The role of stereotactic body radiotherapy in oligoprogressive malignant disease (RADIANT): oncologic outcomes from a phase 2 non-randomized controlled trial.

BACKGROUND: In oligoprogressive (OP) cancer there are a limited numbers of metastatic areas progressing on a background of stable or responding widespread cancer. While the standard-of-care for OP is changing systemic therapy (ST), stereotactic body radiotherapy (SBRT) is being explored as an alternative local therapy targeting the sites of progression. MATERIALS/METHODS: XXX (NCTXXX) was a single-centre phase-2 study of patients with metastatic genitourinary (GU), breast and gastrointestinal (GI) cancers, receiving ST for >3 months, with radiographic OP disease in <5 sites. Patients received SBRT to all OP disease in 1-5 fractions, and were maintained on ST. The primary endpoint was the cumulative incidence of change in ST estimated using Aalen-Johansen method. Secondary endpoints included progression-free survival (PFS) and overall survival (OS) estimated using Kaplan-Meier method, toxicity, and health-related quality-of-life (HRQOL). Comparisons between diagnosis groups were done using log-rank test. A two-sided p-value of <0.05 was considered as statistical significance. RESULTS: Seventy patients were analyzed, with median age 69 years; 32 patients (46%) were female; median number of lines of prior ST was 3. Primary sites were GU (n=32; 46%), breast (n=23; 33%) and GI (n=15; 21%). Median follow-up was 12.3 months (IQR 8.2-21.6). At 1-year, change in ST occurred in 47% (95% CI 36-61%) (GU 45%, breast 41%, GI 60%, p=0.23). PFS at 1-year was 32% (95% CI 23-45%), and median PFS was 4.7 months (95% CI 3.8-8.1) (GU 4.8, breast 6.5, GI 3.2), which significantly differed by disease type (p=0.006). OS was 75% at 1-year (95% CI 65-87%), which significantly differed between cancer type (GU 86%, breast 96%, GI 22%, p<0.001). Cumulative incidence of late grade >2 toxicity was 1.2%, with 1 patient experiencing late grade 3 toxicity, and no grade 4-5 acute or late toxicities. HRQOL declined from mean (standard deviation) of 66.9 (20.2) at baseline to 60.5 (22.2) at 6 months, which did not meet the threshold for a minimal clinically important difference. CONCLUSIONS: SBRT for OP metastases delayed change in ST in approximately half of patients, warranting investigation in randomized trials.

Palliative radiotherapy versus best supportive care in patients with painful hepatic cancer (CCTG HE1): a multicentre, open-label, randomised, controlled, phase 3 study.

BACKGROUND: Palliative treatment options for painful hepatic cancer can be restricted due to patients eventually becoming refractory to standard treatment. The aim of this study was to determine whether radiotherapy improves hepatic pain from cancer. METHODS: In this open-label, randomised, controlled, phase 3 trial (CCTG HE1) done in nine cancer centres across Canada, we included patients aged 18 years or older with hepatocellular carcinoma or liver metastases, who were refractory to standard treatment, with an Eastern Cooperative Oncology Group performance status of 0-3, with life expectancy of more than 3 months, and pain or discomfort at its worst in the past 24 hours on the Brief Pain Inventory (BPI) of at least 4 out of 10, which was stable for up to 7 days before randomisation. Patients were randomly assigned (1:1), via a minimisation method after stratification by centre and type of cancer (hepatocellular carcinoma vs liver metastases), to single-fraction radiotherapy (8 Gy) to the liver with 8 mg ondansetron (or equivalent) orally and 4 mg dexamethasone orally given 1-2 h before radiotherapy plus best supportive care (including non-opioid or opioid analgesia, or dexamethasone, or a combination of these) or best supportive care alone. The primary endpoint was improvement in patient-reported liver cancer pain or discomfort of at least 2 points on worst pain intensity on the BPI at 1 month after randomisation. All patients with both baseline and 1-month assessments were included in the primary endpoint analysis. Safety was assessed in all patients randomly assigned to treatment. This trial is registered with ClinicalTrials.gov, NCT02511522, and is complete. FINDINGS: Between July 25, 2015, and June 2, 2022, 66 patients were screened and randomly assigned to radiotherapy plus best supportive care (n=33) or best supportive care (n=33). Median age was 65 years (IQR 57-72), 37 (56%) of 66 patients were male, 29 (44%) were female, 43 (65%) had liver metastases, and 23 (35%) had hepatocellular carcinoma (data on race and ethnicity were not collected). As of data cutoff (Sept 8, 2022), median follow-up was 3·2 months (95% CI 3·0-3·4). 24 (73%) of 33 in the radiotherapy plus best supportive care group and 18 (55%) of 33 in the best supportive care only group completed baseline and 1-month assessments. An improvement in hepatic pain of at least 2 points in worst pain intensity on the BPI at 1 month was seen in 16 (67%) of 24 patients in the radiotherapy plus best supportive care group versus four (22%) of 18 patients in the best supportive care group (p=0·0042). The most common grade 3-4 adverse events within 1 month after randomisation were abdominal pain (three [9%] of 33 in the radiotherapy group vs one [3%] of 33 in best supportive care group) and ascites (two [6%] vs one [3%]). No serious adverse events or treatment-related deaths were observed. INTERPRETATION: Single-fraction radiotherapy plus best supportive care improved pain compared with best supportive care alone in patients with liver cancer, and could be considered a standard palliative treatment. FUNDING: Canadian Cancer Society.

