Human papillomavirus (HPV) DNA methylation changes in HPV-associated head and neck cancer.

Despite the rising incidence, currently, there are no early detection methods for HPV-driven HNC (HPV-HNC). Cervical cancer studies suggest that HPV DNA methylation changes can be used as a biomarker to discriminate cancer patients from HPV-infected individuals. As such, this study was designed to establish a protocol to evaluate DNA methylation changes in HPV late genes and long control region (LCR) in saliva samples of HPV-HNC patients and HPV-positive controls. Higher methylation levels were detected in HPV late genes (L1 and L2) in both tumour and saliva samples of HPV-HNC patients compared with HPV-positive controls. Moreover, methylation patterns between tumours and corresponding saliva samples were observed to have a strong correlation (Passing-Bablok regression analysis; τ = 0.7483, P < 0.0001). Considering the differences between HNC and controls in methylation levels in late genes, and considering primer amplification efficiencies, 13 CpG sites located at L1 and L2 genes were selected for further evaluation. A total of 18 HNC saliva samples and 10 control saliva samples were assessed for the methylation levels in the selected sites. From the CpG sites evaluated statistically significant differences were identified for CpG sites at L2-CpG 6 (P = 0.0004), L1-CpG 3 (P = 0.0144), L1-CpG 2 (P = 0.0395) and L2-CpG 19 (P = 0.0455). Our pilot data indicate that higher levels of DNA methylation in HPV late genes are indicative of HPV-HNC risk, and it is a potential supplementary biomarker for salivary HPV detection-based HPV-HNC screening.

Nutrition outcomes and treatment toxicities in patients with head and neck cancer receiving helical intensity-modulated radiotherapy.

BACKGROUND: Helical intensity-modulated radiotherapy (H-IMRT) provides excellent limitation of dose to tissues not requiring treatment, although acute toxicity still occurs. The present study aimed to determine how treatment-related acute toxicities affect nutrition outcomes in patients with head and neck cancer. METHODS: A prospective observational study was conducted in 194 patients undergoing curative intent H-IMRT with or without other treatment modalities. Weight outcomes (kg) and acute toxicity and dysphagia data were collected during treatment using Common Toxicity Criteria for Adverse Effects (CTCAE), version 4.0. RESULTS: Significant weight loss (> 10%) was observed in 30% of high nutritional risk patients and 7% of low nutritional risk patients. Nausea, adjusted for baseline dysphagia, in high nutritional risk patients and nausea, dysphagia and pharyngeal mucositis in low nutritional risk patients were significant factors in explaining the percentage loss in baseline weight to treatment completion. CONCLUSIONS: Significant weight loss remains an issue during treatment, despite improvements in radiotherapy technology and high-level multidisciplinary care.

Head and neck cancer patient-derived tumouroid cultures: opportunities and challenges.

Head and neck cancers (HNC) are the seventh most prevalent cancer type globally. Despite their common categorisation, HNCs are a heterogeneous group of malignancies arising in various anatomical sites within the head and neck region. These cancers exhibit different clinical and biological manifestations, and this heterogeneity also contributes to the high rates of treatment failure and mortality. To evaluate patients who will respond to a particular treatment, there is a need to develop in vitro model systems that replicate in vivo tumour status. Among the methods developed, patient-derived cancer organoids, also known as tumouroids, recapitulate in vivo tumour characteristics including tumour architecture. Tumouroids have been used for general disease modelling and genetic instability studies in pan-cancer research. However, a limited number of studies have thus far been conducted using tumouroid-based drug screening. Studies have concluded that tumouroids can play an essential role in bringing precision medicine for highly heterogenous cancer types such as HNC.

Circulating tumour DNA alterations: emerging biomarker in head and neck squamous cell carcinoma.

Head and Neck cancers (HNC) are a heterogeneous group of upper aero-digestive tract cancer and account for 931,922 new cases and 467,125 deaths worldwide. About 90% of these cancers are of squamous cell origin (HNSCC). HNSCC is associated with excessive tobacco and alcohol consumption and infection with oncogenic viruses. Genotyping tumour tissue to guide clinical decision-making is becoming common practice in modern oncology, but in the management of patients with HNSCC, cytopathology or histopathology of tumour tissue remains the mainstream for diagnosis and treatment planning. Due to tumour heterogeneity and the lack of access to tumour due to its anatomical location, alternative methods to evaluate tumour activities are urgently needed. Liquid biopsy approaches can overcome issues such as tumour heterogeneity, which is associated with the analysis of small tissue biopsy. In addition, liquid biopsy offers repeat biopsy sampling, even for patients with tumours with access limitations. Liquid biopsy refers to biomarkers found in body fluids, traditionally blood, that can be sampled to provide clinically valuable information on both the patient and their underlying malignancy. To date, the majority of liquid biopsy research has focused on blood-based biomarkers, such as circulating tumour DNA (ctDNA), circulating tumour cells (CTCs), and circulating microRNA. In this review, we will focus on ctDNA as a biomarker in HNSCC because of its robustness, its presence in many body fluids, adaptability to existing clinical laboratory-based technology platforms, and ease of collection and transportation. We will discuss mechanisms of ctDNA release into circulation, technological advances in the analysis of ctDNA, ctDNA as a biomarker in HNSCC management, and some of the challenges associated with translating ctDNA into clinical and future perspectives. ctDNA provides a minimally invasive method for HNSCC prognosis and disease surveillance and will pave the way in the future for personalized medicine, thereby significantly improving outcomes and reducing healthcare costs.

