Long-term outcomes of SBRT for PSMA PET detected oligometastatic prostate cancer.

BACKGROUND: Oligometastatic disease in prostate cancer (PCa) is a challenging clinical scenario encountered more frequently with the widespread adoption of PSMA-PET. SBRT aims to defer androgen deprivation and may deliver sustained biochemical failure (BF) free survival in selected patients. Little long-term data is currently available regarding the effectiveness of this approach. METHODS: A retrospective single institution study of PSMA-PET directed SBRT without initial ADT for oligo-metachronous PCa. Median dose/fractionation was 24 Gy in 2# to bones and 30 Gy in 3# to lymph nodes. The primary endpoint was time to BF (PSA + 0.2 ug/L above nadir). Secondary endpoints included time to ADT for relapse (i.e. palliative ADT), BF defined as PSA nadir + 2 ug/L, toxicity, patterns of failure and survival. Patients were excluded if they received ADT with their SBRT, had short disease-free interval, or > 3 metastases on PSMA-PET. RESULTS: 103 patients treated from November-2014 to December-2019 were analysed from our prospective database. Median follow-up was 5 years. 64 patients were treated for nodal only disease, 35 bone only and 4 mixed. 15% were free of any BF at 5 years with median time to BF of 1.1 years. 32% (33/103) of patients had further curative-intent radiation treatment following their first BF after SBRT, including subsequent SBRT. Eight patients underwent potentially curative treatment for their second or third relapse. Allowing for salvage treatment, 29/103 (28%) were biochemically disease free at last follow up. At 5 years, 39% of patients had never received any ADT and 55% had not started ADT for relapse with a median time to ADT for relapse of 5.5 years. There were 2 grade 3 toxicities (rib fracture and lymphoedema), and no local failures. CONCLUSION: PSMA-PET guided SBRT for oligo-metachronous PCa recurrence in appropriately triaged patients results in excellent local control, low toxicity and over 50% ADT free at 5 years.

Ductal Carcinoma of the Prostate: An Uncommon Entity With Atypical Behaviour.

AIMS: Ductal adenocarcinoma is a rare variant of prostate cancer, and as such clinical outcomes and best management are not well defined. This series demonstrates the atypical presentation and unusual clinical behaviour of ductal adenocarcinoma and proposes management guidelines to assist clinicians. MATERIALS AND METHODS: A retrospective review of pure (nine patients) and mixed (18 patients) ductal adenocarcinoma of the prostate referred to the Departments of Radiation Oncology of the Sydney Cancer Centre, Royal Prince Alfred Hospital and Northern Sydney Cancer Centre, Royal North Shore Hospital, between 2000 and 2015. RESULTS: Twenty-seven patients were treated with definitive radiotherapy, nine patients (33%) with pure ductal and 18 (67%) with mixed ductal-acinar adenocarcinoma. The median follow-up was 38 months. Four patients (15%) failed locally, all of whom received less than 80 Gy, or no brachytherapy boost. Five patients (19%) failed distantly, four with biopsy-proven lung metastases. All distant failures occurred with a prostate-specific antigen (PSA) < 3 ng/ml. CONCLUSION: This series shows the atypical clinical presentation of this entity, as well as its propensity to metastasise to unusual sites. Relapse may occur at low absolute PSA values and is often asymptomatic. Ductal cancer should not simply be regarded as a high Gleason grade cancer. We propose management guidelines, including regular computed tomography examinations (rather than relying solely on PSA levels) as part of the follow-up for patients with any component of ductal adenocarcinoma.

Late Genitourinary Toxicity Outcomes in 300 Prostate Cancer Patients Treated With Dose-escalated Image-guided Intensity-modulated Radiotherapy.

