What is access to radiation therapy? A conceptual framework and review of influencing factors.

OBJECTIVES: Optimal radiation therapy (RT) utilisation rates (RURs) have been defined for various cancer indications through extensive work in Australia and overseas. These benchmarks remain unrealised. The gap between optimal RUR and actual RUR has been attributed to inadequacies in 'RT access'. We aimed to develop a conceptual framework for the consideration of 'RT access' by examining the literature for existing constructs and translating it to the context of RT services. We further aimed to use this framework to identify and examine factors influencing 'RT access'. METHODS: Existing models of health care access were reviewed and used to develop a multi-dimensional conceptual framework for 'RT access'. A review of the literature was then conducted to identify factors reported to affect RT access and utilisation. The electronic databases searched, the host platform and date range of the databases searched were Ovid MEDLINE, 1946 to October 2014 and PsycINFO via OvidSP,1806 to October 2014. RESULTS: The framework developed demonstrates that 'RT access' encompasses opportunity for RT as well as the translation of this opportunity to RT utilisation. Opportunity for RT includes availability, affordability, adequacy (quality) and acceptability of RT services. Several factors at the consumer, referrer and RT service levels affect the translation of this opportunity for RT to actual RT utilisation. CONCLUSION: 'Access' is a term that is widely used in the context of health service related research, planning and political discussions. It is a multi-faceted concept with many descriptions. We propose a conceptual framework for the consideration of 'RT access' so that factors affecting RT access and utilisation may be identified and examined. Understanding these factors, and quantifying them where possible, will allow objective evaluation of their impact on RT utilisation and guide implementation of strategies to modify their effects.

Barriers to radiotherapy utilisation in New South Wales Australia: Health professionals' perceptions of impacting factors.

INTRODUCTION: Utilisation of radiation therapy (RT) in Australia is below recommended evidence-based benchmarks. Barriers to the referral of patients for RT and the uptake of RT by patients may be affecting RT utilisation. The current study aimed to examine health professionals' (HPs) perceptions of potential barriers to RT referral and uptake. METHODS: A custom survey was developed to assess perceptions regarding the degree to which a range of issues affect decisions regarding RT. Hard copy surveys were disseminated to HPs involved in the care of cancer patients across New South Wales (NSW): medical, radiation and surgical oncologists, physicians (including palliative care), and general practitioners with an interest in oncology. Electronic versions of the survey were disseminated via oncology multidisciplinary teams and professional networks at participating hospitals. RESULTS: Two hundred fifty-three HPs participated via hard copy (n = 208) or electronic (n = 45) surveys. Two-thirds of HPs perceived acute side effects of RT, their management and impact on daily commitments, as well as fear and anxiety about RT, to exert moderate to significant influence on RT decisions. Treatment-related travel, need for accommodation and relocation were also perceived by 64% of HPs to do the same. Over half of HPs rated concern regarding late effects of RT, disruption to family and work life, and the ability to organise family and work commitments around RT, as moderate to significant influences on RT uptake. CONCLUSION: Perceptions of HPs in NSW reveal potential important influencers of RT decisions by patients and clinicians. An understanding of these additional issues and their actual impact on RT-related decisions may inform future interventions to improve RT access and utilisation.

Factors influencing the use of RT in NSW: a qualitative study exploring consumer and health professional perspectives.

INTRODUCTION: Radiotherapy (RT) is an essential and cost-effective cancer treatment. It is underutilised in Australia. Bridging the gap between actual and optimal RT utilisation requires not only provision of adequate RT infrastructure but also an understanding of the factors that influence the extent to which this opportunity for RT is utilised. This study explored factors perceived to affect RT-related decision making by consumers and health professionals (HPs). METHODS: Six semi-structured focus groups (FGs) and 13 interviews were conducted at three geographical locations in NSW, Australia (n = 26 consumers and 30 HPs). Audio recordings of FGs and interviews were transcribed verbatim and analysed thematically. RESULTS: An exhaustive list of issues perceived to affect consumer and HP RT decisions was identified. There were common themes across participant groups and locations. Perceptions of RT and its benefits, as well as accurate communication of the expected benefits and risks of RT, were highlighted as important to decision making. Perceived factors relating to 'inconvenience' of RT were multifaceted and included travel, relocation, accommodation, time away from work and financial challenges. Perceived potential barriers to RT referral included knowledge of RT and RT services, availability of a local or visiting RT service, referrer bias, and the low profile of RT. CONCLUSIONS: Important drivers during RT decisions appear to include the perceived benefit, risks and inconvenience of RT. Underutilisation of RT may also result from multiple barriers at the referrer level. Further research into whether these factors influence actual RT decisions is needed.

Metastatic head and neck cutaneous squamous cell carcinoma: defining a low-risk patient.

