Stereotactic Radiation for Ultra-Central Non-Small Cell Lung Cancer: A Safety and Efficacy Trial (SUNSET).

PURPOSE: The use of stereotactic body radiation therapy for tumors in close proximity to the central mediastinal structures has been associated with a high risk of toxicity. This study (NCT03306680) aimed to determine the maximally tolerated dose of stereotactic body radiation therapy for ultracentral non-small cell lung carcinoma, using a time-to-event continual reassessment methodology. METHODS AND MATERIALS: Patients with T1-3N0M0 (≤6 cm) non-small cell lung carcinoma were eligible. The maximally tolerated dose was defined as the dose of radiation therapy associated with a ≤30% rate of grade (G) 3 to 5 prespecified treatment-related toxicity occurring within 2 years of treatment. The starting dose level was 60 Gy in 8 daily fractions. The dose-maximum hotspot was limited to 120% and within the planning tumor volume; tumors with endobronchial invasion were excluded. This primary analysis occurred 2 years after completion of accrual. RESULTS: Between March 2018 and April 2021, 30 patients were enrolled at 5 institutions. The median age was 73 years (range, 65-87) and 17 (57%) were female. Planning tumor volume was abutting proximal bronchial tree in 19 (63%), esophagus 5 (17%), pulmonary vein 1 (3.3%), and pulmonary artery 14 (47%). All patients received 60 Gy in 8 fractions. The median follow-up was 37 months (range, 8.9-51). Two patients (6.7%) experienced G3-5 adverse events related to treatment: 1 patient with G3 dyspnea and 1 G5 pneumonia. The latter had computed tomography findings consistent with a background of interstitial lung disease. Three-year overall survival was 72.5% (95% CI, 52.3%-85.3%), progression-free survival 66.1% (95% CI, 46.1%-80.2%), local control 89.6% (95% CI, 71.2%-96.5%), regional control 96.4% (95% CI, 77.2%-99.5%), and distant control 85.9% (95% CI, 66.7%-94.5%). Quality-of-life scores declined numerically over time, but the decreases were not clinically or statistically significant. CONCLUSIONS: Sixty Gy in 8 fractions, planned and delivered with only a moderate hotspot, has a favorable adverse event rate within the prespecified acceptability criteria and results in excellent control for ultracentral tumors.

Overall survival in advanced hepatocellular carcinoma treated with concomitant systemic therapy and stereotactic body radiation therapy or systemic therapy alone.

Introduction: First-line systemic therapy (ST) options for advanced hepatocellular carcinoma (HCC) include tyrosine kinase inhibitors and immunotherapy (IO). Evolving data suggest prolonged overall survival (OS) when ST is combined with stereotactic body radiation therapy (SBRT), although evidence is significantly limited in HCC populations. We hypothesized that advanced HCC patients in the National Cancer Database (NCDB) would have improved OS when receiving ST+SBRT vs ST alone. Methods: Stage III/IV HCC patients diagnosed from 2010-2020 and treated with first-line ST±SBRT were identified from the NCDB. The primary endpoint was OS from date of diagnosis stratified by the receipt of SBRT (ST+SBRT vs ST alone). Survival was estimated using Kaplan-Meier methodology and compared via log-rank. Multivariate analysis (MVA) was performed by Cox regression. Results: Of 10,505 eligible patients with stage III disease, 115 (1.1%) received ST+SBRT and 10,390 (98.9%) received ST alone. Of 9,617 eligible patients with stage IV disease, 127 (1.3%) received ST+SBRT and 9,490 (98.7%) received ST alone. Median follow-up time was 6.8 months. Baseline characteristics were similar between cohorts. Patients with stage III disease receiving ST+SBRT had improved median OS (12.62 months vs 8.38 months) and higher rates of survival at 1-year (53.0% vs 38.7%) and 2-years (27.0% vs 20.7%) compared to those receiving ST alone (log-rank P=0.0054). Similarly, patients with stage IV disease receiving ST+SBRT had improved median OS (11.79 months vs 5.72 months) and higher rates of survival at 1-year (49.6% vs 26.2%) and 2-years (23.6% vs 12.0%) (log-rank P<0.0001). On MVA, receipt of SBRT predicted improved OS (HR=0.748, 95%CI 0.588-0.951; P=0.0178) and receipt of IO trended towards improved OS (HR=0.859, 95%CI 0.735-1.003; P=0.0538). Conclusion: In advanced HCC, patients receiving ST+SBRT had improved OS compared to those receiving ST alone. Prospective clinical trials are warranted to better identify HCC populations which may benefit from combined modality therapy.

