Risk of radiation necrosis after stereotactic radiosurgery for melanoma brain metastasis by anatomical location.

PURPOSE: In this retrospective study, we have explored the anatomical factors that lead to the development of radiation necrosis (RN) in the setting of stereotactic radiosurgery (SRS) for melanoma brain metastases (MBM). METHODS: Between 2014 and 2018, 137 patients underwent SRS for 311 MBM. Lesions were assessed according to anatomical zones: zone 1-peripheral grey-white matter junction and cortical mantle, zone 2-deep white matter, including tumours located at base of sulci, zone 3-tumours adjacent to ependymal lining or in deep locations such as brainstem, basal ganglia and thalamus. Other anatomical factors including lobes, medial-peripheral, supra or infratentorial locations were also recorded. RESULTS: In all, 12.4% (n = 17) of patients and 6.1% (n = 20) of lesions developed RN, actuarial incidence of RN at 12 and 24 months was 10% and 14.2% respectively. Zone 2 lesions recorded the highest rate of development of RN (n = 7/19; 36%), zone 3 (N = 4/24; 16%) and zone 1 (n = 9/268; 3%). Five of 17 patients developed symptomatic RN and 7/17 patients underwent surgery for RN. CONCLUSION: This study raises awareness of the increased likelihood of deep lesions particularly in white matter structures to develop RN after SRS. Further studies including larger cohorts would be useful in identifying statistical differences in the rate of development of RN in different anatomical zones.

A practical guide on the use of imiquimod cream to treat lentigo maligna.

Lentigo maligna (LM) is a common in situ melanoma subtype arising on chronically sun-damaged skin and mostly affects the head and neck region. Localisation in cosmetically sensitive areas, difficulty to obtain wide resection margins and advanced patient age/comorbidities have encouraged investigation of less invasive therapeutic strategies than surgery in managing complex cases of LM. Radiotherapy and imiquimod have emerged as alternative treatment options in this context. The treatment of LM with imiquimod cream can be challenging due to the nature of the disease including its often large size, variegated appearance, involvement of adnexal structures, poorly defined peripheral edge and frequent localisation close to sensitive structures such as the eyes and lips, and elderly patients with multiple comorbidities. Prolonged and unpredictable inflammatory reaction and side effects and compliance with a patient-delivered therapy can also be challenging. In the literature to date, studies evaluating the use of imiquimod to treat LM have utilised varying methodologies and provided short follow-up and these limitations have impaired the development of clear guidelines for dosage and management of side effects. Based on our multidisciplinary experience and review of the literature, we propose practical clinical strategies for the use of imiquimod for treating LM, detailing optimal administration procedures in various clinical scenarios and long-term management, with the aim of facilitating optimal patient outcomes.

Re-examining the role of adjuvant radiation therapy.

Previously important roles for adjuvant radiotherapy (RT) in melanoma patients included improved regional control after resection of high-risk nodal disease, to reduce local recurrence for desmoplastic, and other subtypes of melanoma with neurotropism, reducing in-brain relapse of brain metastases after surgery and other situations on a case-by-case basis. This review evaluates the integration of adjuvant RT into clinical practice at this time of rapidly evolving knowledge and improving outcomes from effective systemic therapy.

Neurotropic melanoma: an analysis of the clinicopathological features, management strategies and survival outcomes for 671 patients treated at a tertiary referral center.

