent chemotherapy), and systemic therapies, including immunotherapy and targeted therapy (6). RT, either alone or combined with chemotherapy, is highly effective, particularly in early-stage HPV-positive patients with 95% locoregional control at 3 years (7). However, it is often associated with long-term side effects, including xerostomia, dysphagia, and dysgeusia. This has led to significant effort aimed at optimising management of this growing cohort of patients with improved risk stratification and deintensification. Transoral surgery (TOS), either alone or in combination with RT, has gained acceptance as an alternative approach to primary chemoradiotherapy (CRT) in select patients. Its use has been increasingly adopted as it has certain benefits, albeit with operative risks, that distinguish it from RT. The “phase II study, randomized trial of RT versus transoral robotic surgery for oropharyngeal squamous cell carcinoma: ORATOR trial”, revealed no significant difference in overall survival (OS), but a clinically insignificant, yet statistical difference in swallowing quality of life outcomes favouring CRT over TOS (8). The “phase II randomized trial of transoral surgery and low-dose intensity modulated radiation therapy in resectable p16+ locally advanced oropharynx cancer: an Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network (ECOG-ACRIN) cancer research group trial (E3311)”, looking at upfront TOS with reduced dose adjuvant RT as a deintensification strategy, revealed promising oncologic and functional outcomes with deintensification protocols for low and intermediate risk patients, but did result in relative treatment intensification for a significant proportion of patients that ultimately received trimodality therapy (TMT) with both surgery and CRT (9,10). The evidence on optimal management in terms of primary and adjuvant treatments is not yet mature with phase III studies needed to answer this conclusively (10).

Given the increasing prevalence of OPC and the need to optimise treatment, we sought to explore trends in its epidemiology and management during a time of potentially changing treatment paradigms, and to examine survival outcomes for patients in Queensland.

Methods

Data source

This retrospective study was conducted under Section 82 of the Hospital and Health Boards Act [2011] (11), which allows the Queensland Cancer Control Safety and Quality Partnership to access identifiable information to fulfil its functions, including clinical research, specific approval from a human research ethics committee was therefore not required. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Because of the retrospective nature of the research, the requirement for informed consent was waived. Deidentified demographic and clinical data used in the study were from the Queensland Oncology Repository, a population-based databank developed to inform and evaluate cancer control and related quality assurance initiatives across the state. The repository is continuously updated and brings together comprehensive details on patient demographics, along with cancer diagnoses, deaths, and public and private treatment. More than 60 data sources feed into the repository, including the Queensland Cancer Register, the Queensland Hospital Admitted Patient Data Collection, and the Registry of Births, Deaths, and Marriages. Records for the same person from the various sources are linked using complex matching algorithms. The linked data is then cleaned and converted into a uniform dataset. The study is reported according to the STROBE reporting guidelines (available at https://www.theajo.com/article/view/10.21037/ajo-25-27/rc).

Study population

For the analysis, we included residents who were 18 years or older and diagnosed with OPC between 1 January 2012 and 31 December 2021 in Queensland. The following International Statistical Classification of Diseases and Related Health Problems, 10^th edition, Australian Modification (ICD-10-AM) topographical site codes were included: C099 (tonsil), C01 (base of tongue), C109 (oropharynx), C090 (tonsillar fossa), C051 (soft palate), C091 (tonsillar pillar), C108 (overlapping lesion of oropharynx), C100 (vallecula), C024 (lingual tonsil), C098 (overlapping lesion of tonsil), C052 (uvula), C103 (posterior wall of oropharynx), C102 (lateral wall of oropharynx), C101 (anterior surface of epiglottis), and C104 (branchial cleft). All tumours selected were squamous cell histologies (morphology codes 80523, 80703, 80713, 80723, 80733, 80743, and 80833). Details of treatment and death were available for each person were available to 31 December 2023.

The definition of surgery in this study was limited to oncological resections, and surgical biopsies were excluded. Remoteness of residence was defined as per the Australian Statistical Geography Standard (ASGS) remoteness structure 2016 (12). Area-based socioeconomic status was defined as per the Socioeconomic Indexes for Areas (SEIFA) classification (13). Tumours were staged at the time of diagnosis as per the AJCC 8^th edition for analysis (4). Patients with staging as per the AJCC 7^th edition were automatically mapped to the 8^th edition if p16 status was available.