BACKGROUND: The purpose of this study was to determine whether there is a "low-risk" subset of patients with regional metastatic head and neck cutaneous squamous cell carcinoma (SCC) suitable for treatment with surgery alone and omission of adjuvant radiotherapy. METHODS: We conducted a retrospective analysis of 168 patients with a single parotid gland or neck nodal metastasis ≤3 cm in size from cutaneous SCC treated with curative intent by surgery ± adjuvant radiotherapy. RESULTS: Disease-specific survival for the 33 patients treated with surgery alone was 97% at 5 years. In the subset of 19 patients without extracapsular nodal spread (ECS), there was 1 regional recurrence which was successfully salvaged yielding a 5-year disease-specific survival of 100%. CONCLUSION: In head and neck cutaneous SCC, the subset with a single node ≤3 cm in size without ECS are at low risk of regional failure and death from cutaneous cancer. These patients may be suitable for single-modality therapy with surgery alone.

Use of cyclin D1 in conjunction with human papillomavirus status to predict outcome in oropharyngeal cancer.

There is increasing use of multiple molecular markers to predict prognosis in human cancer. Our aim was to examine the prognostic significance of cyclin D1 and retinoblastoma (pRb) expression in association with human papillomavirus (HPV) status in oropharyngeal squamous cell carcinoma. Clinical records and specimens of 226 patients with follow-up from 1 to 235 months postdiagnosis were retrieved. Tumor HPV status was determined by HPV E6-targeted multiplex real-time PCR/p16 semiquantitative immunohistochemistry and cyclin D1 and pRb expression by semiquantitative immunohistochemistry. Determinants of recurrence and mortality hazards were modeled using Cox regression with censoring at dates of last follow-up. The HPV-positivity rate was 37% (91% type 16). HPV was a predictor of recurrence, an event (recurrence or death) and death after adjustment for clinicopathological variables. There were inverse relationships between HPV status and cyclin D1 and pRb. On univariate analysis, cyclin D1 predicted locoregional recurrence, event and death and pRb predicted event and death. Within the HPV-positive group, after adjusting for clinicopathological factors, patients with cyclin D1-positive cancers had up to a eightfold increased risk of poor outcome relative to those with cyclin D1-negative tumors. However, within the HPV-negative group, there was only a very small adjusted increased risk. A combination of pRb and HPV did not provide additional prognostic information. Our data provide the first evidence that a combination of HPV and cyclin D1 provides more prognostic information in oropharyngeal cancer than HPV alone. If findings are confirmed, treatment based on HPV and cyclin D1 may improve outcomes.

Lymph node ratio as an independent prognostic factor in oral squamous cell carcinoma.

BACKGROUND: We aimed to validate the lymph node ratio (LNR) as an independent prognostic factor in oral squamous cell carcinoma (OSCC) and compare its utility with the current nodal staging system. METHODS: We conducted a retrospective analysis of 313 patients with OSCC undergoing neck dissection. The LNR was adjusted by relevant covariates in a multivariable Cox regression model. RESULTS: LNR displaced conventional nodal staging and was shown to be an independent predictor of regional failure (p = .020), disease-specific (p = .003) and overall survival (p = .001). Patients with an LNR of 2.5% to 7.5%, 7.5% to 20%, and >20% had 2.6, 3.7, and 4.4 times the risk of death from OSCC, respectively, when compared with patients with an LNR <2.5%. CONCLUSIONS: The LNR is an independent prognostic factor in OSCC and may be used in conjunction with the current TNM staging to enable better risk stratification and selection for adjuvant therapy.

Predicting the prognosis of oral squamous cell carcinoma after first recurrence.

OBJECTIVES: to describe the clinicopathologic features of oral squamous cell carcinoma in patients who develop locoregional recurrence of disease, to identify factors that predict prognosis in the subset of patients treated with salvage surgery, and to determine the adjusted effect of time to recurrence. DESIGN: cohort study. SETTING: a head and neck cancer institute in Sydney, New South Wales, Australia. PATIENTS: a total of 77 patients who underwent salvage surgery for oral squamous cell carcinoma that had been treated initially by surgery, radiotherapy, or surgery with postoperative radiotherapy. MAIN OUTCOME MEASURES: univariable and multivariable analysis of clinical and pathologic risk factors. RESULTS: median time to recurrence from initial treatment was 7.5 months (range, 0.9-143.9 mo), with 86% of recurrences occurring within the first 24 months. Surgical salvage was attempted in 77 patients who had experienced recurrence at the primary site (n = 39), ipsilateral neck (n = 27), and contralateral neck (n = 11). Time to recurrence, initial treatment modality, and site of failure were independent prognostic variables. CONCLUSIONS: the relationship of these prognostic variables displays a dynamic interaction. Initial combined-modality treatment and shorter time to recurrence were associated with worse outcome, while the effect of site of recurrence (local vs regional) was dependent on an interaction with the time to recurrence. The result of this interaction was that local recurrence was worse for those who experienced it early (eg, <6 mo after the initial treatment) and nodal recurrence was worse for those who experienced it late (eg, ≥ 6 mo after the intial treatment).