Neurotropic cutaneous melanoma is a rare melanoma subtype that invades nerves and is often associated with desmoplastic melanoma. Limited data suggest that it has a greater propensity to recur locally, but it is unknown whether its behavior differs from that of other melanoma subtypes, including desmoplastic melanoma. We investigated clinicopathological predictors of outcome in a cohort of 671 patients with neurotropic melanoma to develop evidence-based management recommendations. Patients with primary neurotropic melanoma diagnosed from 1985 to 2013 were identified from the Melanoma Institute Australia database, along with a control cohort of 718 non-neurotropic melanoma patients. Features predictive of sentinel lymph node status, recurrence, melanoma-specific survival and response to adjuvant radiotherapy were sought. Neither local recurrence (hazard ratio: 1.28 (0.73-2.25) P=0.39) nor melanoma-specific survival (hazard ratio: 0.79 (0.55-1.15) P=0.22) were significantly affected by the presence of neurotropism on multivariate analysis. However, there was a markedly reduced likelihood of sentinel node positivity (hazard ratio: 0.61 (0.41-0.89) P=0.01) in neurotropic melanoma patients. Surgical margins ≥8mm halved the recurrence risk compared with <2 mm margins (hazard ratio: 0.46 (0.31-0.68) P<0.001). Additionally, in neurotropic melanoma patients with <8 mm margins, adjuvant radiotherapy halved the recurrence risk (hazard ratio: 0.48 (0.27-0.87) P=0.02). This, the largest study of neurotropic melanoma reported to date, has demonstrated that the presence of neurotropism does not alter the risk of melanoma recurrence or survival but does reduce the likelihood of sentinel node positivity. For successful treatment of neurotropic melanoma, adequate excision margins are of paramount importance. However, when adequate margins cannot be achieved, adjuvant radiotherapy reduces the risk of recurrence.

Debate: adjuvant whole brain radiotherapy or not? More data is the wiser choice.

Every year 170,000 patients are diagnosed with brain metastases (BMs) in the United States. Traditionally, adjuvant whole brain radiotherapy (AWBRT) has been offered following local therapy with neurosurgery (NSx) and/or stereotactic radiosurgery (SRS) to BMs. The aim is to increase intracranial control, thereby decreasing symptoms from intracranial progression and a neurological death. There is a rapidly evolving change in the radiation treatment of BMs happening around the world. AWBRT is now being passed over in favour of repeat scanning at regular intervals and more local therapies as more BMs appear radiologically, BMs that may never become symptomatic. This change has happened after the American Society for Radiation Oncology (ASTRO) in Item 5 of its "Choosing Wisely 2014" list recommended: "Don't routinely add adjuvant whole brain radiation therapy to SRS for limited brain metastases". The guidelines are supposed to be based on the highest evidence to hand at the time. This article debates that the randomised controlled trials (RCTs) published prior to this recommendation consistently showed AWBRT significantly increases intracranial control, and avoids a neurological death, what it is meant to do. It also points out that, despite the enormity of the problem, only 774 patients in total had been randomised over more than three decades. These trials were heterogeneous in many respects. This data can, at best, be regarded as preliminary. In particular, there are no single histology AWBRT trials yet completed. A phase two trial investigating hippocampal avoiding AWBRT (HAWBRT) showed significantly less NCF decline compared to historical controls. We now need more randomised data to confirm the benefit of adjuvant HAWBRT. However, the ASTRO Guideline has particularly impacted accrual to trials investigating this, especially the international ANZMTG 01.07 WBRTMel trial. This is an RCT investigating AWBRT following local treatment in patients with one to three BMs from melanoma. WBRTMel has accrued 196 of a required 220 to date but accrual has slowed. HAWBRT may now never be tested in a randomised setting. Encouraging more data in AWBRT is the wiser choice.

Radiation therapy for advanced and metastatic melanoma.

Radiation therapy (RT) is an important modality in cancer treatment. However, the general perception is that melanoma is radio-resistant. High quality clinical trials are helping to establish the place of RT in select scenarios of advanced disease at primary, regional, and distant sites. New RT techniques need to be integrated with effective new systemic therapies within a multidisciplinary environment to ensure optimum patient outcomes. It is important that radiation oncologists embrace this opportunity.

Longitudinal trajectory of quality of life for patients with melanoma brain metastases: A secondary analysis from a whole brain radiotherapy randomized clinical trial.