Evaluation of Volumetric Response Assessment From SABR for Renal Cell Carcinoma (RCC).

PURPOSE: SABR is increasingly used to treat renal cell carcinoma (RCC). However, the optimal method to assess treatment response is unclear. We aimed to quantify changes in both volume and maximum linear size of tumors after SABR and evaluate the utility of the 2 approaches in treatment response assessment. METHODS AND MATERIALS: We retrospectively studied patients with RCC treated with SABR at our institution between 2013 and 2020. All available follow-up computed tomography scans were aligned, and tumors were contoured on all scans. Volume and maximum linear size were measured at each follow-up, relative to these measurements at the time of computed tomography simulation. RESULTS: Twenty-four patients with 25 tumors were included. Median follow-up was 32 months (range, 16-67). Nineteen tumors (76%) had 30% volumetric response at a median time of 7 months after SABR, and 12 tumors (48%) had 30% decrease in maximum linear size at a median time of 16 months. Eighteen tumors (72%) decreased in volume on first follow-up scan and continued to shrink, and 5 tumors (20%) displayed transient growth after SABR (average 24% increase in volume). Compared with T1a tumors, T1b or larger tumors were more likely to have transient growth (8% vs 33%; P = .16) and had higher average relative volume 24 months after SABR (0.47 vs 0.8; P = .022). CONCLUSIONS: Volume measurement results in more pronounced and earlier change compared with linear size measurement when assessing response to SABR. These findings may provide guidance when assessing treatment response for patients with RCC treated with SABR.

Neuroanatomical location of brain metastases from solid tumours based on pathology: An analysis of 511 patients with a comparison to the provided clinical history.

Brain metastases are a frequent occurrence in neuropathology practices. The literature on their neuroanatomical location is frequently derived from radiological analyses. This work examines brain metastases through the lens of pathology specimens. All brain surgical pathology reports for cases accessioned 2011-2020 were retrieved from a laboratory. Specimens were classified by neuroanatomical location, diagnosis and diagnostic category with a hierarchical free text string-matching algorithm (HFTSMA) and also subsequently audited. All reports classified as probable metastasis were reviewed by a pathologist. The provided history was compared to the final categorization by a pathologist. The cohort had 4,625 cases. The HFTSMA identified 854 cases (including metastases from a definite primary, metastases from primary not known and improperly classified cases). 514/854 cases had one definite primary site per algorithm and on report review 538/854 cases were confirmed as such. The 538 cases originated from 511 patients. Primaries from breast, gynecologic tract, and gastrointestinal tract not otherwise specified were most frequently found in the cerebellum. Kidney metastases were most frequently found in the occipital lobe. Lung, metastatic melanoma and colorectal primaries were most commonly found in the frontal lobe. The provided clinical history predicted the primary in 206 cases (40.3%), was discordant in 17 cases (3.3%) and non-contributory in 280 cases (54.8%). The observed distribution of the metastatic tumours in the brain is dependent on the primary site. In the majority (54.8%) of cases, the provided clinical history was non-contributory; this suggests surgeon-pathologist communication may have the potential for optimization.

The impact of staging FDG-PET/CT on treatment for stage III NSCLC - an analysis of population-based data from Ontario, Canada.