Stereotactic ablative radiotherapy for oligoprogressive solid tumours: A systematic review and meta-analysis.

INTRODUCTION: The aim of this systematic review and meta-analysis was to review evidence and pool outcomes to assess the effectiveness of stereotactic ablative radiotherapy (SABR) in patients treated for oligoprogressive metastases. METHODS AND MATERIALS: A search was conducted January 2010 to January 2023 in five bibliographic databases for studies of patients with oligoprogressive disease treated with SABR to all lesions. Clinical outcomes included PFS (progression-free survival), OS (overall survival) and CST (change in systemic therapy). Descriptive statistics were used to summarize the data. Binary random effects model was used for pooled analyses. RESULTS: 12,366 titles/abstracts screened, of which 25 met eligibility criteria and were included the review. All studies were published after 2017 with approximately 80% of the publications in 2021 and 2022. The primary tumour was prostate (n=8, 32%), kidney (n=6, 24%), colorectal (n=4, 16%) followed by breast (n=3, 12%), lung (n=2, 8%) and mixed (n=3, 12%). At 1 year, the pooled PFS was 44% (95% confidence interval [CI]: 34-53%, I2=91%); 53% (95% CI: 45-60%, I2=46%) in prostate, 49% (95% CI: 33-65%, I2=88%) in kidney, 62% (95% CI: 11-113%, I2=96%) in lung, 13% (95% CI: 3-24%, I2=39%) in breast and 30% (95% CI: 19-41%, I2=59%) in mixed. DISCUSSION: There has been a surge in publications describing the use of SABR in oligoprogressive tumours. Published studies are mostly retrospective reported in prostate and kidney cancers, with limited evidence in other sites. Universal guidelines are recommended to ensure consistency in reporting and comparability of future studies.

Development and validation of an MR-driven dose-of-the-day procedure for online adaptive radiotherapy in upper gastrointestinal cancer patients.

Objective.To develop and validate a dose-of-the-day (DOTD) treatment plan verification procedure for liver and pancreas cancer patients treated with an magnetic resonance (MR)-Linac system.Approach.DOTD was implemented as an automated process that uses 3D datasets collected during treatment delivery. Particularly, the DOTD pipeline's input included the adapt-to-shape (ATS) plan-i.e. 3D-MR dataset acquired at beginning of online session, anatomical contours, dose distribution-and 3D-MR dataset acquired during beam-on (BON). The DOTD automated analysis included (a) ATS-to-BON image intensity-based deformable image registration (DIR), (b) ATS-to-BON contours mapping via DIR, (c) BON-to-ATS contours copying through rigid registration, (d) determining ATS-to-BON dosimetric differences, and (e) PDF report generation. The DIR process was validated by two expert reviewers. ATS-plans were recomputed on BON datasets to assess dose differences. DOTD analysis was performed retrospectively for 75 treatment fractions (12-liver and 5-pancreas patients).Main results.The accuracy of DOTD process relied on DIR and mapped contours quality. Most DIR-generated contours (99.6%) were clinically acceptable. DICE correlated with depreciation of DIR-based region of interest mapping process. The ATS-BON plan difference was found negligible (<1%). The duodenum and large bowel exhibited highest variations, 24% and 39% from fractional values, for 5-fraction liver and pancreas. For liver 1-fraction, a 62% variation was observed for duodenum.Significance.The DOTD methodology provides an automated approach to quantify 3D dosimetric differences between online plans and their delivery. This analysis offers promise as a valuable tool for plan quality assessment and decision-making in the verification stage of the online workflow.