Statistical analysis

All statistical analyses and visualisations were performed using the software R (version 4.2.2; R Foundation for Statistical Computing, Vienna, Austria). Patient characteristics data were described in counts and percentages for categorical variables and medians for continuous variables. Demographic and clinical characteristics were assessed using the Chi-squared test, excluding any missing values. Age-standardised incidence rates (ASRs) per 100,000 population were calculated using direct standardisation to the 2001 Australian standard population (14). The Joinpoint Regression program (version 5.3.0; Surveillance Research Program, United States National Cancer Institute) was used to analyse trends in ASRs of OPC for the overall cohort and stratified by p16 status. The model was run with zero joinpoints to evaluate a single linear trend over the study period, and the annual percent change (APC) was computed. Multivariable binary logistic regression analysis was performed using the “glm” function to identify factors associated with p16-positive status. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed for each covariate.

To calculate survival, patients were followed-up from their date of diagnosis until the date of death, the end of the study period, or for a total of 5 years from diagnosis, whichever came first. Five-year OS rates for the entire cohort and by p16 status were estimated using the Kaplan-Meier method. Disease-specific survival (DSS) curves were also generated using the Kaplan-Meier method to better account for differences in the mortality profile by p16 status, with follow-up censored at the date of death from any other cause apart from OPC. Differences in unadjusted survival were assessed using the log-rank test. To further compare the effect of p16 status on DSS outcomes between early- and late-stage groups, separate multivariable Cox proportional hazards regression models were fitted using the “coxph” function from the “survival” R package to estimate the adjusted excess mortality hazard ratios (HRs) and 95% CIs. The proportional hazards assumption for each covariate was evaluated using Schoenfeld residuals. For all analyses, P values <0.05 were considered statistically significant.

Results

Patient characteristics

Of the 3,060 individuals diagnosed with OPC in Queensland between 2012 and 2021, a total of n=2,957 people (97%) aged over 18 years with squamous cell carcinoma morphologies were included in the study cohort. Most cases involved either the tonsils (44%) or base of tongue (37%), with the remaining 19% arising from other oropharyngeal subsites. Patient demographics and clinical characteristics at diagnosis are summarised in Table 1, including overall and by diagnosis period (2012–2016 vs. 2017–2021). The median age at diagnosis was 61 years (interquartile range, 55–68 years). Of the total cases, 2,499 (85%) were males, and 458 (15%) were females. The majority of the study cohort resided in a major city (n=1,899; 64%), were from middle socioeconomic background (n=1,939; 66%), had no co-morbidities at diagnosis (n=2,097; 71%), and were either active or past smokers (n=1,504; 74% of those with known smoking history). Tumour p16 status was available for 2,550 patients (86%), 81% of whom (n=2,057) tested positive.

Of the 2,552 patients with staging details available (86% of the total study cohort), n=1,662 (65%) were diagnosed with early-stage disease (AJCC stages I/II), while 890 (35%) had late-stage disease (stages III/IV). Individuals aged over 60 years (41%), living in outer regional or remote areas (45%), socioeconomically disadvantaged (44%), or of First Nations background (52%) were more likely to be diagnosed with late-stage disease (all P<0.001; Table S1). p16 status was also closely associated with stage at diagnosis, with 86% of people with p16-negative disease presenting at a late stage (P<0.001). The individual elements of stage at diagnosis were further assessed using the tumour-node-metastasis (TNM) classification system. Among patients with available TNM data (T: n=2,680; N: n=2,561; M: n=2,696), and regardless of overall stage, 57% had tumours classified as T1 or T2, 54% had N1 nodal involvement, and 97% had no evidence of distant metastasis (M0).