Impact of sarcopenia and myosteatosis on survival outcomes for patients with head and neck cancer undergoing curative-intent treatment.

Malnutrition and sarcopenia are prevalent in patients with head and neck squamous cell carcinoma (HNSCC). Pre-treatment sarcopenia and adverse oncological outcomes in this population are well described. The impact of myosteatosis and post-treatment sarcopenia is less well known. Patients with HNSCC (n = 125) undergoing chemoradiotherapy, radiotherapy alone and/or surgery were assessed for sarcopenia and myosteatosis, using cross-sectional computed tomography (CT) imaging at the third lumbar (L3) vertebra, at baseline and 3 months post-treatment. Outcomes were overall survival (OS) at 12 months and 5 years post-treatment. One hundred and one participants had a CT scan evaluable at one or two time points, of which sixty-seven (66 %) participants were sarcopenic on at least one time point. Reduced muscle attenuation affected 93 % (n = 92) pre-treatment compared with 97 % (n = 90) post-treatment. Five-year OS favoured those without post-treatment sarcopenia (hazard ratio, HR 0·37, 95 % CI 0·16, 0·88, P = 0·06) and those without both post-treatment myosteatosis and sarcopenia (HR 0·33, 95 % CI 0·13, 0·83, P = 0·06). Overall, rates of myosteatosis were high at both pre- and post-treatment time points. Post-treatment sarcopenia was associated with worse 5-year OS, as was post-treatment sarcopenia in those who had myosteatosis. Post-treatment sarcopenia should be evaluated as an independent risk factor for decreased long-term survival post-treatment containing radiotherapy (RT) for HNSCC.

Exploring the impact of remoteness on people with head and neck cancer: Utilisation of a state-wide dataset.

OBJECTIVE: Living in regional/rural areas can impact outcomes for people with head and neck cancer (HNC). Using a comprehensive state-wide dataset, the impact of remoteness on key service parameters and outcomes for people with HNC was examined. METHODS: Retrospective quantitative analysis of routinely collected data held within the Queensland Oncology Repository. DESIGN: Quantitative methods (descriptive statistics, multivariable logistic regression and geospatial analysis). SETTING: All people diagnosed with HNC in Queensland, Australia. PARTICIPANTS: The impact of remoteness was examined in 1991 people (1171 metropolitan, 485 inner-regional, 335 rural) with HNC cancer diagnosed between 2013 and 2015. MAIN OUTCOME MEASURES: This paper reports key demographics and tumour characteristics (age, gender, socioeconomic status, First Nations status, co-morbidities, primary tumour site and staging), service use/uptake (treatment rates, attendance at multidisciplinary team review and timing to treatment) and post-acute outcomes (readmission rates, causes of readmission and 2-year survival). In addition to this, the distribution of people with HNC across QLD, distances travelled and patterns of readmission were also analysed. RESULTS: Regression analysis revealed remoteness significantly (p < 0.001) impacted access to MDT review, receiving treatment, and time to treatment commencement, but not readmission or 2-year survival. Reasons for readmission did not differ by remoteness, with dysphagia, nutritional inadequacies, gastrointestinal disorders and fluid imbalance indicated in the majority of readmissions. Rural people were significantly (p < 0.0001) more likely to travel to care and to readmit to a different facility than provided primary treatment. CONCLUSIONS: This study provides new insights into the health care disparities for people with HNC residing in regional/rural areas.

Analysis of human leukocyte antigen associations in human papillomavirus-positive and -negative head and neck cancer: Comparison with cervical cancer.

BACKGROUND: Although the majority of human papillomavirus (HPV) infections are cleared by the immune system, a small percentage of them progress to develop HPV-driven cancers. Cervical cancer studies highlight that HPV persistence and cancer risk are associated with genetic factors, especially at the human leukocyte antigen (HLA) genes. This study was conducted to investigate such associations in head and neck cancer (HNC). METHODS: In all, 192 patients with HNC and 384 controls were genotyped with the Infinium Global Screening Array (Illumina, Inc). HLA variants were imputed with SNP2HLA, and an association analysis was performed by logistic regression. RESULTS: HPV-positive HNCs were significantly associated with single-nucleotide polymorphisms (SNPs) at DRB1_32660090 (P = 1.728 × 10-6 ) and DRB1_32660116 (P = 1.728 × 10-6 ) and with the amino acid variant DRB1_11_32660115 (P = 1.728 × 10-6 ). None of these associations were observed in the HPV-negative cohort, and this suggested their specificity to convey risk for HPV-associated HNCs. In general, associations observed for HPV-negative HNC were relatively weak, and variants in the HLA-DPA1 region were the strongest among them (P = 4.531 × 10-4 ). Several lead signals reported by previous HNC genome-wide association studies, including SNPs rs3135001 (P = .012), rs1049055 (P = .012), and rs34518860 (P = .029) and allele HLA-DQB1*06 (P = .009), were replicated in the current study. However, these associations were limited to the HPV-positive HNC group. Several cervical cancer-associated HLA variants, including SNPs rs9272143 (P = .002) and rs9271858 (P = .002) and alleles HLA-B-1501 (P = .009) and HLA-B-15 (P = .015), were also exclusively associated with HPV-positive HNC. CONCLUSIONS: HPV-positive HNC risk is associated with distinct HLA variants, and some of them are shared by both cervical cancer and HPV-positive HNC. Human papillomavirus (HPV)-positive head and neck cancer (HNC) risk is associated with distinct human leukocyte antigen variants, and some of them are shared by both cervical cancer and HPV-positive HNC. LAY SUMMARY: Cervical cancer studies highlight that human papillomavirus (HPV)-driven cancer risk is linked with human leukocyte antigen (HLA) polymorphism. Hence, the current study was designed to investigate the HLA associations in HPV-positive and HPV-negative head and neck cancer (HNC) and compare these associations with cervical cancer. Several lead signals reported by previous HNC and cervical genome-wide association studies were replicated in the current study. However, these associations were limited to the HPV-positive HNC group, and this suggests that HPV-positive HNC risk is associated with distinct HLA variants, and some of them are shared by both cervical cancer and HPV-positive HNC.