Purpose: Brain metastases are common in patients with advanced melanoma. This study describes 12-month quality of life (QoL) trajectories following local management of 1-3 melanoma brain metastases. Methods: This study assessed QoL data collected during a multi-center, prospective, open-label, phase III randomized controlled trial comparing the efficacy of adjuvant whole brain radiotherapy (WBRT) with observation after local treatment of 1-3 melanoma brain metastases. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Core (QLQ-C30) and Brain Tumour (BN-20) questionnaires at baseline and every 2 months, for 12 months.Using growth mixture modelling, QoL trajectories were identified for global health status, QLQ-C30 and BN-20 subscales for patients with baseline and at least one follow-up assessment. Multivariable logistic regression was used to examine associations between trajectories, demographic, and clinical factors. Results: After combining QoL data from observation and WBRT arms, QLQ-C30 and BN-20 trajectories were calculated for 139 and 137 patients respectively. Depending on the QoL domain, 9-54 % of patients reported a deterioration in QoL. Older age (≥65 years) was significantly associated with deterioration in global health status (OR = 2.88, 95 %CI = 1.27-6.54), physical (OR = 3.49, 95 %CI = 1.29-9.41), role (OR = 4.15, 95 %CI = 1.77-9.71), social (OR = 4.42, 95 % CI = 1.57-12.46), cognitive (OR = 6.70, 95 % CI = 1.93-23.29) and motor functioning (OR = 4.95, 95 %CI = 1.95-12.61) and increased future uncertainty (OR = 0.20, 95 %CI = 0.07-0.53). Female sex (OR = 0.10, 95 %CI = 0.02-0.41), not having neurosurgery at baseline (OR = 0.09, 95 %CI = 0.02-0.52), 2-3 brain metastases (OR = 5.75, 95 %CI = 1.76-18.85) or receiving adjuvant WBRT (OR = 6.77, 95 %CI = 2.00-22.99) were associated with poorer physical, emotional, cognitive and social outcomes respectively. Conclusions: Poorer QoL outcomes in the first 12 months after diagnosis of melanoma brain metastases were observed in patients aged ≥ 65 years, females, having 2-3 brain metastases, non-surgical treatment of metastases or adjuvant WBRT.Clinical Trial Registration Number:Whole Brain Radiotherapy Trial (WBRTMel) was registered with the Australian Clinical Trials Registry (ACTRN12607000512426) and ClinicalTrials.gov (NCT01503827).Study Support:This project was funded by Cancer Australia PdCCRS (Grants No. 512358, 1009485, and 1084046) and the National Helath and Medical Research Coucil of Australia (NHMRC; Grant No. 1135285).ADT was supported by a Cancer Australia Priority-driven Collaborative Cancer Research Scheme. Project #1046923. RLM was supported by an NHMRC Fellowship #1194703 and a University of Sydney, Robinson Fellowship. JFT was supported by an NHMRC Program Grant #1093017.

High-dose rate brachytherapy compared with open radical prostatectomy for the treatment of high-risk prostate cancer: 10 year biochemical freedom from relapse.

OBJECTIVE: • To compare long-term biochemical control of high-risk prostate cancer in those men receiving high-dose rate brachytherapy (HDRB) and radical prostatectomy (RP). PATIENTS AND METHODS: • The 10-year biochemical freedom from relapse (BFR) was calculated for 243 patients who underwent either RP or combined therapy with HDRB + external beam radiotherapy + androgen deprivation between 1998 and 2000. • INCLUSION CRITERIA: clinical stage ≥ T2b, or Gleason sum ≥ 8, or PSA level of > 20 ng/mL. Groups were appraised using the Kattan nomogram for surgery to calculate progression-free probability (PFP). RESULTS: • For the RP group (153 patients) the median PSA level was 8.1 ng/mL and the median age was 62.2 years. The median 5- and 10-year predicted PFP for RP was 64% and 56 %, respectively. The 5- and 10-year BFR was 65.5% and 55.4%. There was no significant difference between the predicted and the actual PFP for the RP group (P= 0.525). • For HDRB group (90 patients). The median PSA level was 14.2 ng/mL and the median age was 67.6 years. The median 5- and 10-year predicted PFP for HDRB was 46% and 35%, respectively. The 5- and 10-year BFR was 79.6% and 53.6%. There was a significant improvement between the actual and the predicted PFP for the HDRB group (P= 0.002). CONCLUSIONS: • Amongst a high-risk cohort, patients undergoing RP performed as predicted by the pre-treatment surgical nomogram, whereas the patients undergoing HDRB performed significantly better than was predicted by the surgical nomogram at 10 years.