Significant differences in patient characteristics were observed between the two 5-year diagnosis periods (Table 1). The proportion of patients aged 60 years and over increased notably, rising from 51% in 2012–2016 to 61% in 2017–2021 (P<0.001). Similarly, the percentage of patients with at least one comorbidity went up from 25% in 2012–2016 to 32% in 2017–2021 (P<0.001). The proportion of patients presented in multidisciplinary team (MDT) meetings also increased from 88% to 95% (P<0.001). p16 positivity remained stable over time (P=0.41).

Factors associated with p16 status

Several significant differences were found in the distribution of patient characteristics between p16-positive and p16-negative OPC cases (Table S2). Compared with p16-negative patients, p16-positive patients were more likely to be male (87% vs. 77%, P<0.001), aged under 60 years (49% vs. 29%), living in major cities (67% vs. 58%), from affluent or middle socioeconomic background (78% vs. 70%), presenting without comorbidities (75% vs. 59%), have never smoked (22% vs. 6%) and diagnosed at an early stage (76% vs. 17%), with P<0.001 for all of these comparisons. The majority of p16-positive cases originated from the tonsils (57%) and base of tongue (36%), whereas p16-negative cases were more commonly located in the soft palate (14%) and unspecified oropharynx (15%) (P<0.001).

Multivariable analysis showed that several factors were independently associated with p16-positive status (Figure 1). Male OPC patients were more likely to be p16-positive than females (OR =2.61; 95% CI: 1.89–3.62; P<0.001), as were patients aged 60 years or older compared to those under 60 (OR =2.37; 95% CI: 1.80–3.10; P<0.001). Patients presenting with early-stage disease were far more likely to be p16-positive compared to those with advanced-stage disease (OR =18.12; 95% CI: 13.77–23.84; P<0.001). In contrast, current smokers (OR =0.16; 95% CI: 0.10–0.25) and former smokers (OR =0.35; 95% CI: 0.22–0.55) were significantly less likely to be p16-positive compared to never smokers (P<0.001 for both). Similarly, patients living in outer regional, remote or very remote areas had significantly lower odds of being diagnosed with p16-positive disease compared to those in major cities (OR =0.63; 95% CI: 0.44–0.91; P=0.01).

Figure 1 Factors associated with p16-positivity. Forest plot of multivariate logistic regression analysis for p16-positivity in OPC patients. For each predictor, the adjusted OR (circles) and 95% CI (whiskers) is displayed. Predictor labels include subgroup categories, with numbers in brackets indicating the number of individuals in each group. The vertical dashed line at OR =1, which implies no association. The red circle indicates the reference group. The asterisks denote statistical significance: ***, P<0.001; *, P<0.05. Patients with unknown p16 status were not included in this analysis. CI, confidence interval; OPC, oropharyngeal cancer; OR, odds ratio.

Incidence rate by p16 status

ASR trends for OPC, including overall and stratified by p16 status, are presented in Figure 2. A marginally significant upward trend was observed from 2012 to 2021 in the overall incidence rates of OPC (including cases with unknown p16 status), with an APC of +2.4% (95% CI: −0.2% to +4.9%, P=0.07). Similar non-significant increasing trends were exhibited from 2012 to 2021 by p16 status: APC of +2.9% (95% CI: −3.3% to +9.4%; P=0.33) for the p16-positive group and +2.7% (95% CI: −4.1% to +9.8%; P=0.39) for the p16-negative group.

Figure 2 Trends in ASRs of OPC for the overall cohort and by p16 status from 2012 to 2021, modelled using joinpoint regression with no joinpoints. Observed rates are shown as solid shapes, and the fitted line represents the modelled trend (APC) over the period 2012–2021. APC, annual percent change; ASR, age-standardised incidence rate; OPC, oropharyngeal cancer.

