Gerald Fogarty

Prospective Comparison of 18F-Fluoromethylcholine Versus 68Ga-PSMA PET/CT in Prostate Cancer Patients Who Have Rising PSA After Curative Treatment and Are Being Considered for Targeted Therapy

In prostate cancer with biochemical failure after therapy, current imaging techniques have a low detection rate at the prostate-specific antigen (PSA) levels at which targeted salvage therapy is effective. 11C-choline and 18F-fluoromethylcholine, though widely used, have poor sensitivity at low PSA levels. 68Ga-PSMA (Glu-NH-CO-NH-Lys-(Ahx)-[68Ga-N,N′-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid]) has shown promising results in retrospective trials. Our aim was to prospectively compare the detection rates of 68Ga-PSMA versus 18F-fluoromethylcholine PET/CT in men who were initially managed with radical prostatectomy, radiation treatment, or both and were being considered for targeted therapy. Methods: A sample of men with a rising PSA level after treatment, eligible for targeted treatment, was prospectively included. Patients on systemic treatment were excluded. 68Ga-PSMA, 18F-fluoromethylcholine PET/CT, and diagnostic CT were performed sequentially on all patients between January and April 2015, and the images were assessed by masked, experienced interpreters. The findings and their impact on management were documented, together with the results of histologic follow-up when feasible. Results: In total, 38 patients were enrolled. Of these, 34 (89%) had undergone radical prostatectomy and 4 (11%) had undergone radiation treatment. Twelve (32%) had undergone salvage radiation treatment after primary radical prostatectomy. The mean PSA level was 1.74 ± 2.54 ng/mL. The scan results were positive in 26 patients (68%) and negative with both tracers in 12 patients (32%). Of the 26 positive scans, 14 (54%) were positive with 68Ga-PSMA alone, 11 (42%) with both 18F-fluoromethylcholine and 68Ga-PSMA, and only 1 (4%) with 18F-fluoromethylcholine alone. When PSA was below 0.5 ng/mL, the detection rate was 50% for 68Ga-PSMA versus 12.5% for 18F-fluoromethylcholine. When PSA was 0.5–2.0 ng/mL, the detection rate was 69% for 68Ga-PSMA versus 31% for 18F-fluoromethylcholine, and when PSA was above 2.0, the detection rate was 86% for 68Ga-PSMA versus 57% for 18F-fluoromethylcholine. On lesion-based analysis, 68Ga-PSMA detected more lesions than 18F-fluoromethylcholine (59 vs. 29, P < 0.001). The tumor-to-background ratio in positive scans was higher for 68Ga-PSMA than for 18F-fluoromethylcholine (28.6 for 68Ga-PSMA vs. 9.4 for 18F-fluoromethylcholine, P < 0.001). There was a 63% (24/38 patients) management impact, with 54% (13/24 patients) being due to 68Ga-PSMA imaging alone. Histologic follow-up was available for 9 of 38 patients (24%), and 9 of 9 68Ga-PSMA–positive lesions were consistent with prostate cancer (68Ga-PSMA was true-positive). The lesion positive on 18F-fluoromethylcholine imaging and negative on 68Ga-PSMA imaging was shown at biopsy to be a false-positive 18F-fluoromethylcholine finding (68Ga-PSMA was true-negative). Conclusion: In patients with biochemical failure and a low PSA level, 68Ga-PSMA demonstrated a significantly higher detection rate than 18F-fluoromethylcholine and a high overall impact on management.

Improving Management and Patient Care in Lentigo Maligna by Mapping With In Vivo Confocal Microscopy

IMPORTANCE Lentigo maligna (LM) is a clinical, pathologic, and therapeutic challenge with a higher risk of local recurrence than other types of melanoma correctly treated and also carries the cosmetically sensitive localization of head and neck. OBJECTIVE To determine whether in vivo reflectance confocal microscopy (RCM) mapping of difficult LM cases might alter patient care and management. DESIGN Analysis of LM and LM melanoma (LMM) in a series of patients with large facial lesions requiring complex reconstructive surgery and/or recurrent or poorly delineated lesions at any body sites were investigated. SETTINGS Two tertiary referral melanoma centers in Sydney, Australia. PARTICIPANTS Thirty-seven patients with LM (including 5 with LMM) were mapped with RCM. Fifteen patients had a recurrent LM, including 9 with multiple prior recurrences. The LM was classified amelanotic in 10 patients, lightly pigmented in 9, and partially pigmented in 18. INTERVENTIONS The RCM images were obtained in 4 radial directions (allowing for anatomic barriers) for LM margin delineation using an RCM LM score previously described by our research team. MAIN OUTCOME MEASURES Differences in the margin of LM as determined by RCM vs dermoscopy vs histopathologic analysis. RESULTS Seventeen of 29 patients (59%) with dermoscopically visible lesions had subclinical (RCM-identified) disease evident more than 5 mm beyond the dermoscopy margin (ie, beyond the excision margin recommended in published guidelines). The RCM mapping changed the management in 27 patients (73%): 11 patients had a major change in their surgical procedure, and 16 were offered radiotherapy or imiquimod treatment as a consequence of the RCM findings. Treatment was surgical in 17 of 37 patients. Surgical excision margins (based on the RCM mapping) were histopathologically involved in only 2 patients, each of whom had an LM lesion larger than 6 cm. CONCLUSIONS AND RELEVANCE In vivo RCM can provide valuable information facilitating optimal patient care management.