Cutaneous squamous cell carcinoma metastatic to parotid - analysis of prognostic factors and treatment outcome.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) comprises 20% of all skin cancer of the head and neck. A minority will metastasize to regional parotid lymph nodes. This study evaluates the St Vincent's Hospital, Sydney experience between 1996 and 2006. METHODS: A retrospective review was performed of patients who were evaluated in our multidisciplinary head and neck clinic with metastatic cSCC to parotid, and all treatment and pathologic details were reviewed. Statistical analysis, including univariate and multivariate analyses, were performed using Cox proportional hazards regression mode, overall and disease-specific survival were estimated by the Kaplan-Meier method. RESULTS: Sixty-seven patients were identified. Some 90 % were male, and with a mean age of 72.8 years. One died on the first postoperative day. The remaining 66 patients received radiotherapy. For these 66 patients, the two-year and five-year overall survival rate was 0.83 and 0.72, respectively. The two-year and five-year disease-free survival rate was 0.91 and 0.83 respectively. Overall survival was only significantly correlated to the extent of parotidectomy (superficial versus total; P = 0.0256). Margin status was available in 59 patients. The only parameter that significantly correlated with disease-free survival was margin status (close/negative versus positive P = 0.0348). Other parameters of immune suppression, perineural invasion, extra capsular extension, degree of tumour differentiation, number of positive nodes, extent of neck dissection and radiotherapy dosage delivered did not confer prognostic significance. CONCLUSIONS: This study confirmed the association of adverse prognostic implication of positive margins on disease-free survival. Immune compromise was not a significant factor in this small group. Further studies are warranted in this population.

Cost Analysis of Adjuvant Whole-Brain Radiotherapy Treatment Versus No Whole-Brain Radiotherapy After Stereotactic Radiosurgery and/or Surgery Among Adults with One to Three Melanoma Brain Metastases: Results from a Randomized Trial.

PURPOSE: We aimed to compare Australian health system costs at 12 months for adjuvant whole-brain radiotherapy (WBRT) treatment after stereotactic radiosurgery (SRS) and/or surgery versus observation among adults with one to three melanoma brain metastases. We hypothesized that treatment with adjuvant WBRT and subsequent healthcare would be more expensive than SRS/surgery alone. METHODS: The analysis was conducted alongside a multicentre, randomized phase III trial. A bespoke cost questionnaire was used to measure healthcare use, including hospitalizations, specialist and primary care visits, imaging, and medicines over 12 months. Mean per-patient costs were calculated based on the quantity of resources used and unit costs, reported in Australian dollars ($AU), year 2018 values. Skewness of cost data was determined using normality tests and censor-adjusted costs reported using the Kaplan-Meier sample average method. The analysis of difference in mean costs at each 2-month time point and at 12 months was performed and checked using Kruskal-Wallis, generalized linear models with gamma distribution and log link, modified Park test, ordinary least squares, and non-parametric bootstrapping. RESULTS: In total, 89 patients with similar characteristics at baseline were included in the cost analysis (n = 43 WBRT; n = 46 observation). Hospitalization cost was the main cost, ranging from 63 to 89% of total healthcare costs. The unadjusted 12-monthly cost for WBRT was $AU71,138 ± standard deviation 41,475 and for observation $AU69,848 ± 33,233; p = 0.7426. The censor-adjusted 12-monthly cost for WBRT was $AU90,277 ± 36,274 and $AU82,080 ± 34,411 for observation. There was no significant difference in 2-monthly costs between groups (p > 0.30 for all models). CONCLUSIONS: Most costs were related to inpatient hospitalizations associated with disease recurrence. Adding WBRT after local SRS/surgery for patients with one to three melanoma brain metastases did not significantly increase health system costs during the first 12 months. TRIAL REGISTRATION: ACTRN12607000512426, prospectively registered 14 September 2007.