Treatment

Details of treatment modalities in OPC patients, stratified by diagnosis period and p16 status, are presented in Figure 3. Overall, 92% (n=2,710) of the cohort received treatment, including RT (84%, n=2,472) and intravenous systemic therapy (IVST; 73%, n=2,155) with individuals represented across one or more treatment modalities. Concurrent RT/IVST was the most common treatment modality, administered to 66% (n=1,947) of patients. This was followed by RT alone in 12% (n=355), surgery-based treatments in 8% (n=238). IVST alone in 4% (n=105), and non-concurrent RT/IVST in 2% (n=65). The percentage of patients who received treatment remained stable between 2012–2016 and 2017–2021 (92% vs 91%, P=0.59). However, a significant shift in treatment modalities was observed between the two diagnosis periods (P<0.001; Figure 3A,3B). The proportion of patients undergoing surgery-based treatment increased from 6% in 2012–2016 to 10% in 2017–2021. RT treatment increased from 81% (n=1,047) to 85% (n=1,427) over this period. Systemic therapy increased in total numbers, 982 to 1173, but declined as a percentage of cases from 76% to 70%. Treatment varied by p16 status, with 95% (n=1,958) of p16-positive and 87% (n=431) of p16-negative patients receiving treatment (P<0.001; Figure 3C,3D). People with p16-positive disease were more likely to receive concurrent RT/IVST compared to their p16-negative counterparts (74% vs. 47%). In contrast, p16-negative patients were more likely to undergo surgery-based treatments (15% vs. 6%) or receive RT alone (10% vs. 7%) than p16-positive patients.

Figure 3 Treatment patterns (%) in the oropharyngeal cohort by diagnosis period and p16 status. (A,B) Distribution of treatment modalities across the two 5-year diagnosis periods: 2012–2016 and 2017–2021. (C,D) Distribution of treatment modalities in patients with known p16 status, p16-positive vs. p16-negative. Surgery-based treatment refers to patients who either received surgery alone or in combination with RT and/or IVST. IVST, intravenous systemic therapy; RT, radiotherapy.

Of the 238 patients that underwent surgery, 58% (n=137) required no other treatment modality, 29% (n=70) required adjuvant RT, and 12% (n=28) required TMT with CRT within 90 days of their surgery. Among individuals who received treatment, the proportion undergoing surgery varied by OPC subsite: 10% for base of tongue cancers (100/1,000 treated cases), 7% of tonsillar cancers (90/1,384), and 24% of the palate subsite (26/107). The use of adjuvant RT or CRT among those who underwent surgery was similar between base of tongue cancers at 39% (39/100) and tonsillar cancers at 41% (37/90). The proportion requiring TMT after surgery appeared higher for the base of tongue cancers at 15% (15/100) compared to 8% for tonsillar cancers (7/90); however, this was not significant (P=0.12).

Surgery utilisation was higher for individuals residing outside of metropolitan areas (10%, 94/950) compared to those in metropolitan areas (8%, 144/1,760), but this difference was not statistically significant (P=0.15). In contrast, RT utilisation was lower for rural patients at 90% (857/950), compared to 92% (1,617/1,760) for their urban counterparts, but again the difference was not significant (P=0.16).

Outcomes

The 5-year OS for OPC was 72% (95% CI: 70–73%). When stratified by p16 status, OS was higher among p16-positive patients at 82% (95% CI: 80–83%), compared to 45% (95% CI: 40–49%) in p16-negative patients (P<0.001).

There were significant differences in 5-year DSS across the four groups stratified by p16 status and disease stage (P<0.001; Figure 4). Overall, patients with early-stage disease had better survival outcomes than those with late-stage disease. Within both early- and late-stage groups, p16-positive patients showed improved survival compared to p16-negative patients. However, this difference was only statistically significant in late-stage disease (log-rank P<0.001), but not in early-stage disease (log-rank P=0.15). The unadjusted 5-year DSS of the four groups ranked from best to worse was: early-stage p16-positive (92%; 95% CI: 90–93%), early-stage p16-negative (88%; 95% CI: 82–96%), late-stage p16-positive (67%; 95% CI: 62–72%), and late-stage p16-negative (51%; 95% CI: 46–57%).

Figure 4 Kaplan-Meier curves showing 5-year DSS by p16 status and disease stage at diagnosis among OPC patients in Queensland, 2012–2021. Only patients with known p16 status and disease stage were included in the analysis. Blue lines represent early-stage disease and red lines represents late-stage disease. Patients within each stage group where further stratified into p16-positive (dashed line) and p16-negative (solid line) status. The overall rank-log test comparing all four groups shown on the plot was statistically significant (P<0.001). Separate log-rank tests comparing p16-positive and p16-negative patient within each stage group was computed, which showed significant difference in late-stage (P<0.001), but not in early-stage (P=0.2). DSS, disease-specific survival; OPC, oropharyngeal cancer.