AIMS: To quantify and qualify late genitourinary toxicity in a cohort of patients with localised prostate cancer treated with image-guided intensity-modulated radiotherapy (IMRT) to doses ≥78 Gy. MATERIALS AND METHODS: The cohort consisted of 300 patients treated with definitive dose-escalated IMRT between 2007 and 2013. Ninety-seven patients received 78-80 Gy in 38 fractions, and 203 received 82-84 Gy in 40 fractions. International Prostate Symptoms Score (IPSS) and supplemental quality of life data were recorded at baseline, weekly during treatment and at follow-up. Genitourinary toxicities were recorded using modified Radiation Therapy Oncology Group criteria during weekly treatment review and at each follow-up. Kaplan-Meier curves were used to assess the cumulative incidence of grade ≥ 2 genitourinary toxicity at 3 years. Baseline patient characteristics and symptoms were then used in univariate and multivariate analyses to identify predictors of late urinary toxicity. RESULTS: The median follow-up was 58 months (range 9-109 months). The actuarial cumulative 3 year rates of grade ≥ 2 and grade 3 genitourinary toxicity were 14.9% and 2.8%, respectively. There was no grade 4 toxicity. History of transurethral resection of the prostate (TURP), alpha blocker use before radiation, any hormone use, baseline IPSS ≥ 14 and pre-existing incontinence or nocturia were significantly associated with late ≥ 2 genitourinary toxicity on univariate analysis. On multivariate analysis, only previous TURP retained significance, with a hazard ratio of 2.54 (P=0.002). CONCLUSION: Our study showed acceptable levels of late grade 2 genitourinary toxicity and low rates of late grade 3 genitourinary toxicity in a cohort of patients with prostate cancer treated with image-guided IMRT to doses between 78 and 84 Gy. Variables associated with increased late ≥ 2 genitourinary toxicity include previous TURP, alpha blocker use, hormone use and pre-existing urinary dysfunction.

Reducing radiation dose to normal brain through a risk adapted dose reduction protocol for patients with favourable subtype anaplastic glioma.

AIM: In patients with isocitrate dehydrogenase (IDH) mutated anaplastic glioma determine the dosimetric benefits of delivering radiation therapy using a PET guided integrated boost IMRT technique (ib-IMRT) compared with standard IMRT (s-IMRT) in reducing dose to normal brain. METHODS: Ten patients with anaplastic glioma, identified as a favourable molecular subgroup through presence of IDH mutation, and managed with radiation therapy using an ib-IMRT were enrolled into a dosimetric study comparing two RT techniques: s-IMRT to 59.4Gy or ib-IMRT with 59.4/54Gy regions. Gross Tumour volume (GTV) and Clinical Target Volumes (CTV) were determined by MRI, 18F-Fluoroethyltyrosine (FET) and 18F-Fluorodeoxyglucose (FDG) PET imaging. A standard risk Planning Target Volume (PTVsr) receiving 59.4Gy (PTV59.4) in the s-IMRT technique was determined by MRI T2Flair and FET PET. For the ib-IMRT technique this PTVsr volume was treated to 54Gy, and the high-risk PTV (PTVhr) receiving 59.4Gy was determined as a higher risk region by FDG PET and MRI gadolinium enhancement. Standard dosimetric criteria and normal tissue constraints based on recent clinical trials were used in target delineation and planning. Normal Brain was defined as Brain minus CTV. Endpoints for dosimetric evaluation related to mean Brain dose (mBrainDose), brain volume receiving 40Gy (Brainv40) and 20Gy (Brainv20). The variation between the dosimetric endpoints for both techniques was examined using Wilcoxon analysis. RESULTS: The 10 patients had tumours located in temporal (1), parietal (3), occipital (2) and bifrontal (4) regions. In ib-IMRT technique the median volume of PTVhr was 25.5 cm3 compared with PTVsr of 300.0 cm3. For dose to PTVhr the two treatments were equivalent (p = 0.33), and although the ibIMRT had a prescribed 10% dose reduction from 59.4Gy to 54Gy the median reduction was only 5.9%. The ib-IMRT dosimetry was significantly improved in normal brain endpoints specifically mBrainDose (p = 0.007), Brainv40 (p = 0.005) and Brainv20 (p = 0.001), with a median reduction of 9.3%, 19.0 and 10.8% respectively. After a median follow-up of 38 months two patients have progressed, with no isolated relapse in the dose reduction region. CONCLUSION: An approach using ib-IMRT for anaplastic glioma produces significant dosimetric advantages in relation to normal brain dose compared with s-IMRT plan. This is achieved without a significant reduction to the target volume dose despite the reduction in prescribed dose. This technique has advantages to minimise potential late neurocognitive effects from high dose radiation in patients with favorable subtype anaplastic glioma with predicted median survival beyond ten years.