Confocal microscopy, dermoscopy, and histopathology features of atypical intraepidermal melanocytic proliferations associated with evolution to melanoma in situ.

BACKGROUND: Atypical intraepidermal melanocytic proliferations (AIMP) is a descriptive term sometimes applied to biopsies that do not fulfill diagnostic criteria of melanoma. They are common on sun-damaged skin, but their definition and management are controversial. OBJECTIVE: To describe dermoscopic (DS), reflectance confocal microscopic (RCM) and histopathological features of AIMP and identify features associated with subsequent melanoma in situ (MIS). METHODS: A retrospective analysis of AIMP lesions correlated with patient outcome at two melanoma tertiary centers between 2005 and 2015. RESULTS: Thirty-four patients were included. Nine (26%) patients had MIS in subsequent biopsies. Predictors of later MIS were target-like pattern (OR:12.0 [CI: 1.23, 117.41]; P = 0.032) and high-density vascular network (OR:12 [CI: 1.23-117.41], P: 0.032) on DS, and presence of dendritic cells touching each other (OR:9.1 [CI: 1.54, 54.59], P = 0.014) on RCM. Clinical predictors of worse outcome included a previous history of MIS at the same site. Radiotherapy for AIMP had a high failure rate (all patients presented with recurrent disease, three as AIMP and two as MIS). CONCLUSIONS: Considering that most cases in this series received non-surgical treatment at baseline, we recommend close monitoring for lesions with target-like pattern and density vascular network on DS and treatment for lesions with progression of atypia and/or with "confluent" dendritic cells on RCM. Although the number of patients in this series is very low, early surgery is recommended for MIS cases that recur as AIMP.

Whole brain radiotherapy after local treatment of brain metastases in melanoma patients--a randomised phase III trial.

BACKGROUND: Cerebral metastases are a common cause of death in patients with melanoma. Systemic drug treatment of these metastases is rarely effective, and where possible surgical resection and/or stereotactic radiosurgery (SRS) are the preferred treatment options. Treatment with adjuvant whole brain radiotherapy (WBRT) following neurosurgery and/or SRS is controversial. Proponents of WBRT report prolongation of intracranial control with reduced neurological events and better palliation. Opponents state melanoma is radioresistant; that WBRT yields no survival benefit and may impair neurocognitive function. These opinions are based largely on studies in other tumour types in which assessment of neurocognitive function has been incomplete. METHODS/DESIGN: This trial is an international, prospective multi-centre, open-label, phase III randomised controlled trial comparing WBRT to observation following local treatment of intracranial melanoma metastases with surgery and/or SRS. Patients aged 18 years or older with 1-3 brain metastases excised and/or stereotactically irradiated and an ECOG status of 0-2 are eligible. Patients with leptomeningeal disease, or who have had previous WBRT or localised treatment for brain metastases are ineligible. WBRT prescription is at least 30 Gy in 10 fractions commenced within 8 weeks of surgery and/or SRS. Randomisation is stratified by the number of cerebral metastases, presence or absence of extracranial disease, treatment centre, sex, radiotherapy dose and patient age. The primary endpoint is the proportion of patients with distant intracranial failure as determined by MRI assessment at 12 months. Secondary end points include: survival, quality of life, performance status and neurocognitive function. DISCUSSION: Accrual to previous trials for patients with brain metastases has been difficult, mainly due to referral bias for or against WBRT. This trial should provide the evidence that is currently lacking in treatment decision-making for patients with melanoma brain metastases. The trial is conducted by the Australia and New Zealand Melanoma Trials Group (ANZMTG-study 01-07), and the Trans Tasman Radiation Oncology Group (TROG) but international participation is encouraged. Twelve sites are open to date with 43 patients randomised as of the 31st March 2011. The target accrual is 200 patients. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12607000512426.

In vivo real-time dosimetric verification in high dose rate prostate brachytherapy.