After adjusting for potential confounding factors (Figure 5), it was again observed that p16-negative status was significantly associated with worse survival in late-stage disease (HR =1.49; 95% CI: 1.16–1.92; P=0.002), whereas no significant association was observed between p16 status and survival in early-stage disease (P=0.77). Additionally, increasing age at diagnosis was associated with worse survival outcomes regardless of disease stage. In the early-stage group (Figure 5A), the 65–74 years (HR =2.06; 95% CI: 1.21–3.52; P=0.008) and 75+ years (HR =5.73; 95% CI: 3.20–10.25; P<0.001) age groups were associated with worse survival compared to people under 55 years old, while the 55–64 years group showed no significant difference. In the late-stage group (Figure 5B), compared to individuals under 55 years, those aged 55–64 (HR =1.70; 95% CI: 1.15–2.51; P=0.008), 65–74 years (HR =1.87; 95% CI: 1.27–2.75; P=0.002), and 75+ years (HR =3.32; 95% CI: 2.13–5.17; P<0.001) had significantly poorer survival. Survival was worse for First Nations peoples, with a significant association observed in those with late-stage disease (HR =2.31; 95% CI: 1.51–3.53; P<0.001) and a marginal association noted in those with early-stage disease (HR =2.10; 95% CI: 0.96–4.48; P=0.06), while people from outer regional, remote or very remote areas had significantly lower survival compared to those from major cities for early-stage disease only (HR =2.08; 95% CI: 1.27–3.39; P=0.003).

Figure 5 Forest plot from multivariable Cox regression analysis showing the effect of predictors on DSS of OPC in Queensland, 2012–2021, stratified by stage at diagnosis: (A) early stage and (B) late stage. For each predictor, the adjusted HR (circles) and 95% CI (whiskers) are displayed. Predictor labels include subgroup categories, with numbers in brackets indicating the number of individuals in each group. The vertical dashed line at HR =1 represents no association. The red circle indicates the reference group. Asterisks denote statistical significance: ***, P<0.001; **, P<0.01. Only patients with known p16 status and disease stage were included in the analysis. CI, confidence interval; DSS, disease-specific survival; HR, hazard ratio; OPC, oropharyngeal cancer.

Discussion

This is the largest study of OPC management and mortality outcomes in Australia. The demographic profile in our study is consistent with other large population studies, such as the work by Lechner et al. (2), showing a marked predominance of older males afflicted, as seen with the median age of diagnosis of 61, and only 15% of the cohort of female sex. The demographic characteristics of the study cohort were also generally consistent with the general population of Queensland in terms of remoteness of residence, socioeconomic status, and First Nations peoples (15,16).

A key change across the two 5-year time periods was the significant increase in age of diagnosed individuals. Previous observations have been made in Australia of increasing age at the time of diagnosis of OPC (3). We have seen this continue with an increase of older individuals diagnosed between the two time periods, with those older than 70 years now approaching a quarter of all diagnosed. This has been mirrored in other studies, observing a shift with HPV-positive OPC no longer being a younger person’s disease, for example as reported by Rettig et al. (17). It likely explains the increase in the number of co-morbidities seen across the two time periods. This may also be partly reflective of improvements in reporting practices and staging audits in the latter period, which was also seen with the decrease in patients without complete staging data.

We observed a trend towards increasing incidence of OPC overall and both p16-positive and p16-negative groups. While marginally significant, the APC of 2.4% in Queensland between 2012 and 2021 is markedly less than the significant 5.2% APC seen across Australia overall between 2007 and 2017 (18). Our study demonstrates a further rise in the p16 positivity rate with 81% of patients with confirmed p16 status now positive as compared to a 61% rate seen in Australia between 2006 and 2010 (3). In comparison, the rate of p16 positivity in France remained considerably lower despite increasing from 43% to 57% from 2011 to 2021 (19). Interestingly, there was no significant difference across the two 5-year periods in terms of the p16 positivity rate of OPC, suggesting the proportion of HPV positivity may have plateaued. Socioeconomic status and rurality were independently associated with p16-negative OPC in univariate analysis. However, in the multivariate analysis, unlike age, sex, smoking status, and stage at diagnosis, they were not significantly linked to p16 status. Their apparent dependent risk likely reflects their correlation with higher rates of smoking seen in more rural and disadvantaged populations of Australia (20).