Evaluation of a speech pathology service delivery model for patients at low dysphagia risk during radiotherapy for HNC.

PURPOSE: There are no evidence-based guidelines informing which patients with head and neck cancer (HNC) require regular speech pathology (SP) support during radiation treatment (RT). Hence, some services use a "one-size-fits-all" model, potentially over-servicing those patients at low risk for dysphagia. This study evaluated the clinical safety and efficiency of an interdisciplinary service model for patients identified prospectively as "low risk" for dysphagia during RT. METHODS: A prospective cohort of 65 patients with HNCs of the skin, thyroid, parotid, nose, and salivary glands, receiving curative RT, were managed on a low-risk pathway. Patients with baseline dysphagia (functional oral intake score ≤ 5) were excluded. The model involved dietitians conducting dysphagia screening at weeks 3, 5, and 6/7 within scheduled appointments. Patients at risk of dysphagia were referred to SP for assessment, then management if required. To validate the model, SP assessed swallow status/toxicities at week 5/6/7 during RT and confirmed dysphagia status at weeks 2 and 6 post RT. RESULTS: Most (89.3%) patients did not require dysphagia support from SP services. Of the 18 patients identified on screening, only 7 (10.7%) had sufficient issues to return to SP care. Week 5/6/7 SP review confirmed low levels of toxicity. No post-treatment dysphagia was observed. There was an incremental benefit of A$15.02 for SP staff costs and a recovery of 5.31 appointments per patient. CONCLUSION: The pathway is a safe and effective service model to manage patients with HNC at low risk for dysphagia during RT, avoiding unnecessary SP appointments for the patient and service.

Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): 10-year results from a randomised, phase 3, factorial trial.

BACKGROUND: The optimal duration of androgen suppression for men with locally advanced prostate cancer receiving radiotherapy with curative intent is yet to be defined. Zoledronic acid is effective in preventing androgen suppression-induced bone loss, but its role in preventing castration-sensitive bone metastases in locally advanced prostate cancer is unclear. The RADAR trial assessed whether the addition of 12 months of adjuvant androgen suppression, 18 months of zoledronic acid, or both, can improve outcomes in men with locally advanced prostate cancer who receive 6 months of androgen suppression and prostatic radiotherapy. This report presents 10-year outcomes from this trial. METHODS: For this randomised, phase 3, 2 × 2 factorial trial, eligible men were 18 years or older with locally advanced prostate cancer (either T2b-4, N0 M0 tumours or T2a, N0 M0 tumours provided Gleason score was ≥7 and baseline prostate-specific antigen [PSA] concentration was ≥10 µg/L). We randomly allocated participants in a 2 × 2 factorial design by computer-generated randomisation (using the minimisation technique, and stratified by centre, baseline PSA concentration, clinical tumour stage, Gleason score, and use of a brachytherapy boost) in a 1:1:1:1 ratio to four treatment groups. Patients in the control group received 6 months of neoadjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly) and radiotherapy alone (short-term androgen suppression [STAS]); this treatment was either followed by another 12 months of adjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly; intermediate-term androgen suppression [ITAS]), or accompanied by 18 months of zoledronic acid (4 mg every 3 months, intravenously) starting at randomisation (STAS plus zoledronic acid), or both (ITAS plus zoledronic acid). All patients received radiotherapy to the prostate and seminal vesicles, starting from the end of the fifth month of androgen suppression; dosing options were 66, 70, and 74 Gy in 2-Gy fractions per day, or 46 Gy in 2-Gy fractions followed by a high-dose-rate brachytherapy boost dose of 19·5 Gy in 6·5-Gy fractions. Treatment allocation was open label. The primary endpoint was prostate cancer-specific mortality and was analysed according to intention-to-treat using competing-risks methods. The trial is closed to follow-up and this is the final report of the main endpoints. This trial is registered with ClinicalTrials.gov, number NCT00193856. FINDINGS: Between Oct 20, 2003, and Aug 15, 2007, 1071 men were enrolled and randomly assigned to STAS (n=268), ITAS (n=268), STAS plus zoledronic acid (n=268), and ITAS plus zoledronic acid (n=267). Median follow-up was 10·4 years (IQR 7·9-11·7). At this 10-year follow-up, no interactions were observed between androgen suppression and zoledronic acid so the treatment groups were collapsed to compare treatments according to duration of androgen suppression: 6 months of androgen suppression plus radiotherapy (6AS+RT) versus 18 months of androgen suppression plus radiotherapy (18AS+RT) and to compare treatments according to whether or not patients received zoledronic acid. The total number of deaths was 375 (200 men receiving 6AS+RT and 175 men receiving 18AS+RT), of which 143 (38%) were attributable to prostate cancer (81 men receiving 6AS+RT and 62 men receiving 18AS+RT). When analysed by duration of androgen suppression, the adjusted cumulative incidence of prostate cancer-specific mortality was 13·3% (95% CI 10·3-16·0) for 6AS+RT versus 9·7% (7·3-12·0) for 18AS+RT, representing an absolute difference of 3·7% (95% CI 0·3-7·1; sub-hazard ratio [sHR] 0·70 [95% CI 0·50-0·98], adjusted p=0·035). The addition of zoledronic acid did not affect prostate cancer-specific mortality; the adjusted cumulative incidence of prostate cancer-specific mortality was 11·2% (95% CI 8·7-13·7) with zoledronic acid vs 11·7% (9·2-14·1) without, representing an absolute difference of -0·5% (95% CI -3·8 to 2·9; sHR 0·95 [95% CI 0·69-1·32], adjusted p=0·78). Although safety analysis was not prespecified for this 10-year analysis, one new serious adverse event (osteonecrosis of the mandible, in a patient who received 18 months of androgen suppression plus zoledronic acid) occurred since our previous report, bringing the total number of cases of this serious adverse event to three (<1% out of 530 patients who received zoledronic acid evaluated for safety) and the total number of drug-related serious adverse events to 12 (1% out of all 1065 patients evaluable for safety). No treatment-related deaths occurred during the study. INTERPRETATION: 18 months of androgen suppression plus radiotherapy is a more effective treatment option for locally advanced prostate cancer than 6 months of androgen suppression plus radiotherapy, but the addition of zoledronic acid to this treatment regimen is not beneficial. Evidence from the RADAR and French Canadian Prostate Cancer Study IV trials suggests that 18 months of androgen suppression with moderate radiation dose escalation is an effective but more tolerable option than longer durations of androgen suppression for men with locally advanced prostate cancer including intermediate and high risk elements. FUNDING: National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, AbbVie Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, Cancer Standards Institute New Zealand, University of Newcastle (Australia), Hunter Medical Research Institute, Calvary Mater Newcastle Radiation Oncology Fund, and Maitland Cancer Appeal.