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.

Single vs. multiple fraction non-inferiority trial of stereotactic ablative radiotherapy for the comprehensive treatment of oligo-metastases/progression: SIMPLIFY-SABR-COMET.

BACKGROUND: Radiotherapy delivery regimens can vary between a single fraction (SF) and multiple fractions (MF) given daily for up to several weeks depending on the location of the cancer or metastases. With limited evidence comparing fractionation regimens for oligometastases, there is support to explore toxicity levels to nearby organs at risk as a primary outcome while using SF and MF stereotactic ablative radiotherapy (SABR) as well as explore differences in patient-reported quality of life and experience. METHODS: This study will randomize 598 patients in a 1:1 ratio between the standard arm (MF SABR) and the experimental arm (SF SABR). This trial is designed as two randomized controlled trials within one patient population for resource efficiency. The primary objective of the first randomization is to determine if SF SABR is non-inferior to MF SABR, with respect to healthcare provider (HCP)-reported grade 3-5 adverse events (AEs) that are related to SABR. Primary endpoint is toxicity while secondary endpoints include lesional control rate (LCR), and progression-free survival (PFS). The second randomization (BC Cancer sites only) will allocate participants to either complete quality of life (QoL) questionnaires only; or QoL questionnaires and a symptom-specific survey with symptom-guided HCP intervention. The primary objective of the second randomization is to determine if radiation-related symptom questionnaire-guided HCP intervention results in improved reported QoL as measured by the EuroQoL-5-dimensions-5levels (EQ-5D-5L) instrument. The primary endpoint is patient-reported QoL and secondary endpoints include: persistence/resolution of symptom reporting, QoL, intervention cost effectiveness, resource utilization, and overall survival. DISCUSSION: This study will compare SF and MF SABR in the treatment of oligometastases and oligoprogression to determine if there is non-inferior toxicity for SF SABR in selected participants with 1-5 oligometastatic lesions. This study will also compare patient-reported QoL between participants who receive radiation-related symptom-guided HCP intervention and those who complete questionnaires alone. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT05784428. Date of Registration: 23 March 2023.

Defining Minimum Treatment Parameters of Ablative Radiation Therapy in Patients With Hepatocellular Carcinoma: An Expert Consensus.

PURPOSE: External beam radiation therapy (EBRT) is a highly effective treatment in select patients with hepatocellular carcinoma (HCC). However, the Barcelona Clinic Liver Cancer system does not recommend the use of EBRT in HCC due to a lack of sufficient evidence and intends to perform an individual patient level meta-analysis of ablative EBRT in this population. However, there are many types of EBRT described in the literature with no formal definition of what constitutes "ablative." Thus, we convened a group of international experts to provide consensus on the parameters that define ablative EBRT in HCC. METHODS AND MATERIALS: Fundamental parameters related to dose, fractionation, radiobiology, target identification, and delivery technique were identified by a steering committee to generate 7 Key Criteria (KC) that would define ablative EBRT for HCC. Using a modified Delphi (mDelphi) method, experts in the use of EBRT in the treatment of HCC were surveyed. Respondents were given 30 days to respond in round 1 of the mDelphi and 14 days to respond in round 2. A threshold of ≥70% was used to define consensus for answers to each KC. RESULTS: Of 40 invitations extended, 35 (88%) returned responses. In the first round, 3 of 7 KC reached consensus. In the second round, 100% returned responses and consensus was reached in 3 of the remaining 4 KC. The distribution of answers for one KC, which queried the a/b ratio of HCC, was such that consensus was not achieved. Based on this analysis, ablative EBRT for HCC was defined as a BED10 ≥80 Gy with daily imaging and multiphasic contrast used for target delineation. Treatment breaks (eg, for adaptive EBRT) are allowed, but the total treatment time should be ≤6 weeks. Equivalent dose when treating with protons should use a conversion factor of 1.1, but there is no single conversion factor for carbon ions. CONCLUSIONS: Using a mDelphi method assessing expert opinion, we provide the first consensus definition of ablative EBRT for HCC. Empirical data are required to define the a/b of HCC.