It was evident in our cohort that RT remains the dominant treatment modality with 84% of patients receiving it in some form, either with concurrent chemotherapy, alone, or on an adjuvant basis postoperatively. CRT was the most common treatment combination overall, administered to 66% of patients. TOS is gaining interest as part of the de-escalation paradigm in OPC and is increasingly being adopted internationally (8). In Australia, there is evidence of interest and adoption amongst ear, nose, and throat (ENT) surgeons, but no large-scale data on its regular use in clinical practice (21). We have found that now one in ten patients undergo TOS in Queensland. There has been an incremental increase in the use of surgery from 6% to 10% over the periods 2012–2016 to 2017–2021, reflecting gradual uptake as centres become more versed in its use and a selective approach taken by Queensland’s ENT surgeons. There is some evidence that surgically resectable p16-negative OPC may fare better with surgery as opposed to CRT, particularly early-stage disease, and this principle was evident in management with increased use of TOS in these patients (22). There was a possible indication of higher rates of TOS for patients of regional and rural locations, likely stemming from the higher burden of p16-negative disease demonstrated in this population. It may also reflect the centralised health network in Queensland and the logistical challenges inherent with the duration of RT treatments. Furthermore, it is a positive sign for equitable distribution of surgical expertise and resource availability in the public and private health systems. The gradual adoption of TOS is also reflective of the evidence base. While there are retrospective and phase II trials such as ECOG-ACRIN (E3311), showing excellent functional and oncological outcomes in selected patients with TOS, there are no phase 3 studies defining it as a preferred treatment strategy (8). As such, its use often comes down to clinician/centre preference and experience. Upcoming trials, such as post-operative adjuvant treatment for HPV-positive tumours (PATHOS): a phase II/III trial of risk-stratified, reduced intensity adjuvant treatment in patients undergoing TOS for HPV-positive OPC may provide more clarity for its indications and subsequently see more marked differences in its use over time (23).

Treatment de-escalation approaches with TOS may result in inadvertent TMT and hence treatment intensification for a proportion of patients. There are concerns for worse long-term treatment-related toxicity with TMT. In our study, 12% of surgically treated patients underwent TMT within 90 days. This compares favourably to the 31% seen in the ECOG-ACRIN (E3311) study who underwent CRT post-TOS, revealing perhaps more judicious patient selection in the current cohort (8). While the numbers are small, the majority of these patients had a base of tongue SCC, potentially reflecting it as a more difficult surgical subsite to achieve an adequate oncological resection. There are some indications that the long-term toxicities from TMT are less significant with modern surgical and RT techniques in the generally healthier HPV-positive patients (24). The encouraging finding of a high and improving rate of MDT review may have also helped in patient selection for de-escalation approaches with TOS.

The 5-year OS outcomes in the cohort of 82% for p16-positive cases and 45% for p16-negative cases compare well to other large population analyses, such as Mehanna et al.’s multinational, multicentre review with 7,895 patients that had a 5-year OS of 81% and 40%, respectively (25). Our study reiterates the well-defined prognostic implications of HPV status. When accounting for stage at diagnosis and DSS, the difference narrows, particularly for early-stage disease with p16-negative patients still achieving a relatively high 5-year DSS of 88%. Unfortunately, early-stage disease was less common in the p16-negative cohort, reflecting the differences in tumour biology of HPV-negative OPC, as well as differences in age, co-morbidities, and potentially health-seeking behaviour of this demographic (20,26). It was unsurprising to see the effect age has on outcomes with those older than 60 years, and particularly over 70 years, having significantly worse DSS. The observed increase of the elderly population with OPC may have management implications as we enter the era of treatment de-escalation, as it has been seen that the survival advantage of HPV-positive disease is attenuated in older individuals, highlighting the need for tailored treatment approaches (17).