Radiotherapy for cutaneous head and neck cancer and parotid tumours: a prospective investigation of treatment-related acute swallowing and toxicity patterns.

PURPOSE: Reports of acute treatment-related dysphagia and toxicities for patients with parotid tumours or cutaneous head and neck cancer (HNC) are limited. This study aimed to describe the severity and timing of dysphagia and related toxicities experienced during radiotherapy for cutaneous HNC and parotid tumours, to inform the nature of future speech pathology (SP) service models required during treatment. METHODS: Prospective study of 32 patients with parotid tumours and 36 with cutaneous HNC undergoing curative non-surgical management. Dysphagia and acute toxicity data was collected weekly during treatment and at 2, 4 and 12 weeks post-treatment using the Functional Oral Intake Scale, diet descriptors and CTCAE v4.0. RESULTS: In both groups, minimal treatment toxicities (grades 0-1) were observed. Xerostomia and dysgeusia were the most frequently reported grade 2 toxicities. Only 3% of parotid patients and 6% with cutaneous HNC experienced grade 3 dysphagia. Full or soft texture diets were maintained by > 70% of patients in both groups. Symptoms peaked in the final week of treatment and rapidly improved thereafter. Apart from xerostomia < 10% of patients had any grade 2 toxicity at 12 weeks post-treatment. CONCLUSION: Patients in these subgroups of HNC experienced minimal treatment-related toxicity during radiotherapy. As such, the need for supportive symptom management by SP is low. Models that involve interdisciplinary surveillance of symptoms with referral to SP only when required may be best suited for these individuals to ensure issues are identified whilst minimising patient burden created by unnecessary routine SP appointments.

The ENHANCES study: a randomised controlled trial of a nurse-led survivorship intervention for patients treated for head and neck cancer.

PURPOSE: A randomised controlled trial was conducted to evaluate the effectiveness of a nurse-delivered Head and Neck Cancer Survivor Self-Management Care Plan (HNCP) for patients who had completed treatment for head and neck cancer (HNC). METHODS: Ten oncology nurses were trained to deliver the HNCP. The HNCP consisted of one face-to-face hour-long meeting in which the patient's treatment was recorded, as were contact details of health professionals involved in their care and follow-up schedules. Patients were guided to nominate up to three goals for their future well-being and assisted to devise an action plan to achieve these. The HNCP was given to the patient and a copy was forwarded to their primary care physician. One hundred and nine patients were randomised after definitive curative intent treatment, 36 to HNCP, 36 to receive information about survivorship, and 37 to usual care. The primary outcome, analysed by intention-to-treat, was change in quality of life measured by the FACT-H&N from baseline to 6-month follow-up. RESULTS: Quality of life of all groups decreased at 3 months but was close to baseline at 6 months. Compared with the usual care group, the only statistically significant mean difference at 6 months was for the information group on the physical well-being domain (mean difference 0.4, 95% - 1.8, 2.6, p < 0.05). CONCLUSIONS: A single-session nurse-delivered intervention is insufficient to improve the quality of life in HNC survivors compared with usual care. Provision of detailed written information about HNC survivorship is associated with improved physical well-being. TRIAL REGISTRATION: ACTRN12613000542796.