Human papillomavirus modifies the prognostic significance of T stage and possibly N stage in tonsillar cancer

BACKGROUND Despite the association with more advanced nodal stage, patients with human papillomavirus (HPV) positive oropharyngeal cancers have better outcomes. We examined whether the HPV can modify the effect of known prognostic factors in tonsillar cancer. PATIENTS AND METHODS A total of 489 patients from 10 centres were followed up for recurrence or death for a median of 3.2 years. Determinants of the rate of locoregional recurrence, death from tonsillar cancer and overall survival were modelled using Cox regression. RESULTS The prognostic value of T and N stages were modified by HPV as indicated by statistically significant interaction terms. After adjusting for age, gender and treatment, T stage appeared relevant only for HPV-positive cancers (where a higher T stage was associated with worse outcomes). There was some evidence that N stage was a more relevant prognostic factor for HPV-negative than -positive cancers. There was no evidence that the HPV modifies the effect of age, gender or grade on outcomes. CONCLUSIONS This study suggests that the prognostic significance of the conventional staging system in tonsillar cancer is modified by HPV.

Treatment of Melanoma Brain Metastases: A New Paradigm

AbstractBrain metastases occur commonly in patients with metastatic melanoma, are associated with a poor prognosis, and cause significant morbidity. Both surgery and stereotactic radiosurgery are used to control brain metastases and, in selected patients, improve survival. In those with extensive brain involvement, whole-brain radiotherapy can alleviate symptoms. Historically, systemic therapy has had little role to play in the management of melanoma brain metastases; however, early clinical trials of BRAF inhibitors have shown promising activity. This review examines the evidence for local and systemic treatments in the management of patients with melanoma brain metastases. We present a new treatment algorithm for melanoma patients with brain metastases, which integrates the evolving evidence for the use of BRAF inhibitors.

Hippocampal avoidance with volumetric modulated arc therapy in melanoma brain metastases - the first Australian experience.

PurposeVolumetric modulated arc therapy (VMAT) can deliver intensity modulated radiotherapy (IMRT) like dose distributions in a short time; this allows the expansion of IMRT treatments to palliative situations like brain metastases (BMs). VMAT can deliver whole brain radiotherapy (WBRT) with hippocampal avoidance and a simultaneous integrated boost (SIB) to achieve stereotactic radiotherapy (SRT) for BMs. This study is an audit of our experience in the treatment of brain metastases with VMAT in our institution.Methods and materialsMetastases were volumetrically contoured on fused diagnostic gadolinium enhanced T1 weighted MRI/planning CT images. Risk organs included hippocampus, optic nerve, optic chiasm, eye, and brain stem. The hippocampi were contoured manually as one paired organ with assistance from a neuroradiologist. WBRT and SIB were integrated into a single plan.ResultsThirty patients with 73 BMs were treated between March 2010 and February 2012 with VMAT. Mean follow up time was 3.5 months. For 26 patients, BMs arose from primary melanoma and for the remaining four patients from non-small cell lung cancer (n= 2), primary breast cancer, and sarcoma. Mean age was 60 years. The male to female ratio was 2:1. Five patients were treated without hippocampal avoidance (HA) intent. The median WBRT dose was 31 Gy with a median SIB dose for BMs of 50 Gy, given over a median of 15 fractions. Mean values for BMs were as follows: GTV = 6.9 cc, PTV = 13.3 cc, conformity index = 8.6, homogeneity index = 1.06. Mean and maximum hippocampus dose was 20.4 Gy, and 32.4 Gy, respectively, in patients treated with HA intent. Mean VMAT treatment time from beam on to beam off for one fraction was 3.43 minutes, which compared to WBRT time of 1.3 minutes. Twenty out of 25 assessable lesions at the time of analysis were controlled. Treatment was well tolerated; grade 4 toxicity was reported in one patient. The median overall survival was 9.40 monthsConclusionsVMAT for BMs is feasible, safe and associated with a similar survival times and toxicities to conventional SRT+/−WBRT. The advantage of VMAT is that WBRT and SRT can be delivered at the same time on one machine.