Stereotactic Ablative Body Radiotherapy for the Treatment of Spinal Oligometastases.

AIMS: To report multicentre outcomes of patients with spinal oligometastases treated with stereotactic ablative body radiotherapy (SABR). The primary objective was to estimate the widespread failure-free survival (WFFS) at 2 years - defined as freedom from metastases not amenable to local salvage therapy and death. MATERIALS AND METHODS: Patients with one to three metastases treated with spinal SABR between January 2010 and July 2014 at four academic institutions were included in this retrospective review. The median dose/fractionation was 24 Gy (range 16-52.5 Gy) in two fractions (range one to three) and the median biologically effective dose (α/ß=10) was 52.5 Gy (range 40-144.4 Gy). The WFFS, overall survival, freedom from local progression and toxicity rates were described using Kaplan-Meier statistics. RESULTS: In total, 60 patients with 72 spinal metastases were analysed. The median follow-up was 21 months. Patients had a median age of 66 years, Eastern Cooperative Oncology Group performance 0-1 in 97% and metachronous oligometastases in 85%. The 1 and 2 year WFFS rates were 67% (95% confidence interval 55-80) and 59% (95% confidence interval 47-75), respectively. The 1 and 2 year overall survival rates were 90% (95% confidence interval 83-98) and 76% (95% confidence interval 64-91), respectively. The 1 and 2 year freedom from local progression were 92% (95% confidence interval 85-99) and 86% (95% confidence interval 75-99), respectively. There were four cases (6.7%) of vertebral compression fracture and no cases of radiation myelopathy. CONCLUSION: Despite the use of relatively low biological doses respecting spinal cord constraints, SABR results in excellent 2 year local control rates with low morbidity. Through careful selection of patients with oligometastases, most patients are alive and free from widespread metastases at 2 years. This cohort warrants further investigation in clinical trials of SABR.

Role of neck dissection in metastatic squamous cell carcinoma to the parotid gland.

OBJECTIVE: To investigate the rate of occult neck disease in patients with metastatic squamous cell carcinoma to the parotid gland following parotidectomy and neck dissection. METHODS: A consecutive series of patients treated between 2000 and 2014 for metastatic squamous cell carcinoma to the parotid were analysed. Patients were included if they had no clinical or radiological evidence of neck disease. Pathology of parotidectomy and neck dissection specimens was reviewed. Other variables analysed included patient immune status, surgery type, complications, use of positron emission tomography scanning and treatment with radiotherapy. RESULTS: Sixty-five patients had no clinical or radiological evidence of neck disease initially. Forty-six patients (70.8 per cent) underwent neck dissection. Occult neck disease was only found in 8 of the 46 patients (17.3 per cent). Occult neck disease was found more often in those with immunocompromise (5.7 vs 38.5 per cent, p = 0.003). Patients who were immunocompromised had a significantly worse disease-specific survival rate at five years (0 vs 92 per cent, p = 0.0001). CONCLUSION: Occult neck disease was seen in 17.3 per cent of patients and immunosuppression was a significant predictor for this.

SpaceOAR Hydrogel in Dose-escalated Prostate Cancer Radiotherapy: Rectal Dosimetry and Late Toxicity.