Perioperative optimisation in low- and middle-income countries (LMICs): A systematic review and meta-analysis of enhanced recovery after surgery (ERAS).

Background: Enhanced recovery after surgery (ERAS) protocols have largely been incorporated into practice in high-income settings due to proven improvement in perioperative outcomes. We aimed to review the implementation of ERAS protocols and other perioperative optimisation strategies in low- and middle-income countries (LMICs) and their impact on length of hospital stay (LOS). Methods: We searched MEDLINE, PubMed, Global Health (CABI), WHO Global Index Medicus, Index Medicus, and Latin American and Caribbean Health Sciences Literature (LILACS) for studies incorporating ERAS or other prehabilitation approaches in LMICs. We conducted a pooled analysis of LOS using a random-effects model to evaluate the impact of such programs. This systematic review was pre-registered on PROSPERO. Results: We screened 1205 studies and included 70 for a full-text review; six were eligible for inclusion and five for quantitative analysis, two of which were randomised controlled trials. ERAS was compared to routine practice in all included studies, while none implemented prehabilitation or other preoperative optimisation strategies. Pooled analysis of 290 patients showed reduced LOS in the ERAS group with a standardised mean difference of -2.18 (95% confidence interval (CI) = -4.13, -.0.05, P < 0.01). The prediction interval was wide (95% CI = -7.85, 3.48) with substantial heterogeneity (I2 = 94%). Conclusions: Perioperative optimisation is feasible in LMICs and appears to reduce LOS, despite high levels of between-study heterogeneity. There is a need for high-quality data on perioperative practice in LMICs and supplementary qualitative analysis to further understand barriers to perioperative optimisation implementation. Registration: PROSPERO: CRD42021279053.

Clinical Outcomes of Patients with Metastatic Breast Cancer Treated with Hypo-Fractionated Liver Radiotherapy.

PURPOSE: To retrospectively review the clinical outcomes of patients with metastatic breast cancer (MBCa) following liver directed ablative intent radiotherapy (RT). METHODS: Demographics, disease and treatment characteristics of patients with MBCa who received liver metastasis (LM) directed ablative RT between 2004-2020 were analysed. The primary outcome was local control (LC), secondary outcomes included overall survival (OS) and progression-free survival (PFS) analyzed by univariate (UVA) and multi-variable analysis (MVA). RESULTS: Thirty MBCa patients with 50 LM treated with 5-10 fraction RT were identified. Median follow-up was 14.6 (range 0.9-156.2) months. Class of metastatic disease was described as induced (12 patients, 40%), repeat (15 patients, 50%) and de novo (three patients, 10%). Median size of treated LM was 3.1 cm (range 1-8.8 cm) and median biologically effective dose delivered was 122 (Q1-Q3; 98-174) Gy3. One-year LC rate was 100%. One year and two-year survival was 89% and 63%, respectively, with size of treated LM predictive of OS (HR 1.35, p = 0.023) on UVA. Patients with induced OMD had a significantly higher rate of progression (HR 4.77, p = 0.01) on UVA, trending to significance on MVA (HR 3.23, p = 0.051). CONCLUSIONS: Hypo-fractionated ablative liver RT in patients with MBCa provides safe, tolerable treatment with excellent LC.

Climate toxicity: An increasingly relevant clinical issue in Cancer Care.

In recent years the terms time and financial toxicities have entered the vocabulary of cancer care. We would like to introduce another toxicity: climate toxicity. Climate toxicity is a double-edge sword in cancer care. Increasing cancer risk by exposure to carcinogens, and consequently increasing treatment requirements leads to ever growing damage to our environment. This article assesses the impact of climate change on patients, the climate toxicity caused by both healthcare workers and healthcare facilities, and suggests actions that may be taken mitigate them.

Impact of endorectal filling on interobserver variability of MRI based rectal primary tumor delineation.