Randomised controlled trial of early prophylactic feeding vs standard care in patients with head and neck cancer.

BACKGROUND: Weight loss remains significant in patients with head and neck cancer, despite prophylactic gastrostomy and intensive dietary counseling. The aim of this study was to improve outcomes utilising an early nutrition intervention. METHODS: Patients with head and neck cancer at a tertiary hospital in Australia referred for prophylactic gastrostomy prior to curative intent treatment were eligible for this single centre randomised controlled trial. Exclusions included severe malnutrition or dysphagia. Patients were assigned following computer-generated randomisation sequence with allocation concealment to either intervention or standard care. The intervention group commenced supplementary tube feeding immediately following tube placement. Primary outcome measure was percentage weight loss at three months post treatment. RESULTS: Recruitment completed June 2015 with 70 patients randomised to standard care (66 complete cases) and 61 to intervention (56 complete cases). Following intention-to-treat analysis, linear regression found no effect of the intervention on weight loss (10.9±6.6% standard care vs 10.8±5.6% intervention, P=0.930) and this remained non-significant on multivariable analysis (P=0.624). No other differences were found for quality of life or clinical outcomes. No serious adverse events were reported. CONCLUSIONS: The early intervention did not improve outcomes, but poor adherence to nutrition recommendations impacted on potential outcomes.

Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): an open-label, randomised, phase 3 factorial trial.

BACKGROUND: We investigated whether 18 months of androgen suppression plus radiotherapy, with or without 18 months of zoledronic acid, is more effective than 6 months of neoadjuvant androgen suppression plus radiotherapy with or without zoledronic acid. METHODS: We did an open-label, randomised, 2 × 2 factorial trial in men with locally advanced prostate cancer (either T2a N0 M0 prostatic adenocarcinomas with prostate-specific antigen [PSA] ≥10 µg/L and a Gleason score of ≥7, or T2b-4 N0 M0 tumours regardless of PSA and Gleason score). We randomly allocated patients by computer-generated minimisation--stratified by centre, baseline PSA, tumour stage, Gleason score, and use of a brachytherapy boost--to one of four groups in a 1:1:1:1 ratio. Patients in the control group were treated with neoadjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly) for 6 months (short-term) and radiotherapy alone (designated STAS); this procedure was either followed by another 12 months of androgen suppression with leuprorelin (intermediate-term; ITAS) or accompanied by 18 months of zoledronic acid (4 mg every 3 months for 18 months, intravenously; STAS plus zoledronic acid) or by both (ITAS plus zoledronic acid). The primary endpoint was prostate cancer-specific mortality. This analysis represents the first, preplanned assessment of oncological endpoints, 5 years after treatment. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00193856. FINDINGS: Between Oct 20, 2003, and Aug 15, 2007, 1071 men were randomly assigned to STAS (n=268), STAS plus zoledronic acid (n=268), ITAS (n=268), and ITAS plus zoledronic acid (n=267). Median follow-up was 7·4 years (IQR 6·5-8·4). Cumulative incidences of prostate cancer-specific mortality were 4·1% (95% CI 2·2-7·0) in the STAS group, 7·8% (4·9-11·5) in the STAS plus zoledronic acid group, 7·4% (4·6-11·0) in the ITAS group, and 4·3% (2·3-7·3) in the ITAS plus zoledronic acid group. Cumulative incidence of all-cause mortality was 17·0% (13·0-22·1), 18·9% (14·6-24·2), 19·4% (15·0-24·7), and 13·9% (10·3-18·8), respectively. Neither prostate cancer-specific mortality nor all-cause mortality differed between control and experimental groups. Cumulative incidence of PSA progression was 34·2% (28·6-39·9) in the STAS group, 39·6% (33·6-45·5) in the STAS plus zoledronic acid group, 29·2% (23·8-34·8) in the ITAS group, and 26·0% (20·8-31·4) in the ITAS plus zoledronic acid group. Compared with STAS, no difference was noted in PSA progression with ITAS or STAS plus zoledronic acid; however, ITAS plus zoledronic acid reduced PSA progression (sub-hazard ratio [SHR] 0·71, 95% CI 0·53-0·95; p=0·021). Cumulative incidence of local progression was 4·1% (2·2-7·0) in the STAS group, 6·1% (3·7-9·5) in the STAS plus zoledronic acid group, 1·5% (0·5-3·7) in the ITAS group, and 3·4% (1·7-6·1) in the ITAS plus zoledronic acid group; no differences were noted between groups. Cumulative incidences of bone progression were 7·5% (4·8-11·1), 14·6% (10·6-19·2), 8·4% (5·5-12·2), and 7·6% (4·8-11·2), respectively. Compared with STAS, STAS plus zoledronic acid increased the risk of bone progression (SHR 1·90, 95% CI 1·14-3·17; p=0·012), but no differences were noted with the other two groups. Cumulative incidence of distant progression was 14·7% (10·7-19·2) in the STAS group, 17·3% (13·0-22·1) in the STAS plus zoledronic acid group, 14·2% (10·3-18·7) in the ITAS group, and 11·1% (7·6-15·2) in the ITAS plus zoledronic acid group; no differences were recorded between groups. Cumulative incidence of secondary therapeutic intervention was 25·6% (20·5-30·9), 28·9% (23·5-34·5), 20·7% (16·1-25·9), and 15·3% (11·3-20·0), respectively. Compared with STAS, ITAS plus zoledronic acid reduced the need for secondary therapeutic intervention (SHR 0·67, 95% CI 0·48-0·95; p=0·024); no differences were noted with the other two groups. An interaction between trial factors was recorded for Gleason score; therefore, we did pairwise comparisons between all groups. Post-hoc analyses suggested that the reductions in PSA progression and decreased need for secondary therapeutic intervention with ITAS plus zoledronic acid were restricted to tumours with a Gleason score of 8-10, and that ITAS was better than STAS in tumours with a Gleason score of 7 or lower. Long-term morbidity and quality-of-life scores were not affected adversely by 18 months of androgen suppression or zoledronic acid. INTERPRETATION: Compared with STAS, ITAS plus zoledronic acid was more effective for treatment of prostate cancers with a Gleason score of 8-10, and ITAS alone was effective for tumours with a Gleason score of 7 or lower. Nevertheless, these findings are based on secondary endpoint data and post-hoc analyses and must be regarded cautiously. Long- term follow-up is necessary, as is external validation of the interaction between zoledronic acid and Gleason score. STAS plus zoledronic acid can be ruled out as a potential therapeutic option. FUNDING: National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, Abbott Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, University of Newcastle (Australia), Calvary Health Care (Calvary Mater Newcastle Radiation Oncology Fund), Hunter Medical Research Institute, Maitland Cancer Appeal, Cancer Standards Institute New Zealand.

