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.

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.

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.

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.

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.

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.

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.

Adjuvant Whole-Brain Radiation Therapy Compared With Observation After Local Treatment of Melanoma Brain Metastases: A Multicenter, Randomized Phase III Trial.

PURPOSE: The brain is a common site of metastasis for patients with high-risk melanoma. Although surgery or stereotactic radiosurgery are highly effective local treatments for a small number of metastases, there is a high risk of developing additional brain metastases. The role of adjuvant whole-brain radiotherapy (WBRT) in reducing new metastases is controversial, with a lack of high-level evidence specifically for melanoma. METHODS: In this randomized phase III trial, patients who had local treatment of one to three melanoma brain metastases were randomly assigned to WBRT or observation. The primary end point was distant intracranial failure within 12 months, and secondary end points included time to intracranial failure, survival, and time to deterioration in performance status. RESULTS: Between April 2009 and September 2017, 215 patients were randomly assigned from 24 centers. Median follow-up was 48.1 months (range, 39.6 to 68 months). Forty-two percent of patients in the WBRT group and 50.5% of those in the observation developed distant intracranial failure within 12 months (odds ratio, 0.71; 95% CI, 0.41 to 1.23; P = .22) and the rates over the entire follow-up period were 52.0% and 57.9%, respectively (odds ratio, 0.79; 95% CI, 0.45 to 1.36; P = .39). Local failure rate was lower after WBRT (20.0% v 33.6%; P = .03). At 12 months, 41.5% of patients in the WBRT group and 51.4% of patients in the observation group had died (P = .28), with no difference in the rate of neurologic death. Median time to deterioration in performance status was 3.8 months after WBRT and 4.4 months with observation (P = .32). WBRT was associated with more grade 1 to 2 acute toxicity. CONCLUSION: After local treatment of one to three melanoma brain metastases, adjuvant WBRT does not provide clinical benefit in terms of distant intracranial control, survival, or preservation of performance status.

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.

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.

Experience with Treating Lentigo Maligna with Definitive Radiotherapy.

Lentigo maligna (LM) is a form of melanoma in situ that occurs on exposed, sun-damaged skin; LM can progress to invasive melanoma. Conventional surgical treatment is the preferred management option as it is usually a one-treatment episode and generates a histopathology report that records completion of excision. Some patients may not be surgical candidates due to comorbidities, patient preference, impact on function, and cosmesis or they have failed surgery with a positive margin. Other therapies, including radiotherapy (RT) and topical medicines, may then become appropriate. There is a currently accruing multi-institutional randomized trial of imiquimod versus definitive RT for this population (NCT02394132). This review is about the experience from the centre that has generated the trial and enrolled the most patients to date. The purpose of the review is to pass on experience to other centers who may want to join the trial, especially to supplement the experience of local radiation oncologists. The review covers decisions that need to be made in RT planning and treatment and how to manage side effects and other common scenarios including LM in immunosuppressed patients and in poorly vascularised tissue, after surgery, of the eyelid and of mucous membrane (mouth and nose) that are in the radiation field.

Quality assurance analysis of hippocampal avoidance in a melanoma whole brain radiotherapy randomized trial shows good compliance.

BACKGROUND: Melanoma brain metastases (MBM) often cause morbidity and mortality for stage IV melanoma patients. An ongoing randomised phase III trial (NCT01503827 - WBRT-Mel) evaluates the role of adjuvant whole brain radiotherapy (WBRT) following local treatment of MBM. Hippocampal avoidance during WBRT (HA-WBRT) has shown memory and neurocognitive function (NCF) preservation in the RTOG-0933 phase II study. This study assessed the quality assurance of HA-WBRT within the WBRT-Mel trial according to RTOG-0933 study criteria. METHODS: Hippocampal avoidance was allowed in approved centres with intensity-modulated radiotherapy capability. Patients treated by HA-WBRT were not randomized within the WBRT arm. The RTOG 0933 contouring Atlas was used to contour hippocampi. In the trial co-ordinating centre, patients were treated with volumetric modulated arc therapy using complementary arcs; similar techniques were used at other sites. Dosimetric data were extracted retrospectively and analysed in accordance with RTOG 0933 study constraints criteria. RESULTS: Among the 215 patients accrued to the WBRT-Mel study between April 2009 and September 2017, 107 were randomized to the WBRT arm, 22 were treated by HA-WBRT in 4 centers. Eighteen patients were treated in the same centre. The median age was 65 years. The commonest (91%) HA-WBRT schema was 30 Gy in 10 fractions. Prior to HA-WBRT, 10 patients had been treated by surgery alone, six by radiosurgery alone, four by surgery and radiosurgery and two exclusively by simultaneous integrated boost concurrent to HA-WBRT. Twenty patients were treated with intention to spare both hippocampi and two patients had MBM close to one hippocampus and were treated with intention to spare the contralateral hippocampus. According to RTOG-0933 study criteria, 18 patients (82%) were treated within constraints and four patients (18%) had unacceptable deviation in just one hippocampus. CONCLUSIONS: This dosimetric quality assurance study shows good compliance (82%) according to RTOG-0933 study dosimetric constraints. Indeed, all patients respected RTOG hippocampal avoidance constraints on at least one hippocampus. In the futureanalysis of the WBRT-Mel trial, the NCF of patients on the observation arm, WBRT arm and with HA-WBRT arm will be compared.