Background: Online adaptive MR-guided radiotherapy allows for the reduction of safety margins in dose escalated treatment of rectal tumors. With the use of smaller margins, precise tumor delineation becomes more critical. In the present study we investigated the impact of rectal ultrasound gel filling on interobserver variability in delineation of primary rectal tumor volumes. Methods: Six patients with locally advanced rectal cancer were scanned on a 1.5 T MRI-Linac without (MRI_e) and with application of 100 cc of ultrasound gel transanally (MRI_f). Eight international radiation oncologists expert in the treatment of gastrointestinal cancers delineated the gross tumor volume (GTV) on both MRI scans. MRI_f scans were provided to the participating centers after MRI_e scans had been returned. Interobserver variability was analyzed by either comparing the observers' delineations with a reference delineation (approach 1) and by building all possible pairs between observers (approach 2). Dice Similarity Index (DICE) and 95 % Hausdorff-Distance (95 %HD) were calculated. Results: Rectal ultrasound gel filling was well tolerated by all patients. Overall, interobserver agreement was superior in MRI_f scans based on median DICE (0.81 vs 0.74, p < 0.005 for approach 1 and 0.76 vs 0.64, p < 0.0001 for approach 2) and 95 %HD (6.9 mm vs 4.2 mm for approach 1, p = 0.04 and 8.9 mm vs 6.1 mm, p = 0.04 for approach 2). Delineated median tumor volumes and inter-quartile ranges were 26.99 cc [18.01-50.34 cc] in MRI_e and 44.20 [19.72-61.59 cc] in MRI_f scans respectively, p = 0.012. Conclusions: Although limited by the small number of patients, in this study the application of rectal ultrasound gel resulted in higher interobserver agreement in rectal GTV delineation. The endorectal gel filling might be a useful tool for future dose escalation strategies.

Evaluation of dosimetric predictors of toxicity after IMRT with concurrent chemotherapy for anal cancer.

BACKGROUND: This study investigates the impact of dosimetric parameters on acute and late toxicity for patients with anal squamous cell carcinoma (SCC) treated with image-guided intensity modulated radiation therapy (IG-IMRT) and concurrent chemotherapy. MATERIALS AND METHODS: Patients were enrolled in an observational cohort study between 2008 and 2013 (median follow-up 3.4 years). They were treated with standardized target and organ-at-risk (OAR) contouring, planning, and IG-IMRT. Radiotherapy dose, based on clinicopathologic features, ranged from 45 Gy to 63 Gy to gross targets and 27 Gy to 36 Gy to elective targets. Chemotherapy was concurrent 5-fluorouracil and mitomycin C (weeks 1&5). Toxicity was prospectively graded using NCI CTCAE v.3 and RTOG scales. Logistic regression was used to assess the association between dose/volume parameters (e.g small bowel V5) and corresponding grade 2 + and 3+ (G2+/3 + ) toxicities (e.g. diarrhea). RESULTS: In total, 87 and 79 patients were included in the acute and late toxicity analyses, respectively. The most common acute G2 + toxicities were skin (dermatitis in 87 % [inguino-genital skin], 91 % [perianal skin]) and hematologic in 58 %. G2 + late anal toxicity (sphincter dysfunction), gastrointestinal toxicity, and skin toxicity were respectively experienced by 49 %, 38 %, and 44 % of patients. Statistically significant associations were observed between: G2 + acute diarrhea and small bowel V35; G2 + acute genitourinary toxicity and bladder D0.5cc; G2 + inguino-genital skin toxicity and anterior skin V35; G2 + perianal skin toxicity and posterior skin V15; G2 + anemia and lower pelvis bone V45. D0.5 cc was significantly predictive of late toxicity (G2 + anal dysfunction, intestinal toxicity, and inguino-genital/perianal dermatitis). Maximum skin toxicity grade was significantly correlated with the requirement for a treatment break. CONCLUSION: Statistically significant dose-volume parameters were identified and may be used to offer individualized risk prediction and to inform treatment planning. Additional validation of the results is required.

The Impact of Parent and Family Caregiver Roles Among Canadian Radiation Oncologists.