Impact of androgen suppression and zoledronic acid on bone mineral density and fractures in the Trans-Tasman Radiation Oncology Group (TROG) 03.04 Randomised Androgen Deprivation and Radiotherapy (RADAR) randomized controlled trial for locally advanced prostate cancer.

OBJECTIVE: To study the influence of adjuvant androgen suppression and bisphosphonates on incident vertebral and non-spinal fracture rates and bone mineral density (BMD) in men with locally advanced prostate cancer. PATIENTS AND METHODS: Between 2003 and 2007, 1071 men with locally advanced prostate cancer were randomly allocated, using a 2 × 2 trial design, to 6 months i.m. leuprorelin (androgen suppression [AS]) before radiotherapy alone ± 12 months additional leuprorelin ± 18 months zoledronic acid (ZdA), commencing at randomization. The main endpoint was incident thoraco-lumbar vertebral fractures, which were assessed radiographically at randomization and at 3 years, then reassessed by centralized review. Subsidiary endpoints included incident non-spinal fractures, which were documented throughout follow-up, and BMD, which was measured in 222 subjects at baseline, 2 years and 4 years. RESULTS: Incident vertebral fractures at 3 years were observed in 132 subjects. Their occurrence was not increased by 18 months' AS, nor reduced by ZdA. Incident non-spinal fractures occurred in 72 subjects and were significantly related to AS duration but not to ZdA. Osteopenia and osteoporosis prevalence rates at baseline were 23.4 and 1.4%, respectively, at the hip. Treatment for 6 and 18 months with AS caused significant reductions in hip BMD at 2 and 4 years (P < 0.01) and ZdA prevented these losses at both time points. CONCLUSION: In an AS-naïve population, 18 months of ZdA treatment prevented the sustained BMD losses caused by 18 months of AS treatment; however, the study power was insufficient to show that AS duration or ZdA influenced vertebral fracture rates.

Protocol for a randomized controlled trial of early prophylactic feeding via gastrostomy versus standard care in high risk patients with head and neck cancer.

BACKGROUND: Patients with head and neck cancer are at high risk of malnutrition and dysphagia. Enteral tube feeding via a gastrostomy or nasogastric tube is often required in response to dysphagia, odynophagia or side effects of treatment that lead to dehydration and/or weight-loss. A recent systematic review concluded that the optimal method of tube feeding remains unclear; however prophylactic gastrostomy, placed in anticipation of its use during and after treatment, is common practice, following a number of demonstrated benefits. However the majority of these studies have been undertaken in patients receiving radiotherapy alone. More recent studies in patient populations receiving concurrent chemoradiotherapy are showing that despite prophylactic gastrostomy placement significant weight loss still occurs, placing the patient at risk of the consequences of malnutrition. Therefore we set out to investigate innovative prophylactic nutrition support via the gastrostomy to optimise the nutritional outcomes of patients with head and neck cancer. METHODS/DESIGN: Patients with head and neck cancer will be eligible for this single centre randomised controlled trial if they are identified for referral for a prophylactic gastrostomy using local guidelines. Patients will be excluded if they are: under the age of eighteen; pregnant; unable to give informed consent; or severely malnourished or moderately malnourished with significant dysphagia requiring a liquid or puree diet. All eligible patients who consent for the study will be allocated randomly to either the intervention or control group (usual care). The intervention group will commence prophylactic supplementary nutrition support via the gastrostomy immediately following placement compared to usual care where nutrition support is commenced via the gastrostomy when clinically indicated during treatment. Key outcome measures will be percentage weight loss, body composition, nutritional status and quality of life, measured at baseline and three months post treatment. DISCUSSION: To our knowledge this is the first study to evaluate the effectiveness of early prophylactic tube feeding compared to commencement of feeding during treatment, as per current standard practice, in patients undergoing prophylactic gastrostomy prior to treatment for head and neck cancer. TRIAL REGISTRATION: This trial has been registered in the Australian New Zealand Clinical Trials registry as ACTRN12612000579897.