AIM: To investigate the feasibility, dosimetric benefits and late toxicity of a temporary hydrogel spacer between the rectum and the prostate for prostate intensity-modulated radiotherapy. MATERIALS AND METHODS: Thirty patients with prostate cancer were enrolled on a phase I/II study. All patients underwent magnetic resonance imaging before and after placement of 10 cm(3) of hydrogel. The first 10 patients had an additional magnetic resonance imaging after the completion of radiation treatment. SpaceOAR hydrogel was injected under general anaesthetic using a transperineal approach with transrectal ultrasound guidance. Primary end points were perioperative toxicity and comparison of rectal dosimetry. Secondary end points included cute and late radiation toxicity. All patients were planned on both pre- and post-hydrogel scans to a D95 of 80 Gy in 40 fractions. A contemporary control group of 110 prostate cancer patients treated with the same prescription was identified for comparison. RESULTS: There were no perioperative complications. Rectal doses were significantly lower for the post-hydrogel plans, especially above 65 Gy (V82 = 0.2% versus 1.3%; V80 = 0.8% versus 5.3%; V75 = 2.2% versus 9.5%; V70 = 3.7% versus 12.3%; V65 = 5.4% versus 14.7%; V40 = 22.9% versus 32% and V30 = 42.7% versus 49.4%). There was no significant difference in acute grade 1 and 2 gastrointestinal toxicity, which was 43% versus 51% and 0% versus 4.5% in the hydrogel and control groups, respectively. Late grade 1 was significantly less frequent in the hydrogel group (16.6% versus 41.8%, P = 0.04). CONCLUSION: SpaceOAR hydrogel was inserted with minimal side-effects. Dosimetric benefits were greatest at higher rectal doses (V65 to V82). Late grade 1 gastrointestinal toxicity was significantly lower than that seen in patients treated without hydrogel.

Promising results with image guided intensity modulated radiotherapy for muscle invasive bladder cancer.

AIM: To describe the feasibility of image guided intensity modulated radiotherapy (IG-IMRT) using daily soft tissue matching in the treatment of bladder cancer. METHODS: Twenty-eight patients with muscle-invasive carcinoma of the bladder were recruited to a protocol of definitive radiation using IMRT with accelerated hypofractionation with simultaneous integrated boost (SIB). Isotropic margins of .5 and 1 cm were used to generate the high risk and intermediate risk planning target volumes respectively. Cone beam CT (CBCT) was acquired daily and a soft tissue match was performed. Cystoscopy was scheduled 6 weeks post treatment. RESULTS: The median age was 83 years (range 58-92). Twenty patients had stage II or III disease, and eight were stage IV. Gross disease received 66 Gy in 30 fractions in 11 patients (ten with concurrent chemotherapy) or 55 Gy in 20 fractions for those of poorer performance status or with palliative intent. All patients completed radiation treatment as planned. Three patients ceased chemotherapy early due to toxicity. Six patients (21 %) had acute Grade ≥ 2 genitourinary (GU) toxicity and six (21 %) had acute Grade ≥ 2 gastrointestinal (GI) toxicity. Five patients (18 %) developed Grade ≥2 late GU toxicity and no ≥2 late GI toxicity was observed. Nineteen patients underwent cystoscopy following radiation, with complete response (CR) in 16 cases (86 %), including all patients treated with chemoradiotherapy. Eight patients relapsed, four of which were local relapses. Of the patients with local recurrence, one underwent salvage cystectomy. For patients treated with definitive intent, freedom from locoregional recurrence (FFLR) and overall survival (OS) was 90 %/100 % for chemoradiotherapy versus 86 %/69 % for radiotherapy alone. CONCLUSION: IG- IMRT using daily soft tissue matching is a feasible in the treatment of bladder cancer, enabling the delivery of accelerated synchronous integrated boost with good early local control outcomes and low toxicity.

Calculating radiotherapy margins based on Bayesian modelling of patient specific random errors.