PURPOSE: To evaluate the performance of a diode array in the routine verification of planned dose to points inside the rectum from prostate high dose rate (HDR) brachytherapy using a real-time planning system. METHODS: A dosimetric study involving 28 patients was undertaken where measured doses received during treatment were compared to those calculated by the treatment planning system (TPS). After the ultrasound imaging required for treatment planning had been recorded, the ultrasound probe was replaced with a geometric replica that contained an 8 mm diameter cylindrical cavity in which a PTW diode array type 9112 was placed. The replica probe was then positioned inside the rectum with the individual diode positions determined using fluoroscopy. Dose was then recorded during the patients' treatment and compared to associated coordinates in the planning system. RESULTS: Factors influencing diode response and experimental uncertainty were initially investigated to estimate the overall uncertainty involved in dose measurements, which was determined to be +/- 10%. Data was acquired for 28 patients' first fractions, 11 patients' second fractions, and 13 patients' third fractions with collection dependent upon circumstances. Deviations between the diode measurements and predicted values ranged from -42% to +35% with 71% of measurements experiencing less than a 10% deviation from the predicted values. If the +/- 10% measurement uncertainty was combined with a tolerated dose discrepancy of +/- 10% then over 95% of the diode results exhibited agreement with the calculated data to within +/- 20%. It must also be noted that when large dose discrepancies were apparent they did not necessarily occur for all five diodes in the one measurement. CONCLUSIONS: This technique provided a method that could be utilized to detect gross errors in dose delivery of a real-time prostate HDR plan. Limitations in the detection system used must be well understood if meaningful results are to be achieved.

Phase I/II trial of concurrent extracranial palliative radiation therapy with Dabrafenib and Trametinib in metastatic BRAF V600E/K mutation-positive cutaneous Melanoma.

BACKGROUND: Concurrent treatment with BRAF inhibitors and palliative radiation therapy (RT) could be associated with increased toxicity, especially skin toxicity. Current Eastern Cooperative Oncology Group (ECOG) consensus guideline recommend ceasing BRAF inhibitors during RT. There is a lack of data regarding concurrent RT with combined BRAF and MEK inhibitors. This single-arm phase I/II trial was designed to assess the safety and tolerability of palliative RT with concurrent Dabrafenib and Trametinib in patients with BRAF-mutant metastatic melanoma. MATERIALS AND METHODS: Patients received Dabrafenib and Trametinib before and during palliative RT to soft tissue, nodal or bony metastases. The RT dose was escalated stepwise during the study period. Toxicity data including clinical photographs of the irradiated area was collected for up to 12 months following completion of RT. RESULTS: Between June 2016 to October 2019, ten patients were enrolled before the study was stopped early due to low accrual rate. Six patients were treated at level 1 (20 Gy in 5 fractions, any location) and 4 patients at level 2a (30 Gy in 10 fractions with no abdominal viscera exposed). All alive patients completed one year of post-RT follow-up. Of the 82 adverse events (AEs) documented, the majority (90%) were grade 1 and 2. Eight grade 3 events (10%) occurred in five patients, only one was treatment-related (grade 3 fever due to Dabrafenib and Trametinib). No patients experienced grade 3 or 4 RT related toxicities, including skin toxicities. One serious AE was documented in relation to a grade 3 fever due to Dabrafenib and Trametinib requiring hospitalisation. CONCLUSIONS: The lack of grade 3 and 4 RT-related toxicities in our study suggests that Dabrafenib and Trametinib may be continued concurrently during fractionated non-visceral palliative RT to extracranial sites.

Cost-Effectiveness of Subsequent Whole-Brain Radiotherapy or Hippocampal-Avoidant Whole-Brain Radiotherapy Versus Stereotactic Radiosurgery or Surgery Alone for Treatment of Melanoma Brain Metastases.