Purpose: Fluoro-2-deoxyglucose positron-emission tomography (FDG-PET/CT) is now considered a standard investigation for the staging of new cases of stage III NSCLC. However, there is not published level 3 evidence demonstrating the impact of FDG-PET/CT on appropriate therapy in this setting. Using retrospective population-based data, we sought to examine the role and timing that FDG-PET/CT scans play in influencing treatment choice, as well as survival in patients diagnosed with stage III NSCLC. Materials and methods: A retrospective cohort of patients diagnosed with stage III NSCLC from 2009-2017 in Ontario were identified from the IC/ES (formerly Institute of Clinical Evaluative Sciences) database. FDG-PET/CT utilization over time, trends in mediastinal biopsy technique and usage, the impact of FDG-PET/CT on overall survival (OS), and its influence on use of concurrent chemoradiotherapy (CRT) were explored. The impact of timing of pre-treatment FDG-PET/CT on OS was also analyzed (≤28 days prior to treatment, 29-56 days prior, and >56 days prior). Results: Between 2007 and 2017, a total of 13 796 people were diagnosed with stage III NSCLC in Ontario. FDG-PET/CT utilization increased over time with 0% of cases in 2007 and 74% in 2017 with pre-treatment FDG-PET/CT scans. The number of patients who received a mediastinal biopsy similarly increased in this timeframe increasing from 41% to 53%. More patients with pre-treatment FDG-PET/CT scans received curative-intent therapy than those who did not: 23% vs 13% for CRT (p<0.001), and 23% vs 10% for surgery (p<0.001). Median OS was longer in those with FDG-PET/CT scans prior to treatment (17 vs 11 months), as was 5-year survival (22% vs 14%, p<0.001), and this held true on both univariate and multivariate analyses. Timing of FDG-PET/CT scan relative to treatment was not associated with differences in OS. Conclusion: Improvements in OS were seen in this cohort of stage III NSCLC patients who underwent a pre-treatment FDG-PET/CT scan. This can likely be attributed to stage-appropriate therapy due to more complete staging using FDG-PET/CT. This study stresses the importance of complete staging for suspected stage III NSCLC using FDG-PET/CT, and a need for continued advocacy for increased access to FDG-PET/CT scans.

Current and Future Treatment Options in the Management of Stage III NSCLC.

For much of the past two decades, the treatment options for patients with stage III NSCLC were mostly stagnant. In the past 5 years, ongoing innovations have dovetailed alongside advances in biomarker testing, novel therapeutics, precision surgery, and radiotherapy, all of which are leading to an increase in more personalized option for the treatment. This review article will focus on several completed and ongoing initiatives involving treatment of patients with stage III NSCLC. First, it will tackle the progress made in curative treatment of unresectable stage III NSCLC, starting with PACIFIC, and branching out into topics such as concurrent immunotherapy and chemoradiation, intensification of consolidative immunotherapy, dual immunotherapy consolidation, and a reflection on those subpopulations that may not benefit from consolidative immunotherapy. Second, there will be discussion of novel strategies in the setting of resectable stage III disease, most notably neoadjuvant therapy using combined chemoimmunotherapy and immunotherapy alone before surgical resection. Third, it will delve into recent data evaluating adjuvant immunotherapy for resectable stage III NSCLC, including adjuvant targeted therapy (for those harboring driver mutations) and postoperative radiotherapy. Finally, a look to future trials/initiatives will be interspersed throughout the review, to reveal the ongoing efforts being made to continue to improve outcomes in this group of patients.

Survival in Metastatic Renal Cell Carcinoma Treated With Immunotherapy and Stereotactic Radiation Therapy or Immunotherapy Alone: A National Cancer Database Analysis.

