The role of a radiopaque peri-rectal hydrogel spacer in aiding accurate daily image-guidance for prostate stereotactic radiotherapy.

Introduction: Precise patient positioning with image guidance (IGRT) is essential for safe prostate radiotherapy. We present the first report of utilizing a CT-visible hydrogel spacer, used to decrease rectal radiation dose, as a surrogate fiducial marker to aid in daily IGRT with cone-beam CT (CBCT) in stereotactic radiotherapy (SABR) for prostate cancer. Materials and methods: Prior to CT simulation, patients underwent placement of three intraprostatic gold fiducial markers and radiopaque hydrogel spacer per standard practice. At treatment, after initial setup, a CBCT was acquired and fused to the planning CT based on 3-dimensional matching of the spacer. A second alignment was then performed based on the fiducial markers. The six directional shifts (three linear and three rotational) were recorded, and the differences compared. Results: 140 individual fractions across 41 consecutive patients were evaluated. Mean/median differences between hydrogel spacer-based and fiducial-based alignment in linear (vertical, longitudinal, lateral) and rotational (rotation, pitch, roll) shifts were 0.9/0.6mm, 0.8/0.5mm, and 0.6/0.4mm, and 0.38/0, 0.62/0, and 0.35/0 degrees, respectively. No difference was observed in 9.9%, 22.9%, and 22.14% of linear shifts, and 65.7%, 65%, and 66.4% rotational shifts, respectively. Significantly smaller differences were observed in the latter 70 fractions vs. the former, and results were consistent across evaluators. Conclusions: For precise daily IGRT with CBCT for prostate SABR, alignment using a radiopaque hydrogel spacer was highly comparable to intraprostatic fiducial markers. This represents the first report supporting an additional indication of IGRT for a CT-visible hydrogel spacer, to further enhance treatment accuracy and potentially obviate the need for the additional fiducial marker procedure.

Acute Toxicity and Early Prostate Specific Antigen Response After Two-Fraction Stereotactic Radiation Therapy for Localized Prostate Cancer Using Peri-Rectal Spacing - Initial Report of the SABR-Dual Trial.

PURPOSE: SABR-Dual is a phase-III trial with an initial phase-I safety cohort, of 2-fraction stereotactic radiotherapy (SABR) with optional magnetic resonance imaging (MRI)-based focal boost, using peri-rectal spacing, for localized prostate cancer. This represents the initial report from the phase-I non-randomized cohort. METHODS AND MATERIALS: Subjects had favorable intermediate risk (FIR) or low risk prostate adenocarcinoma, and gland volume <80 cc. All underwent radiopaque hydrogel spacer and fiducial marker placement before simulation (computed tomography and 3-tesla T2 MRI). The clinical target volume included the entire prostate, and in FIR patients, 1-2 cm of seminal vesicle. A 2-mm expansion was applied for planning target volume (PTV), and a dose of 27 Gy was prescribed to the PTV-prostate, 23 Gy to the PTV-seminal vesicle, with an optional 30 Gy simultaneous boost to an MRI-defined dominant lesion. Primary endpoint was 3-month patient-reported changes in quality of life based on the Expanded Prostate Cancer Index Composite-26, International Prostate Symptom Score, and Sexual Health Inventory for Men questionnaires. Secondary endpoints were 6-month quality of life, acute toxicity (using Common Terminology Criteria for Adverse Events version 5.0) and early Prostate specific antigen (PSA) response. RESULTS: Among the 20 patients in the phase-I cohort, 95% had FIR disease, and 50% received a simultaneous boost. At median follow-up of 8 months, a 3-month minimally clinically important change occurred in 1/20 (5%), 6/20 (30%), 2/20 (10%), 4/20 (20%), and 5/20 (25%) in urinary incontinence, urinary obstructive, bowel, sexual, and hormonal domains. There was a mean increase of 1 ± 5.4 in International Prostate Symptom Score and decrease of 1.8 ± 6.5 in Sexual Health Inventory for Men scores. Rates of grade 2 urinary and bowel toxicity were 10% and 0%, respectively, with no grade ≥3 toxicities. Mean PSA decrease at last follow-up was 70.4% ± 17.7%. CONCLUSION: This generalizable protocol of 2-fraction prostate SABR using peri-rectal spacing is a safe approach for ultra-hypofractionated dose-escalation, with minimal acute toxicity. Longer-term outcomes and direct comparison with standard 5-fraction SABR are being studied in the phase-III randomized portion of SABR-Dual.

Celiac plexus radiosurgery for pain management in advanced cancer: a multicentre, single-arm, phase 2 trial.