BACKGROUND: A randomized phase III trial comparing whole-brain radiotherapy (WBRT) to observation following definitive local treatment of intracranial melanoma metastases with neurosurgery and/or stereotactic surgery (SRS) is underway. OBJECTIVE: We sought to assess the pre-trial cost-effectiveness of WBRT, hippocampal-avoidant WBRT (HA-WBRT), and observation (SRS or surgery alone) for this population to guide trial data collection efforts and reduce decision uncertainty. METHODS: A time-dependent Markov model followed patients treated with neurosurgery or SRS who received subsequent WBRT, HA-WBRT or observation over a 5-year time horizon. Model inputs were sourced from published literature and results tested for robustness using probabilistic sensitivity analysis. Value of information (VOI) analysis was undertaken to guide data collection for the randomized trial. RESULTS: Over 5 years, the WBRT strategy produced 1.74 QALYs (2.38 life-years) at a mean cost of $40,128 (costs in 2017 Australian dollars); HA-WBRT produced 1.88 QALYs (2.38 life-years) and cost $42,977; and SRS/surgery alone produced 1.65 QALYs (2.13 life-years) at a cost of $46,281. Probabilistic sensitivity analysis showed HA-WBRT was the preferred strategy in 77% of simulations. Cost-effectiveness results were most sensitive to utilities of the controlled-disease health state in the WBRT group, and costs of HA-WBRT. The EVPI for a randomized trial was estimated at $6,888 per person. CONCLUSIONS: HA-WBRT may be cost-effective for the treatment of melanoma brain metastases. The results predicted in our model can be validated with prospective trial data when available.

The changing paradigm of managing Merkel cell carcinoma in Australia: An expert commentary.

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine tumor of the skin with an estimated disease-associated mortality of 15-33%. Australia has a higher incidence of MCC compared to the rest of the world, thought to be due to a higher ultraviolet index. The Australian MCC population is distinct from the MCC population of the Northern hemisphere, characterized by a predominantly viral negative etiology with high tumor mutational burden. The optimal management of MCC and the choice of treatment modality vary significantly across the world and even between institutions within Australia. Historically, the treatment for MCC has been resection followed by radiotherapy (RT), though definitive RT is an alternative treatment used commonly in Australia. The arrival of immune checkpoint inhibitors and the mounting evidence that MCC is a highly immunogenic disease is transforming the treatment landscape for MCC. Australia is playing a key role in the further development of treatment options for MCC with two upcoming Australian/New Zealand investigator-initiated clinical trials that will explore the interplay of RT and immunotherapy in the treatment of early and late stage MCC.

Whole brain radiotherapy (WBRT) after local treatment of brain metastases in melanoma patients: Statistical Analysis Plan.

BACKGROUND: The WBRTMel trial is a multinational, open-label, phase III randomised controlled trial comparing whole brain radiotherapy (WBRT) to observation following local treatment of one to three melanoma brain metastases with surgery and/or stereotactic irradiation. The primary trial endpoint was to determine the effect of adding WBRT to local treatment on distant intracranial control, and the secondary endpoints were neurocognitive function, quality of life (QoL), performance status, overall survival, death from intracranial causes, death from melanoma and cost-effectiveness. OBJECTIVE: The objective of this update is to outline and publish the pre-determined statistical analysis plan (SAP) before the database lock and the start of analysis. METHODS: The SAP describes basic analysis principles, methods for dealing with a range of commonly encountered data analysis issues and the specific statistical procedures for analysing efficacy and safety outcomes. The SAP was approved after closure of recruitment and before completion of patient follow-up. It outlines the planned primary analyses and a range of subgroup and sensitivity analyses regarding the clinical and QoL outcomes. Health economic outcomes are not included in this plan but will be analysed separately. The SAP will be adhered to for the final data analysis of this trial to avoid analysis bias arising from knowledge of the data. RESULTS: The resulting SAP is consistent with best practice and will allow open and transparent reporting. CONCLUSION: We have developed a SAP for the WBRTMel trial which will be followed to ensure high-quality standards of internal validity to minimise analysis bias. TRIAL REGISTRATION: ANZ Clinical Trials Registry, ACTRN12607000512426 . Registered on 9 October 2007. ClinicalTrials.gov, NCT01503827 . Registered on 4 January 2012. Trial group reference numbers ANZMTG 01.07, TROG 08.05.