Squamous cell carcinoma of the oropharynx in Australian males induced by human papillomavirus vaccine targets.

This study provides Australian data on the incidence of human papillomavirus (HPV)-related oropharyngeal cancer to aid the debate on extending the HPV vaccination programme to males. The HPV status for 302 oropharyngeal cancers diagnosed between 1987 and 2006 was determined by HPV E6-targeted multiplex real-time PCR/p16 immunohistochemistry. The overall HPV-positivity rate was 36% (94% types 16 and 18). HPV-related cancer increased from 19% (1987-1990) to 47% (2001-2005). HPV data used in conjunction with Australian cancer incidence data 2001-2005 showed that 1.56 cases of oropharyngeal cancer per 100,000 males per year were associated with HPV types targeted by the vaccine. Vaccinating males may substantially reduce the burden of oropharyngeal cancer in Australia.

Predicting the pattern of regional metastases from cutaneous squamous cell carcinoma of the head and neck based on location of the primary.

BACKGROUND: We aimed to analyze the distribution of regional nodal metastases according to primary tumor location in patients with cutaneous squamous cell carcinoma of the head and neck (SCCHN). METHODS: Analysis of 295 neck dissections performed for patients with clinically evident regional metastases from cutaneous SCCHN between 1987 and 2009. RESULTS: Level I involvement in the absence of level II or III only occurred in patients with facial primaries. In patients with clear nodes in level II-III, the risk of level IV-V involvement was 0.0% for external ear primaries, 2.7% for face and anterior scalp, and 15.8% for posterior scalp and neck. CONCLUSION: In patients undergoing parotidectomy for metastatic cutaneous SCCHN with a clinically negative neck, the results of this study support selective neck dissection including level I-III for facial primaries, level II-III for anterior scalp and external ear primaries, and levels II-V for posterior scalp and neck primaries.

Characterization of childhood acute lymphoblastic leukemia xenograft models for the preclinical evaluation of new therapies.

Continuous xenografts from 10 children with acute lymphoblastic leukemia (ALL) were established in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Relative to primary engrafted cells, negligible changes in growth rates and immunophenotype were observed at second and third passage. Analysis of clonal antigen receptor gene rearrangements in 2 xenografts from patients at diagnosis showed that the pattern of clonal variation observed following tertiary transplantation in mice exactly reflected that in bone marrow samples at the time of clinical relapse. Patients experienced diverse treatment outcomes, including 5 who died of disease (median, 13 months; range, 11-76 months, from date of diagnosis), and 5 who remain alive (median, 103 months; range, 56-131 months, following diagnosis). When stratified according to patient outcome, the in vivo sensitivity of xenografts to vincristine and dexamethasone, but not methotrexate, differed significantly (P =.028, P =.029, and P =.56, respectively). The in vitro sensitivity of xenografts to dexamethasone, but not vincristine, correlated significantly with in vivo responses and patient outcome. This study shows, for the first time, that the biologic and genetic characteristics, and patterns of chemosensitivity, of childhood ALL xenografts accurately reflect the clinical disease. As such, they provide powerful experimental models to prioritize new therapeutic strategies for future clinical trials.

The nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse model of childhood acute lymphoblastic leukemia reveals intrinsic differences in biologic characteristics at diagnosis and relapse.

Acute lymphoblastic leukemia cells from 19 children, including 7 who remain in first complete remission (CR1), were engrafted into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. High-level infiltration of bone marrow, spleen, and liver was observed, with variable infiltration of other organs. The immunophenotypes of xenografts were essentially unaltered compared with the original patient sample. In addition, sequencing of the entire p53 coding region revealed no mutations in 14 of 14 xenografts (10 from patients at diagnosis and 4 at relapse). Cells harvested from the spleens of engrafted mice readily transferred the leukemia to secondary and tertiary recipients. To correlate biologic characteristics of xenografts with clinical and prognostic features of the patients, the rates at which individual leukemia samples engrafted in NOD/SCID mice were analyzed. Differences in biologic correlates were encountered depending on stage of disease: a direct correlation was observed between the rate of engraftment and length of CR1 for samples harvested at relapse (r = 0.96; P =.002), but not diagnosis (r = 0.38; P =.40). In contrast, the in vivo responses of 6 xenografts to vincristine showed a direct correlation (r = 0.96; P =.002) between the length of CR1 and the rate at which the leukemia cell population recovered following vincristine treatment, regardless of whether the xenografts were derived from patients at diagnosis or relapse. This study supports previous findings that the NOD/SCID model of childhood ALL provides an accurate representation of the human disease and indicates that it may be of value to predict relapse and design alternative treatment strategies in a patient-specific manner.