Postoperative Concurrent Chemoradiotherapy Versus Postoperative Radiotherapy in High-Risk Cutaneous Squamous Cell Carcinoma of the Head and Neck: The Randomized Phase III TROG 05.01 Trial.

Purpose To report the results of the Trans Tasman Radiation Oncology Group randomized phase III trial designed to determine whether the addition of concurrent chemotherapy to postoperative radiotherapy (CRT) improved locoregional control in patients with high-risk cutaneous squamous cell carcinoma of the head and neck. Patients and Methods The primary objective was to determine whether there was a difference in freedom from locoregional relapse (FFLRR) between 60 or 66 Gy (6 to 6.5 weeks) with or without weekly carboplatin (area under the curve 2) after resection of gross disease. Secondary efficacy objectives were to compare disease-free survival and overall survival. Results Three hundred twenty-one patients were randomly assigned, with 310 patients commencing allocated treatment (radiotherapy [RT] alone, n = 157; CRT, n = 153). Two hundred thirty-eight patients (77%) had high-risk nodal disease, 59 (19%) had high-risk primary or in-transit disease, and 13 (4%) had both. Median follow-up was 60 months. Median RT dose was 60 Gy, with 84% of patients randomly assigned to CRT completing six cycles of carboplatin. The 2- and 5-year FFLRR rates were 88% (95% CI, 83% to 93%) and 83% (95% CI, 77% to 90%), respectively, for RT and 89% (95% CI, 84% to 94%) and 87% (95% CI, 81% to 93%; hazard ratio, 0.84; 95% CI, 0.46 to 1.55; P = .58), respectively, for CRT. There were no significant differences in disease-free or overall survival. Locoregional failure was the most common site of first treatment failure, with isolated distant metastases as the first site of failure seen in 7% of both arms. Treatment was well tolerated in both arms, with no observed enhancement of RT toxicity with carboplatin. Grade 3 or 4 late toxicities were infrequent. Conclusion Although surgery and postoperative RT provided excellent FFLRR, there was no observed benefit with the addition of weekly carboplatin.

Survival and prognostic factors for patients with melanoma brain metastases in the era of modern systemic therapy.

Historically, the prognosis of patients with melanoma brain metastases is poor, with median overall survival (OS) of 4-6 months. Little is known of OS in the era of modern systemic therapies and local therapy with stereotactic radiosurgery (SRS) or surgery. Patients diagnosed with melanoma brain metastases at Melanoma Institute Australia from January 2011 to December 2014 were included. OS and prognostic factors were analysed using Cox regression and Kaplan-Meier survival analyses.355 patients were included. The median OS was 7.1 months (95% confidence interval [CI] 6.0-8.1). Median OS differed by treatment modality: systemic therapy and SRS and/or surgery 14.9 months (95% CI 10.7-19.0), SRS and/or surgery with or without whole brain radiotherapy (WBRT) 6.4 months (95% CI 5.4-7.5), systemic therapy 5.4 months (95% CI 3.1-7.7), systemic therapy and WBRT 5.2 months (95% CI 4.1-6.4), WBRT 4.4 months (95% CI 2.4-6.3), and best supportive care 1.8 months (95% CI 1.2-2.3). OS for patients with melanoma brain metastases appears improved in the modern era, particularly for patients who are candidates for systemic therapy with SRS and/or surgery.