The potential of hydrogel-free tumoroids in head and neck squamous cell carcinoma.

BACKGROUND: Head and neck malignancy, and in particular squamous cell carcinoma (SCC), is responsible for a significant disease burden globally. The lack of an optimal in vitro model system to accurately recapitulate in vivo response to therapy in HNSCC remains a challenge. The development of patient-derived three-dimensional tumour cultures, or tumoroids, has enabled improved modelling of the tumour microenvironment through simulation of important characteristics such as tumour hypoxia, cell-cell interactions and nutrient diffusion characteristics. METHODS: We performed a comprehensive English-language literature review of current methods of tumoroid development utilising Matrigel and Cultrex Basement Membrane Extract 2 (key terms: tumour organoids, tumoroids, hydrogels, Matrigel, Cultrex, squamous cell carcinoma, head and neck)-two common proprietary murine-derived hydrogels containing extracellular matrix proteins. Nascent literature on the establishment of a novel hydrogel-free platform for tumoroid development as distinct from these existing methods was also explored. RESULTS: Whilst useful for facilitating cell-matrix interactions and providing a scaffold for three-dimensional cell growth and organisation, murine-derived cell matrix methods were noted to have notable limitations including temperature sensitivity and the medium forming a barrier to analysis of the supernatant. A novel hydrogel-free method of establishing in vitro tumoroid cultures has been subject to experimentation in colorectal but not head and neck malignancy. The absence of a hydrogel provides for the de novo synthesis of extracellular matrix native to the tumour and self-organisation of cells within this scaffold through the use of ultralow attachment plates. This model demonstrates similar structural and physiological properties to native tissue, whilst enabling more accurate biomimicry of the tumour microenvironment for drug testing. CONCLUSIONS: In the absence of prior experimentation on a hydrogel-free method for establishing HNSCC tumoroids, and comparisons between hydrogel and hydrogel-free models, the future development of a comparative protocol encompassing recruitment, collection, processing and analysis represents a valuable opportunity.

Survival and Patterns of Relapse of Cutaneous Squamous Cell Carcinoma With Large Nerve Perineural Spread After Skull Base Surgery and/or Radiation Therapy.

PURPOSE: The aim of our study was to evaluate survival and patterns of relapse for patients with perineural spread (PNS) of cutaneous squamous cell carcinoma (cSCC), who have undergone curative intent skull base surgery and/or radiation therapy. In addition, we modified the classification of zone 2 disease into 2a and 2b and reported the respective outcome. METHODS AND MATERIALS: A review of a prospective database of patients who received diagnoses of PNS of cSCC and were treated with curative intent skull base surgery and/or radiation therapy between the years of 2013 and 2020 was conducted. Kaplan-Meier methods were used to estimate relapse-free survival (RFS), disease-specific survival (DSS), and overall survival (OS). Cox proportional hazard modeling was performed to test associations between patient factors and survival outcomes. RESULTS: Eighty patients with a median follow-up of 36 months were included in the study. The 5-year RFS was 61% (95% CI, 48%-71%), the DSS was 77% (95% CI, 63%-86%), and OS was 67% (95% CI, 53%-78%). In multivariable modeling, involvement of 2 or more nerves was strongly associated with worse 5-year RFS (HR, 4.0; P ≤ .001), DSS (HR, 4.5; P = .004), and OS (HR, 4.3; P = .002). Age group (≥65 years) (HR, 5.1; P = .010) and immune compromise (HR, 10.7; P = .001) were strongly associated with worse OS but not DSS or RFS. The majority of relapses (60%) occurred at the local skin sites. CONCLUSIONS: Our study demonstrated surgery followed by radiation therapy was safe and effective in the management of cSCC with PNS. We did not detect a difference in outcome between zones 2a and 2b though further study is required. The most common mode of relapse was at the skin epidermis and/or adjacent dermis highlighting the importance of adequate local skin dose delivery.

Quality of life in men with locally advanced prostate cancer treated with leuprorelin and radiotherapy with or without zoledronic acid (TROG 03.04 RADAR): secondary endpoints from a randomised phase 3 factorial trial.