Older patients, or those with First Nations, rural, or disadvantaged backgrounds had more advanced disease at time of diagnosis. Rurality had a significant effect on survival outcomes in early-stage disease, but not so in late-stage disease. First Nations individuals had significantly worse survival outcomes in late-stage disease and marginally significant in early-stage disease. Both patient groups are known to have significantly longer median times from first diagnosis to treatment (27). This paper further adds to evidence of poorer outcomes for First Nations individuals with OPC, who are known to be diagnosed at younger ages and have a significantly worse prognosis (28). In addition to preventative measures targeted at risk factor reduction, addressing barriers to ensure prompt diagnosis and treatment for these groups will improve outcomes. These inequities also reveal the priority demographic groups for which focussed potential future screening measures can be implemented to help reduce the burden of OPC in Queensland and Australia as a whole.

Whilst retrospective in nature, the study has a large modern cohort of patients to provide an overview of the current state of OPC management in Queensland, Australia. Importantly, the study cohort was population-based, providing the full picture of real-world data as opposed to hospital-based studies that may focus on specific patient groups. Mortality outcomes are comprehensive, with the inclusion of DSS in addition to OS, and robust, by nature of the Queensland Oncology Repository being linked to the national death registry. Limitations include the retrospective database restaging of some patients in the cohort from the AJCC 7^th edition to the 8^th edition, lack of other outcome measures such as recurrence rates or side effects of therapy, missing values in some datasets, such as those derived from MDT review documentation and the attribution of treatment to a range of Medicare item codes that don’t always distinguish between diagnostic and therapeutic procedures. We were unable to provide analysis on treatment-specific outcomes due to a lack of provision of source data on time to treatment, intention of treatment, and side effect reporting. We also acknowledge that the use of p16 positivity in the database and in clinical practice as a surrogate for HPV-associated cancers neglects a proportion of patients that are p16-positive yet are HPV-negative, which are known to have poorer outcomes (29).

Conclusions

This study provides important data on the changing trends of an increasingly prevalent cancer and its outcomes with modern therapy. It reveals an increasing number of elderly individuals are being diagnosed with OPC, but that the previously rising percentage of HPV-associated OPC, as determined by p16 status, has plateaued, with 81% of patients positive. RT, alone or in combination with chemotherapy, remains the dominant modality of treatment. However, surgery, alone or in combination with adjuvant therapies, is gradually increasing with now one in ten patients undergoing TOS, reflecting increasing surgical skill, experience, and interest. When this was employed, there was a low rate of adjuvant chemoradiation, likely a reflection of rigorous patient selection and MDT discussion. DSS was high in early-stage disease, and this was not significantly different for p16-negative OPC; however, prognosis was poorer in late-stage disease. The inequities in outcomes in terms of regional, rural, First Nations, and disadvantaged populations reveal key targets for primary prevention, reducing treatment barriers, and potentially future screening. This study also highlights further avenues of research for improving outcomes, particularly the use of adjuvant treatments and unplanned use of tri-modality therapy.

Acknowledgments

The authors wish to thank members of the Head and Neck Cancer subcommittee of the Queensland Cancer Control Safety and Quality Partnership and Cancer Alliance Queensland for their support and ongoing advice. The authors also thank the Queensland Cancer Control Analysis Team who maintain the Queensland Oncology Repository.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://www.theajo.com/article/view/10.21037/ajo-25-27/rc

Data Sharing Statement: Available at https://www.theajo.com/article/view/10.21037/ajo-25-27/dss

Peer Review File: Available at https://www.theajo.com/article/view/10.21037/ajo-25-27/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://www.theajo.com/article/view/10.21037/ajo-25-27/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This retrospective study was conducted under Section 82 of the Hospital and Health Boards Act [2011], which allows the Queensland Cancer Control Safety and Quality Partnership to access identifiable information to fulfil its functions, including clinical research, specific approval from a human research ethics committee was therefore not required. Because of the retrospective nature of the research, the requirement for informed consent was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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