PURPOSE: Working parents, and a rising number of adults delivering care for aging relatives, experience numerous challenges in their personal, family, professional, and financial lives owing to multiple responsibilities. This study describes the experiences of Canadian radiation oncologist (RO) parents and family caregivers, reporting challenges that may exist in providing family care with clinical and academic work commitments. METHODS AND MATERIALS: Canadian ROs, via RO heads of departments in cancer centers across Canada, and physician members of the Canadian Association of Radiation Oncology were invited to participate in an anonymous online survey between November 2021 and January 2022. The survey focused on demographics, experiences of pregnancy and leave, parenting and adult caregiving responsibilities, and self-care. RESULTS: A total of 103 staff ROs (38%) completed the survey and 78 (75.7%) identified as having a parental (76 [89.7%]) and/or other family caregiver (8 [10.3%]) role; 41% were female and 59% were male, with no difference between genders in the number of children (median, 2; interquartile range, 1-3; P = .17). More female respondents took parental leave for their first child compared with male respondents (mean, 29 vs 6 weeks; P < .001). Of male respondents who started caring for their first child during residency, 27% took parental leave, compared with 77% who started caring for their first child as a staff member (P = .003). The majority of respondents described "always/usually" having collegial support for each pregnancy and parental leave. Both genders described parental responsibilities as negatively affecting attendance at conferences (male, 65%; female, 77%; P = .31) and early or late work-related meetings (male, 76%; female, 79%; P = 1.0). More female respondents described parental responsibilities as negatively affecting their career (50% vs 29%; P = .085). Of female respondents, 52% (vs 26% of male respondents; P = .044) identified a physician mentor or positive role model around parenting issues. CONCLUSIONS: Parental and other family caregiving responsibilities are not gender unique in Canadian ROs, but competing work and family roles may affect genders differently.

Safety and Tolerability of Metastasis-Directed Radiation Therapy in the Era of Evolving Systemic, Immune, and Targeted Therapies.

AbstractPurpose: Systemic, immune, and target therapies are growing in use in the management of metastatic cancers. The aim of this review was to describe up-to-date published data on the safety and tolerability of metastasis-directed hypofractionated radiation therapy (RT) when combined with newer systemic, immune, and targeted therapies and to provide suggested strategies to mitigate potential toxicities in the clinical setting. Methods and Materials: A comprehensive search was performed for the time period between 1946 and August 2021 using predetermined keywords describing the use of noncentral nervous system palliative RT with commonly used targeted systemic therapies on PubMed and Medline databases. A total of 1022 articles were screened, and 130 met prespecified criteria to be included in this review. Results: BRAF and MEK inhibitors are reported to be toxic when given concurrently with RT; suspension 3 days and 1 to 2 days, respectively, prior and post-RT is suggested. Cetuximab, erlotinib/gefitinib, and osimertinib were generally safe to use concomitantly with conventional radiation. But in a palliative/hypofractionated RT setting, suspending cetuximab during radiation week, erlotinib/gefitinib 1 to 2 days, and osimertinib ≥2 days pre- and post-RT is suggested. Vascular endothelial growth factor inhibitors such as bevacizumab reported substantial toxicities, and the suggestion is to suspend 4 weeks before and after radiation. Less data exist on sorafenib and sunitinib; 5 to 10 days suspension before and after RT should be considered. As a precaution, until further data are available, for cyclin-dependent kinase 4-6 inhibitors, consideration of suspending treatment 1 to 2 days before and after RT should be given. Ipilimumab should be suspended 2 days before and after RT, and insufficient data exist for other immunotherapy agents. Trastuzumab and pertuzumab are generally safe to use in combination with RT, but insufficient data exist for other HER2 target therapy. Conclusions: Suggested approaches are described, using up-to-date literature, to aid clinicians in navigating the integration of newer targeted agents with hypofractionated palliative and/or ablative metastatic RT. Further prospective studies are required.

Stereotactic body radiation therapy for hepatocellular carcinoma: From infancy to ongoing maturity.

Hepatocellular carcinoma (HCC) accounts for 90% of liver tumours and is one of the leading causes of mortality. Cirrhosis due to viral hepatitis, alcohol or steatohepatitis is the major risk factor, while liver dysfunction due to cirrhosis is a deciding factor in its treatment. The treatment modalities for HCC include liver transplant, hepatectomy, radiofrequency ablation, transarterial chemoembolisation, transarterial radioembolisation, targeted therapy, immunotherapy, and radiation therapy. The role of radiation therapy has been refined with the increasing use of stereotactic body radiation therapy (SBRT). Trials over the past two decades have shown the efficacy and safety of SBRT in recurrent and definitive HCC, leading to its acceptance and adoption in some more recent guidelines. However, high quality level I evidence supporting its use is currently lacking. Smaller randomised trials of external beam radiation therapy suggest high efficacy of radiation therapy compared to other treatments for patients with unresectable HCC, and phase III trials comparing SBRT with other modalities are ongoing. In this review, we discuss the rationale for SBRT in HCC and present evidence on its efficacy, associated toxicity, and technological advances.