Activity and safety of radiotherapy with anti-PD-1 drug therapy in patients with metastatic melanoma

ABSTRACT The anti-PD-1 antibodies nivolumab and pembrolizumab are active in metastatic melanoma; however, there is limited data on combining anti-PD-1 antibody and radiotherapy (RT). We sought to review clinical outcomes of patients receiving RT and anti-PD-1 therapy. All patients receiving anti-PD-1 antibody and RT for metastatic melanoma were identified. RT and systemic treatment, clinical outcome, and toxicity data were collected. Fifty-three patients were included; 35 patients received extracranial RT and/or intracranial stereotactic radiosurgery (SRS) and 21 received whole brain radiotherapy (WBRT) (three of whom also received SRS/extracranial RT). Patients treated with extracranial RT or SRS received treatment either sequentially (RT then anti-PD-1, n = 11), concurrently (n = 16), or concurrent “salvage” treatment to lesions progressing on anti-PD-1 therapy (n = 15). There was no excessive anti-PD-1 or RT toxicity observed in patients receiving extracranial RT. Of six patients receiving SRS, one patient developed grade 3 radiation necrosis. In 21 patients receiving WBRT, one patient developed Stevens–Johnson syndrome, one patient developed acute neurocognitive decline, and one patient developed significant cerebral edema in the setting of disease. Response in irradiated extracranial/intracranial SRS lesions was 44% for sequential treatment and 64% for concurrent treatment (p=0.448). Likewise there was no significant difference between sequential or concurrent treatment in lesional response of non-irradiated lesions. For progressing lesions subsequently irradiated, response rate was 45%. RT and anti-PD-1 antibodies can be safely combined, with no detectable excess toxicity in extracranial sites. WBRT and anti-PD-1 therapy is well tolerated, although there are rare toxicities and the role of either anti-PD-1 or WBRT in the etiology of these is uncertain.

Radiotherapy for lentigo maligna: a literature review and recommendations for treatment

Lentigo maligna (LM) incidence is increasing. LM frequently involves the face near critical anatomical structures and as a consequence clinical management is challenging. Nonsurgical therapies, including radiotherapy (RT), are increasingly used. Evidenced‐based treatment guidelines are lacking. We conducted a review of previously published data analysing RT treatment of LM. A search of PubMed, Embase and Medline databases to June 2012 identified nine clinical studies that examined the use of RT for LM treatment in at least five patients. Nine studies described 537 patients with LM treated with definitive primary RT, between 1941 and 2009, with a median reported follow‐up time of 3 years. Eight articles could be reviewed for oncological outcome data. There were 18 recurrences documented in a total of 349 assessable patients (5%). Salvage was successful in the majority of recurrent LM cases by using further RT, surgery or other therapies. Progression to LM melanoma (LMM) occurred in five patients (five out of 349, 1·4%) who all had poor outcomes. There were five marginal recurrences documented out of 123 assessable patients (4%). There were eight in‐field recurrences documented with either LM (five) or LMM (three) out of 171 assessable patients (5%). A series of recommendations were then developed for RT parameters for treatment of LM. These parameters include treatment volume, dose, dose per fraction and outcome measures. These may be of use in prospective data collection.

Surveillance for treatment failure of lentigo maligna with dermoscopy and in vivo confocal microscopy: new descriptors

Nonsurgical treatment (radiotherapy, imiquimod) is increasingly employed for the management of lentigo maligna (LM). While the diagnosis of LM remains difficult, the detection of treatment failure is even more challenging.

Volumetric modulated arc therapy is superior to conventional intensity modulated radiotherapy--a comparison among prostate cancer patients treated in an Australian centre.

BackgroundRadiotherapy technology is expanding rapidly. Volumetric Modulated Arc Therapy (VMAT) technologies such as RapidArc® (RA) may be a more efficient way of delivering intensity-modulated radiotherapy-like (IM) treatments. This study is an audit of the RA experience in an Australian department with a planning and economic comparison to IM.Methods30 consecutive prostate cancer patients treated radically with RA were analyzed. Eight RA patients treated definitively were then completely re-planned with 3D conformal radiotherapy (3D); and a conventional sliding window IM technique; and a new RA plan. The acceptable plans and their treatment times were compared and analyzed for any significant difference. Differences in staff costs of treatment were computed and analyzed.ResultsThirty patients had been treated to date with eight being treated definitely to at least 74 Gy, nine post high dose brachytherapy (HDR) to 50.4Gy and 13 post prostatectomy to at least 64Gy. All radiotherapy courses were completed with no breaks. Acute rectal toxicity by the RTOG criteria was acceptable with 22 having no toxicity, seven with grade 1 and one had grade 2.Of the eight re-planned patients, none of the 3D (three-dimensional conformal radiotherapy) plans were acceptable based on local guidelines for dose to organs at risk. There was no statistically significant difference in planning times between IM and RA (p = 0.792). IM had significantly greater MUs per fraction (1813.9 vs 590.2 p < 0.001), total beam time per course (5.2 vs 3.1 hours, p = 0.001) and average treatment staff cost per patient radiotherapy course (

Treatment outcomes from 68GaPSMA PET CT informed salvage radiation treatment in men with rising PSA following radical prostatectomy: Prognostic value of a negative PSMA PET

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