Purpose: Immunotherapy (IO) has significantly improved outcomes in metastatic renal cell carcinoma (mRCC). Preclinical evidence suggests that responses to IO may be potentiated via immunomodulatory effects of stereotactic radiation therapy (SRT). We hypothesized that clinical outcomes from the National Cancer Database (NCDB) would demonstrate improved overall survival (OS) in patients with mRCC receiving IO + SRT versus IO alone. Methods and Materials: Patients with mRCC receiving first-line IO ± SRT were identified from the NCDB. Conventional radiation therapy was allowed in the IO alone cohort. The primary endpoint was OS stratified by the receipt of SRT (IO + SRT vs IO alone). Secondary endpoints included OS stratified by the presence of brain metastases (BM) and timing of SRT (before or after IO). Survival was estimated using Kaplan-Meier methodology and compared via the log-rank test. Results: Of 644 eligible patients, 63 (9.8%) received IO + SRT, and 581 (90.2%) received IO alone. Median follow-up time was 17.7 months (range, 2-24 months). Sites treated with SRT included the brain (71.4%), lung/chest (7.9%), bones (7.9%), spine (6.3%), and other (6.3%). OS was 74.4% versus 65.0% at 1 year and 71.0% versus 59.4% at 2 years for the IO + SRT and IO alone groups, respectively, although this difference did not reach statistical significance (log-rank P = .1077). In patients with BM, however, 1-year OS (73.0% vs 54.7%) and 2-year OS (70.8% vs 51.4%) was significantly higher in those receiving IO + SRT versus IO alone, respectively (pairwise P = .0261). Timing of SRT (before or after IO) did not influence OS (log-rank P = .3185). Conclusions: Patients with BM secondary to mRCC had prolonged OS with the addition of SRT to IO. Factors such as International mRCC Database Consortium risk stratification, oligometastatic tumor burden, SRT dose/fractionation, and utilization of doublet therapy should be considered in future analyses to better identify patients who may benefit from combined IO + SRT. Further prospective studies are warranted.

The Judicious Use of Stereotactic Ablative Radiotherapy in the Primary Management of Localized Renal Cell Carcinoma.

Localized renal cell carcinoma is primarily managed surgically, but this disease commonly presents in highly comorbid patients who are poor operative candidates. Less invasive techniques, such as cryoablation and radiofrequency ablation, are effective, but require percutaneous or laparoscopic access, while generally being limited to cT1a tumors without proximity to the renal pelvis or ureter. Active surveillance is another management option for small renal masses, but many patients desire treatment or are poor candidates for active surveillance. For poor surgical candidates, a growing body of evidence supports stereotactic ablative radiotherapy (SABR) as a safe and effective non-invasive treatment modality. For example, a recent multi-institution individual patient data meta-analysis of 190 patients managed with SABR estimated a 5.5% five-year cumulative incidence of local failure with one patient experiencing grade 4 toxicity, and no other grade ≥3 toxic events. Here, we discuss the recent developments in SABR for the management of localized renal cell carcinoma, highlighting key concepts of appropriate patient selection, treatment design, treatment delivery, and response assessment.

Adjuvant therapy for renal cell carcinoma: 2023 Canadian Kidney Cancer Forum consensus statement.

INTRODUCTION: Several recent randomized trials evaluated the impact of adjuvant immune checkpoint inhibitor (ICI)-based therapy on post-surgical outcomes in renal cell carcinoma (RCC), with disparate results. The objective of this consensus statement is to provide data-driven guidance regarding the use of ICIs after complete resection of clear-cell RCC in a Canadian context. METHODS: An expert panel of genitourinary medical oncologists, urologic oncologists, and radiation oncologists with expertise in RCC management was convened in a dedicated session during the 2022 Canadian Kidney Cancer Forum in Toronto, Canada. Topic statements on the management of patients after surgery for RCC, including counselling, risk stratification, indications for medical oncology referral, appropriate followup, eligibility and management for adjuvant ICIs, as well as treatment options for patients with recurrence who received adjuvant immunotherapy, were discussed. Participants were asked to vote if they agreed or disagreed with each statement. Consensus was achieved if greater than 75% of participants agreed with the topic statement. RESULTS: A total of 22 RCC experts voted on 14 statements. Consensus was achieved on all topic statements. The panel felt patients with clear-cell RCC at increased risk of recurrence after surgery, as per the Keynote-564 group definitions, should be counselled about recurrence risk by a urologist, should be informed about the potential role of adjuvant ICI systemic therapy, and be offered referral to discuss risks and benefits with a medical oncologist. The panel felt that one year of pembrolizumab is currently the only regimen that should be considered if adjuvant therapy is selected. Panelists emphasized current opinions are based on disease-free survival given the available results. Significant uncertainty regarding the benefit and harms of adjuvant therapy remains, primarily due to a lack of consistent benefit observed across similar trials of adjuvant ICI-based therapies and immature overall survival (OS) data. CONCLUSIONS: This consensus document provides guidance from Canadian RCC experts regarding the potential role of ICI-based adjuvant systemic therapy after surgery. This rapidly evolving field requires frequent evidence-based re-evaluation.