Applying the intervention Complexity Assessment Tool to brief interventions targeting long-term benzodiazepine receptor agonist use in primary care: Lessons learned.

BACKGROUND: Benzodiazepine receptor agonists (BZRAs) are often prescribed for long-term use. However, guidelines recommend limiting prescriptions to short-term use (< 4 weeks) to reduce the risk of adverse effects and dependence. A recent systematic review reported that brief interventions targeting long-term BZRA use in primary care (e.g., short consultations, written letters to patients) were effective in helping patients to discontinue BZRA medication. However, the complexity of these interventions has not been examined in detail. This study aimed to apply the intervention Complexity Assessment Tool for Systematic Reviews (iCAT_SR) to brief interventions targeting long-term BZRA use.  METHODS: Two reviewers independently assessed the interventions using the six core iCAT_SR dimensions: organisational level/ category targeted, behaviour targeted, number of intervention components, degree of tailoring, skill level required by those delivering and receiving the intervention. The four optional iCAT_SR dimensions were applied where possible. A scoring system was using to calculate a complexity score for each intervention. Pearson's correlations were used to assess the relationship between intervention complexity and effect size, as well as the relationship between intervention complexity and number of component behaviour change techniques (BCTs). Inter-rater reliability was calculated using Cohen's Kappa coefficient. RESULTS: Four of the six core iCAT_SR dimensions were applied to the interventions with high inter-rater reliability (Cohen's Kappa = 0.916). Application of the four optional dimensions was prevented by a lack of detail in study reports. Intervention complexity scores ranged from 8 to 11 (median: 11). There was no relationship detected between intervention complexity and either intervention effect size or number of component BCTs. CONCLUSIONS: This study adds to the literature on worked examples of the practical application of the iCAT_SR. The findings highlight how more detailed reporting of interventions is needed in order to optimise the application of iCAT_SR and its potential to differentiate between interventions across the full range of complexity dimensions. Further work is needed to establish the validity of applying a scoring system to iCAT_SR assessments.

Patient-Reported and Clinical Outcomes From 5-Fraction SBRT for Oligometastases: A Prospective Single-Institution Study.

PURPOSE: To describe the long-term outcomes of a 5-fraction normal tissue tolerance adapted strategy for the management of oligometastases (OM). METHODS AND MATERIALS: Patients with histologically confirmed solid tumors, ≤5 extracranial metastases, suitable for a definitive approach for all metastatic lesions, at least one lesion suitable for Stereotactic Body Radiotherapy (SBRT), Eastern Coooperative Oncology Group Performance Status ≤2 were eligible. Treatment intervention was a 5-fraction (25-55 Gy) normal tissue adapted dosing strategy. The primary outcome was cumulative local progression rate at 12 months. RESULTS: Between March 2013 and January 2018, 137 patients started SBRT. Median follow-up was 35.7 months. In addition, 107 (78%) patients had a solitary OM. The mean planning target volume D95 was 39.6 (standard deviation, 8.8; biological effective dose using an alpha/beta ratio of 10, 70.8) Gy. Mean planning target volume D95 was highest for lung lesions (48.7 [standard deviation, 4.7]; biological effective dose using an alpha/beta ratio of 10, 96.1) Gy but was <40 Gy for all other anatomic sites. Two grade 3 toxicities (gastrointestinal bleed) were observed with stomach D0.05 30.3 Gy and 30.4 Gy. The cumulative local progression rate at 12 of 36 months was 16.1% (95% CI, 10-22) and 38.3% (95% CI 30-46.7); overall survival was 90% and 37%, and progression free survival was 58% and 19%, respectively. Mean symptom burden (Edmonton Symptom Assessment Total Score) worsened in patients with progressive disease (+8.8) at 12 months and was paralleled by changes in mean European Organization for Research and Treatment Quality of Life Core Questionnaire Summary Score and Global Health Quality of Life Score. Systemic therapy was initiated in 55% of patients at an average of 12.7 (standard deviation 12.4) months. CONCLUSIONS: If long-term progression free survival is the primary goal of therapy, SBRT for OM achieved this in <20% of patients attributable to a high risk of distant failure. Favorable local progression free survival is accompanied by preservation of quality of life, avoidance of symptom progression and reduced need of antineoplastic therapies at 12 months. Information on symptom burden, quality of life, as well as pattern of antineoplastic therapy use after progressive disease is useful to support conversations between patients, families, and health care providers. Strategies to improve patient selection and reduce distant progression rate remain a priority for further study.