Collected real-life clinical target volume (CTV) displacement data show that some patients undergoing external beam radiotherapy (EBRT) demonstrate significantly more fraction-to-fraction variability in their displacement ('random error') than others. This contrasts with the common assumption made by historical recipes for margin estimation for EBRT, that the random error is constant across patients. In this work we present statistical models of CTV displacements in which random errors are characterised by an inverse gamma (IG) distribution in order to assess the impact of random error variability on CTV-to-PTV margin widths, for eight real world patient cohorts from four institutions, and for different sites of malignancy. We considered a variety of clinical treatment requirements and penumbral widths. The eight cohorts consisted of a total of 874 patients and 27 391 treatment sessions. Compared to a traditional margin recipe that assumes constant random errors across patients, for a typical 4 mm penumbral width, the IG based margin model mandates that in order to satisfy the common clinical requirement that 90% of patients receive at least 95% of prescribed RT dose to the entire CTV, margins be increased by a median of 10% (range over the eight cohorts -19% to +35%). This substantially reduces the proportion of patients for whom margins are too small to satisfy clinical requirements.

Comparison of Single-fraction and Multi-fraction Stereotactic Radiotherapy for Patients with 18F-fluorodeoxyglucose Positron Emission Tomography-staged Pulmonary Oligometastases.

AIM: To compare outcomes of single-fraction and multi-fraction stereotactic ablative body radiotherapy (SABR) for pulmonary metastases. MATERIALS AND METHODS: A retrospective review from two academic institutions of patients with one to three pulmonary metastases staged with (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) scans. For single-fraction SABR, 26 Gy was prescribed for peripheral targets and 18 Gy for central targets. In the multi-fraction cohort, 48 Gy/4 or 50 Gy/5 was prescribed for peripheral targets and 50 Gy/5 was prescribed for central targets. Three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) plans were delivered using heterogeneity corrections. Conformity indices at an intermediate dose (R50%) and at a high dose (R100%) were used to assess a relationship with the planning target volume (PTV). Overall survival, local and distant progression and toxicity rates were analysed from the date of treatment completion. RESULTS: Between February 2010 and June 2013, 65 patients with 85 pulmonary metastases were reviewed. The median follow-up was 2.1 years. Metastases most commonly originated from colorectal cancer (31%), followed by non-small cell lung cancer (25%). 3D-CRT was used in 52 targets, IMRT in 21 and VMAT in 12. 3D-CRT showed a lower median R50% (P=0.01), but a higher median R100% than IMRT/VMAT (P=0.04). The R50% index was inversely correlated to the PTV with all techniques (P=0.01). Overall survival at 1 and 2 years in all patients was 93% (95% confidence interval 87-100%) and 71% (95% confidence interval 58-86%), respectively. The 2 year freedom from local and distant progression was 93% (95% confidence interval 86-100%) and 38% (95% confidence interval 27-55%), respectively. There were no significant differences between overall survival (P=0 .14), time to distant progression (P=0.06) or toxicity rates (P=0.75) between single- and multi-fraction cohorts. CONCLUSION: We report comparable local control, overall survival and toxicity rates between single-fraction and multi-fraction SABR treatments in patients with FDG-PET-staged pulmonary oligometastases. We propose a guideline for R50% conformity incorporating 3D-CRT/IMRT/VMAT techniques with heterogeneity corrected planning algorithms.

Finding the optimal statistical model to describe target motion during radiotherapy delivery--a Bayesian approach.

Early approaches to characterizing errors in target displacement during a fractionated course of radiotherapy assumed that the underlying fraction-to-fraction variability in target displacement, known as the 'treatment error' or 'random error', could be regarded as constant across patients. More recent approaches have modelled target displacement allowing for differences in random error between patients. However, until recently it has not been feasible to compare the goodness of fit of alternate models of random error rigorously. This is because the large volumes of real patient data necessary to distinguish between alternative models have only very recently become available. This work uses real-world displacement data collected from 365 patients undergoing radical radiotherapy for prostate cancer to compare five candidate models for target displacement. The simplest model assumes constant random errors across patients, while other models allow for random errors that vary according to one of several candidate distributions. Bayesian statistics and Markov Chain Monte Carlo simulation of the model parameters are used to compare model goodness of fit. We conclude that modelling the random error as inverse gamma distributed provides a clearly superior fit over all alternatives considered. This finding can facilitate more accurate margin recipes and correction strategies.

Daily online bony correction is required for prostate patients without fiducial markers or soft-tissue imaging.