BACKGROUND: Refractory upper abdominal pain or lower back pain (retroperitoneal pain syndrome) related to celiac plexus involvement characterises pancreatic and other upper gastrointestinal malignancies and is an unmet need. We hypothesised that ablative radiation delivered to the celiac plexus would decrease pain. METHODS: This multicentre, single-arm, phase 2 study was done at eight hospitals in five countries (Israel, Poland, Canada, the USA, and Portugal). Eligible patients aged 18 years or older with an average pain level of 5-10 on the Brief Pain Inventory short form (BPI-SF), an Eastern Cooperative Oncology Group performance status score of 0-2, and either pancreatic cancer or other tumours involving the celiac axis, received a single fraction of 25 Gy of external-beam photons to the celiac plexus. The primary endpoint was complete or partial pain response based on a reduction of the BPI-SF average pain score of 2 points or more from baseline to 3 weeks after treatment. All evaluable patients with stable pain scores were included in response assessment. The trial is registered with ClinicalTrials.gov, NCT03323489, and is complete. FINDINGS: Between Jan 3, 2018, and Dec 28, 2021, 125 patients were treated, 90 of whom were evaluable. Patients were followed up until death. Median age was 65·5 years (IQR 58·3-71·8), 50 (56%) were female and 40 (44%) were male, 83 (92%) had pancreatic cancer, and 77 (86%) had metastatic disease. Median baseline BPI-SF average pain score was 6 (IQR 5-7). Of the 90 evaluable patients at 3 weeks, 48 (53%; 95% CI 42-64) had at least a partial pain response. The most common grade 3-4 adverse events, irrespective of attribution, were abdominal pain (35 [28%] of 125) and fatigue (23 [18%]). 11 serious adverse events of grade 3 or worse were recorded. Two grade 3 serious adverse events were probably attributed to treatment by the local investigators (abdominal pain [n=1] and nausea [n=1]), and nine were possibly attributed to treatment (seven were grade 3: blood bilirubin increased [n=1], duodenal haemorrhage [n=2], abdominal pain [n=2], and progressive disease [n=2]; and two were grade 5: gastrointestinal bleed from suspected varices 24 days after treatment [n=1] and progressive disease [advanced pancreatic cancer] 89 days after treatment [n=1]). INTERPRETATION: Celiac plexus radiosurgery could potentially be a non-invasive palliative option for patients with retroperitoneal pain syndrome. Further investigation by means of a randomised comparison with conventional celiac block or neurolysis is warranted. FUNDING: Gateway for Cancer Research and the Israel Cancer Association.

SABR-Dual: a phase II/III trial of two-fraction versus five-fraction stereotactic radiotherapy for localized low- and favorable intermediate-risk prostate cancer.

BACKGROUND: Dose-escalated radiotherapy is known to improve progression free survival in patients with localized prostate cancer, and recent advances have led to the standardization of ultrahypofractionated stereotactic ablative radiotherapy (SABR) delivered in just 5-fractions. Based on the known effectiveness of the accepted though invasive 2-fraction treatment method of high-dose-rate brachytherapy and given the ubiquity of prostate cancer, a further reduction in the number of treatments of external-beam SABR is possible. This study aims to evaluate the safety, efficacy, and non-inferiority of generalizable 2-fraction SABR compared to the current 5-fraction regimen. METHODS: 502 patients will be enrolled on this phase II/III randomized control trial. Eligible patients will have previously untreated low- or favorable intermediate-risk adenocarcinoma of the prostate. Patients will be randomized between standard SABR of 40 Gy in 5 fractions given every-other-day and 27 Gy in 2 fractions at least two days apart but completing within seven days. MRI-based planning, radiopaque hydrogel spacer insertion, and fiducial marker placement are required, and SABR will be delivered on either a standard CT-guided linear accelerator or MR-LINAC. The primary endpoint will be freedom from disease progression, with additional secondary clinical, toxicity, and quality of life endpoints. DISCUSSION: This study will be the largest prospective randomized trial, adequately powered to demonstrate non-inferiority, comparing 2-fraction SABR to standard 5-fraction SABR for localized prostate cancer. As the protocol does not obligate use of an MRI-LINAC or other adaptive technologies, results will be broadly generalizable to the wider community. TRIAL REGISTRATION: This trial is registered on Clinicaltrials.gov: ClinicalTrials.gov Identifier: NCT06027892.

Converging survival trends in non-small cell lung cancer patients with and without brain metastasis receiving state-of-the-art treatment.

INTRODUCTION: Historically, patients with brain metastasis (BM) have been excluded from clinical trials investigating treatments for non-small cell lung cancer (NSCLC) due to their unfavorable prognosis. Advanced treatments have increased survival prospects for NSCLC patients with BM. This study evaluated the life expectancy of NSCLC patients with and without BM in the context of contemporary treatments. METHODS: Outcome data were collected for patients with advanced NSCLC attending a tertiary medical center between 2015 and 2020. Patients were stratified according to BM status and compared for overall survival (OS) using log-rank and Cox regression analyses. RESULTS: The cohort included 360 patients with NSCLC of whom 134 (37.2%) had BM. Most (95%) of cases of BM developed within the first two years: 63% at diagnosis, 18% during the first year, 14% during the second year. There was no significant difference in OS between patients without BM and those with BM (median 23.7 vs. 22.3 months, HR = 0.97, p = 0.82); patients with BM and a targetable or non-targetable mutation (40.2 vs. 31.4 months, HR = 0.93, p = 0.84, and 20.7 vs. 19.87 months, HR = 0.95, p = 0.75, respectively); and patients with symptomatic BM (23.7 vs. 19.8 months, HR = 0.95, p = 0.78). Treatment for BM (95% of patients) consisted of stereotactic radiosurgery or tyrosine kinase inhibitors, with corresponding intracranial control rates of 90% and 86%. CONCLUSION: The results imply that the presence of BM has no impact on the prognosis of NSCLC. The practice of excluding NSCLC patients with BM from clinical trials warrants reconsideration.