The Impact of Disease Progression on Health-Related Quality of Life Outcomes in Patients With Oligometastatic Disease at 12 Months Post Stereotactic Body Radiation Therapy.

PURPOSE: There is a paucity of published health-related quality of life (HRQOL) outcomes in patients with oligometastatic disease (OMD) who receive stereotactic body radiation therapy (SBRT) and no available data assessing the effect of disease progression post-SBRT on HRQOL in this patient population. METHODS AND MATERIALS: Patients with OMD who received SBRT in a phase II single-arm research ethics board approved study were included. HRQOL was a secondary outcome. This study hypothesized that there is a different pattern of change from baseline HRQOL in patients with OMD treated with SBRT that have disease progression by 12 months (progressors) compared with those that do not progress by 12 months (nonprogressors), as measured by the European Organisation of Research and Treatment in Cancer Quality of Life Questionnaire Core 30. RESULTS: A total of 107 patients were included in this analysis, 41 without progression and 66 with progression by 12 months; median time to progression was 7.7 (0.3-57) months. A statistically significant decline in the mean global health/quality of life (GHQOL) score (73 [SD, 21.8] to 67.2 [SD, 27.1]; P = .04) from baseline in the entire population at the 12-month follow-up was found. Mean GHQOL change score in nonprogressors was -0.8 and in progressors was -8.8 (P = .07). However, only progressors demonstrated a difference between baseline and 12-month mean GHQOL scores (71.2 vs 62.4; P = .01), which was both statistically and clinically significant (-8.8) in the range of small minimal clinically important difference. There was a higher proportion of patients who experienced a minimal clinically important difference deterioration in progressors compared with nonprogressors (37.4% vs 24.4%; P = .14). CONCLUSIONS: Patients who progressed by 12 months did not have a statistical or clinically significant difference in mean GHQOL change score compared with nonprogressors. However, there were signals to suggest that patients who progressed by 12 months post-SBRT experienced a different pattern of change compared with nonprogressors, which was worse compared with baseline.

Health related quality of life outcomes following stereotactic body radiotherapy in patients with oligo-metastatic disease: A systematic review and individual patient data meta-analysis.

INTRODUCTION: Published health-related quality of life (HRQOL) outcomes are lacking in patients treated for oligo-metastatic disease (OMD). The aim of this systematic review and individual patient data meta-analysis is to determine the effect of stereotactic body radiotherapy (SBRT) on HRQOL outcomes of patients with OMD. METHODS: Studies screened included adults with extra-cranial OMD, defined as ≤ 5 metastases, SBRT intended as definitive treatment, and HRQOL as primary or secondary outcome. Primary outcome was change in HRQOL at 12-months from baseline in patients with OMD who received SBRT (versus not), reported as standardized mean difference (SMD). RESULTS: A total of 7556 publications were identified, four studies met inclusion criteria (2 single arm interventional studies and 2 randomised controlled trials [RCTs]), and individual patient data was available from 3 studies (175 patients). In the two RCTs, there was no SS difference in the SMD between patients who received SBRT and those that did not (0.09 [95 % CI -0.32, 0.5], P = 0.66). On meta-analysis of patients (N = 107) who received SBRT the SMDwas -0.23 (95 % CI [-0.42, -0.04], versus -0.25 (95 % CI [-0.57, 0.07]) in those who did not (N = 37) receive SBRT, demonstrating a small deterioration from baseline. CONCLUSION: In patients with OMD, there is no difference in HRQOL at 12-months from baseline between patients who received SBRT and those that did not. However, a small HRQOL deterioration was found in both groups of patients. More in-depth analysis of relevant HRQOL domains, in the setting of OMD, is required to better understand the potential impact of SBRT.