AIM: To compare online position verification strategies with offline correction protocols for patients undergoing definitive prostate radiotherapy. MATERIALS AND METHODS: We analysed 50 patients with implanted fiducial markers undergoing curative prostate radiation treatment, all of whom underwent daily kilovoltage imaging using an on-board imager. For each treatment, patients were set-up initially with skin tattoos and in-room lasers. Orthogonal on-board imager images were acquired and the couch shift to match both bony anatomy and the fiducial markers recorded. The set-up error using skin tattoos and offline bone correction was compared with online bone correction. The fiducial markers were used as the reference. RESULTS: Data from 1923 fractions were analysed. The systematic error was ≤1 mm for all protocols. The average random error was 2-3mm for online bony correction and 3-5mm for skin tattoos or offline-bone. Online-bone showed a significant improvement compared with offline-bone in the number of patients with >5mm set-up errors for >10% (P<0.001) and >20% (P<0.003) of their fractions. CONCLUSIONS: Online correction to bony anatomy reduces both systematic and random set-up error in patients undergoing prostate radiotherapy, and is superior to offline correction methods for those patients not suitable for fiducial markers or daily soft-tissue imaging.

Volumetric-modulated arc therapy in head and neck radiotherapy: a planning comparison using simultaneous integrated boost for nasopharynx and oropharynx carcinoma.

AIMS: Volumetric-modulated arc therapy (VMAT) allows rapid delivery of radiotherapy. The aim of this planning study was to evaluate VMAT and dynamic intensity-modulated radiotherapy (IMRT) using a simultaneous integrated boost technique PATIENTS AND METHODS: Planning computed tomography data from 10 patients with locoregionally advanced oropharynx or nasopharynx carcinoma were selected. The prescription dose was 70, 63 and 56Gy to the high-dose, intermediate-dose and low-dose planning target volume (PTV), respectively, and planning parameters were according to Radiation Therapy Oncology Group IMRT protocols. VMAT and IMRT plans were calculated, and dose-volume histograms were created for plan evaluation and comparison. RESULTS: Clinically acceptable plans were achieved for both IMRT and VMAT plans, although IMRT plans typically required three times the number of monitor units. The coverage of 95% of the PTV70 was between 96 and 100% of the prescribed dose for IMRT plans and 100% for all VMAT plans. There was a trend of improved dose conformity for IMRT plans. Both IMRT and VMAT achieved acceptable plans in terms of sparing of the spinal cord and brainstem. Contralateral parotid sparing was improved with VMAT, with a mean dose of 25.08Gy (range 21.35-30.02Gy) for oropharynx and 31.37Gy (range 23.47-35.52Gy) for nasopharynx cases. CONCLUSION: Simultaneous integrated boost VMAT achieved comparable plans to dynamic IMRT in complex head and neck cases and used two-thirds less monitor units.

Implementation of an image-guided radiation therapy program: Lessons learnt and future challenges.

The aim of this paper is to detail the experience obtained in implementing an image-guided radiation therapy program at the Northern Sydney Cancer Centre. This required retrofitting a Varian Clinac 21EX with an on-board imager. The commissioning and quality assurance procedures, organisation of a multidisciplinary image guided radiation therapy group, and the development of clinical protocols for orthogonal kV and cone beam computed tomography implementation are described. Reassessment of the image-guided radiation therapy program has continued as new equipment and software versions were made available in the department.

Clinician's guide to prostate IMRT plan assessment and optimisation.

Intensity-modulated radiotherapy (IMRT) offers dosimetric benefit for irregularly shaped treatment volumes compared to three-dimensional conformal approaches. Some groups advocate IMRT as the standard of care for prostate radiotherapy. For clinicians, assessment of an IMRT plan can introduce new opportunities and challenges. Although a standard IMRT plan may be deemed acceptable by meeting pre-set dose constraints, further optimisation may yield a superior treatment plan by further reducing dose to critical structures or improving target volume homogeneity. The aim of this article is to present aspects of IMRT planning relevant to clinicians to aid in plan critiquing.