BACKGROUND: Adjuvant androgen suppression and bisphosphonates with escalating doses of radiotherapy might improve efficacy outcomes in men with locally advanced prostate cancer. In this study, we investigated whether these treatments had a detrimental effect on patient-reported-outcome (PRO) scores. METHODS: We undertook a phase 3 trial with a 2×2 factorial design in 23 centres in Australia and New Zealand in men with non-metastatic adenocarcinoma of the prostate (stage T2b-4 or T2a, Gleason score ≥7, and baseline prostate-specific antigen concentration [PSA] ≥10 µg/L), and without previous lymph node or systemic metastases or comorbidities that could reduce life expectancy to less than 5 years. The men were randomly assigned in a 1:1:1:1 ratio to 6 months of neoadjuvant (short-term) androgen suppression (STAS) with leuprorelin (22·5 mg every 3 months, intramuscularly) or an additional 12 months (intermediate-term androgen suppression [ITAS]) of leuprorelin with or without 18 months of zoledronic acid (4 mg every 3 months, intravenously). Study drug administration commenced at randomisation after which radiotherapy started within the fifth month in all groups. Treatment allocation was open-label, and computer-generated randomisation, stratified by centre, baseline concentrations of PSA, clinical stage of the tumour, Gleason score, and use of a brachytherapy boost, was done by use of the minimisation technique. PRO scores were calculated from European Organization for Research and Treatment of Cancer quality-of-life and prostate-specific quality-of-life module questionnaires and compared with multiple regression models at baseline, and end of radiotherapy, and 18 months and 36 months according to group and radiation dose. The trial is ongoing and the primary endpoint, prostate-cancer-specific mortality, will be reported in 2014. This study is the final report of PRO scores (a secondary endpoint). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00193856. FINDINGS: 1071 men were randomly assigned to STAS (n=268), STAS plus zoledronic acid (n=268), ITAS (n=268), and ITAS plus zoledronic acid (n=267). At the end of radiotherapy, significant detrimental changes in PRO scores (p<0·01) occurred in all groups. There were no significant differences in global health status between groups at any timepoint. At 18 months, PROs that were significantly worse in the ITAS groups when compared with STAS were hormone-treatment-related symptoms (HTRS; STAS, 10·20 [95% CI 8·66-11·75]; ITAS, 17·36 [13·63-21·08], p<0·01; and ITAS plus zoledronic acid, 19·14 [15·43-22·85], p<0·01), sexual activity (STAS, 26·38 [23·50-29·27]; ITAS, 14·40 [7·44-21·36], p<0·01; and ITAS plus zoledronic acid, 16·34 [9·39-23·28], p<0·01), social function (STAS, 90·31 [87·89-92·73]; ITAS, 87·35 [81·52-93·18], p=0·09; and ITAS plus zoledronic acid, 83·66 [77·85-89·48], p<0·01), fatigue (STAS, 17·05 [14·58-19·51]; ITAS 24·52 [18·58-30·46], p<0·01; and ITAS plus zoledronic acid, 24·26 [18·33-30·18], p<0·01), and financial problems (STAS, 3·39 [1·29-5·48]; ITAS, 8·97 [3·92-14·02], p<0·01; and ITAS plus zoledronic acid, 8·92 [3·89-13·96], p<0·01). With the exception of HTRS, in which marginal differences remained, persisting significant differences disappeared by 36 months. Other factors associated with significant detrimental changes in PRO scores were a brachytherapy boost, incomplete testosterone and haemoglobin recoveries, age, and smoking. INTERPRETATION: Compared with 6 months of androgen suppression, 18 months of androgen suppression causes additional detrimental changes at the 18 month follow-up in some PRO scores but not in global quality-of-life scores. However, with the exception of HTRS, these differences resolved by 36 months. The use of zoledronic acid every 3 months over 18 months does not result in additional detrimental changes, but the use of a brachytherapy boost to achieve radiation dose escalation in the prostate can adversely affect emotional function and financial problems. FUNDING: National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, Abbott Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, University of Newcastle (Australia), Hunter Medical Research Institute, Calvary Mater Radiation Oncology Fund, and Maitland Cancer Appeal.

Standards and quality assurance in interventional oncology: The establishment of the International Accreditation System for Interventional Oncology Services (IASIOS).

Quality assurance is integral to benchmarking and continuous improvement in the clinical care of people affected by cancer. Quality assurance systems are built upon agreed clinical and administrative standards. The Cardiovascular and Interventional Radiology Society of Europe (CIRSE) first developed a set of Standards for Interventional Oncology Services modelled on the Standards of Practice in Radiation Oncology developed in Australia and New Zealand. A subset of these Standards has been used to develop a tiered International Accreditation System in Interventional Oncology (IASIOS). This system covers the entirety of the patient care pathway from referral through to discharge and is clearly aimed at setting the benchmark for safe, quality interventional oncology (IO) services. Such a system has multiple benefits, including increasing the awareness of the availability of IO services and assurance in the quality of the care delivered to patients.

A comparison between mutational profiles in tumour tissue DNA and circulating tumour DNA in head and neck squamous cell carcinoma - A systematic review.

BACKGROUND: Head and neck cancer is the seventh most common malignancy globally. Head and neck squamous cell carcinoma (HNSCC) originates from squamous cells and 90% of HNC are HNSCC. The gold standard for diagnosing HNSCC is tissue biopsy. However, given tumour heterogeneity, biopsies may miss important cancer-associated molecular signatures, and more importantly, after the tumour is excised, there is no means of tracking response to treatment in patients. Captured under liquid biopsy, circulating tumour DNA (ctDNA), may identify in vivo molecular genotypes and complements tumour tissue analysis in cancer management. A systematic search was conducted in PubMed, Embase, Scopus and the Cochran Library between 2012 to early 2023 on ctDNA in HNSCC using publications written in English. We summarise 20 studies that compared mutational profiles between tumour tissue DNA (tDNA) and ctDNA, using a cohort of 631 HNSCC patients and 139 controls. Among these studies, the concordance rates varied greatly and the most mutated and the most concordant gene was TP53, followed by PIK3CA, CDKN2A, NOTCH1 and FAT1. Concordant variants were mainly found in Stage IV tumours, and the mutation type is mostly single nucleotide variants (SNV). We conclude that, as a biomarker for HNSCC, ctDNA demonstrates great promise as it recapitulates tumour genotypes, however additional multi-central trials are needed.