Cumulative Intracranial Tumor Volume Augments the Prognostic Value of Diagnosis-Specific Graded Prognostic Assessment Model for Survival in Patients with Melanoma Cerebral Metastases.

BACKGROUND: The diagnosis-specific graded prognostic assessment scale (ds-GPA) for patients with melanoma brain metastasis (BM) utilizes only 2 key prognostic variables: Karnofsky performance status and the number of intracranial metastases. We wished to determine whether inclusion of cumulative intracranial tumor volume (CITV) into the ds-GPA model for melanoma augmented its prognostic value. OBJECTIVE: To determine whether or not CITV augments the ds-GPA prognostic scale for melanoma. METHODS: We analyzed the survival pattern of 344 melanoma patients with BM treated with stereotactic radiosurgery (SRS) at separate institutions and validated our findings in an independent cohort of 201 patients. The prognostic value of ds-GPA for melanoma was quantitatively compared with and without the addition of CITV using the net reclassification index (NRI > 0) and integrated discrimination improvement (IDI) metrics. RESULTS: The incorporation of CITV into the melanoma-specific ds-GPA model enhanced its prognostic accuracy. Addition of CITV to the ds-GPA model significantly improved its prognostic value, with NRI > 0 of 0.366 (95% CI: 0.125-0.607, P = .002) and IDI of 0.024 (95% CI: 0.008-0.040, P = .004). We validated these findings that CITV improves the prognostic utility of melanoma ds-GPA in an independent cohort of 201 melanoma cohort. CONCLUSION: The prognostic value of the ds-GPA scale for melanoma BM is enhanced by the incorporation of CITV.

Treatment Outcomes from 68Ga-PSMA PET/CT-Informed Salvage Radiation Treatment in Men with Rising PSA After Radical Prostatectomy: Prognostic Value of a Negative PSMA PET.

68Ga-PSMA (prostate-specific membrane antigen) PET/CT is increasingly used in men with prostate-specific antigen (PSA) failure after radical prostatectomy (RP) to triage those who will benefit from salvage radiation treatment (SRT). This study examines the value of PSMA-informed SRT in improving treatment outcomes in the context of biochemical failure after RP. Methods: We analyzed men with rising PSA after RP with PSA readings between 0.05 and 1.0 ng/mL, considered eligible for SRT at the time of PSMA. For each patient, clinical and pathologic features as well as scan results, including site of PSMA-positive disease, number of lesions, and a certainty score, were documented. Subsequent management, including SRT, and most recent PSA were recorded using medical records. Treatment response was defined as both PSA ≤ 0.1 ng/mL and >50% reduction in PSA. Multivariate logistic regression analysis was performed for association of clinical variables and treatment response to SRT. Results: One hundred sixty-four men were included. PSMA was positive in 62% (n = 102/164): 38 of 102 in the prostatic fossa, 41 of 102 in pelvic nodes, and 23 of 102 distantly. Twenty-four patients received androgen-deprivation therapy (ADT) and were excluded for outcomes analysis. In total, 99 of 146 received SRT with a median follow-up after radiation treatment of 10.5 mo (interquartile range, 6-14 mo). Overall treatment response after SRT was 72% (n = 71/99). Forty-five percent (n = 27/60) of patients with a negative PSMA underwent SRT whereas 55% (33/60) did not. In men with a negative PSMA who received SRT, 85% (n = 23/27) demonstrated a treatment response, compared with a further PSA increase in 65% (22/34) in those not treated. In 36 of 99 patients with disease confined to the prostate fossa on PSMA, 81% (n = 29/36) responded to SRT. In total, 26 of 99 men had nodal disease on PSMA, of whom 61% (n = 16/26) had treatment response after SRT. On multivariate logistic regression analysis, PSMA and serum PSA significantly correlated with treatment response, whereas pT stage, Gleason score, and surgical margin status did not. Conclusion: PSMA PET is independently predictive of treatment response to SRT and stratifies men into a high treatment response to SRT (negative or fossa-confined PSMA) versus men with poor response to SRT (nodes or distant-disease PSMA). In particular, a negative PSMA PET result predicts a high response to salvage fossa radiotherapy.