Contemporary real-world radiotherapy outcomes of unresected locally advanced non-small cell lung cancer.

Background: Radiotherapy (RT) is used as monotherapy in poor performance patients with unresected locally advanced non-small cell lung cancer (LA-NSCLC), but their outcomes are not well-described. As novel therapies are increasingly considered in this space, it is important to understand contemporary outcomes of RT alone. Here, in this retrospective cohort study we analyzed LA-NSCLC outcomes of RT alone in Ontario, Canada, and contrasted them against those of standard of care (SoC) treatment of concurrent chemo-radiotherapy (cCRT). Methods: Ontario provincial databases were searched through the Institute of Clinical Evaluative Sciences (IC/ES) for stage III NSCLC patients diagnosed between 2007 and 2017. Surgical patients were excluded, and all patients that received RT without or with chemotherapy were selected. Patients were divided in groups of RT dose received (<40 Gy, 40-55.9 Gy, and ≥56 Gy) and whether they underwent diagnostic 18F-deoxy-glucose (FDG)-positron emission tomography (PET). Results: Five thousand five hundred and seventy-seven stage III patients that received chest RT without surgery between January 2007 and March 2017 were included in this analysis. Within this group, 39.8% (2,225) received RT alone, 47.4% (2,645) cCRT and 12.6% (707) received sequential chemo-radiotherapy (sCRT). Median OS with RT alone in three dose groups <40/40-55.9/≥56 Gy was 7.2, 8.5 and 13.3 months compared to 16.5, 15.8 and 22 months for cCRT patients. Higher RT dose and PET utilization were independently associated with improved survival in multivariate analysis. Conclusions: Radiation monotherapy remains a widely used treatment modality in LA-NSCLC. RT dose and utilization of FDG-PET imaging are associated with improved survival in this group. These findings help improve clinical decision making and serve as basis for future trials.

BRACHY: A Randomized Trial to Evaluate Symptom Improvement in Advanced Non-Small Cell Lung Cancer Treated With External Beam Radiation With or Without High-Dose-Rate Intraluminal Brachytherapy.

PURPOSE: Uncontrolled studies suggest that the addition of high-dose-rate intraluminal brachytherapy (HDRIB) to external beam radiation therapy (EBRT) may improve palliation for patients with advanced non-small cell lung cancer (NSCLC). The purpose of this study was to evaluate the potential clinical benefit of adding HDRIB to EBRT in a multicenter randomized trial. METHODS AND MATERIALS: Patients with symptomatic stage III or IV NSCLC with endobronchial disease were randomized to EBRT (20 Gy in 5 daily fractions over 1 week or 30 Gy in 10 daily fractions over 2 weeks) or the same EBRT plus HDRIB (14 Gy in 2 fractions separated by 1 week). The primary outcome was the proportion of patients who achieved symptomatic improvement in patient-reported overall lung cancer symptoms on the Lung Cancer Symptom Scale (LCSS) at 6 weeks after randomization. Secondary outcomes included improvement in individual symptoms, symptom-progression-free survival, overall survival, and toxicity. The planned sample size was 250 patients based on detection of symptomatic improvement from 40% to 60% with a 2-sided α of .05 and 80% power. RESULTS: A total of 134 patients were randomized over 4.5 years: 67 to each arm. The study closed early owing to slow accrual. The mean age was 69.8 years, and 67% of patients had metastatic disease. At 6 weeks, 19 patients (28.4%) in the EBRT arm and 20 patients (29.9%) in the EBRT plus HDRIB arm experienced an improvement in lung cancer symptoms (P = .84). When limited to patients who completed the LCSS, percentages were 40.4% versus 47.6%, respectively (P = .49). Between group differences in mean change scores (0.3-0.5 standard deviations) in favor of EBRT plus HDRIB were observed for overall symptoms, but only hemoptysis was significantly improved (P = .03). No significant differences were observed in progression-free or overall survival. Grade 3/4 toxicities were similar between groups. CONCLUSIONS: Small to moderate improvements were seen in symptom relief with the combined therapy, but they did not reach statistical significance. Further research is necessary before recommending HDRIB in addition to EBRT for palliation of lung cancer symptoms.

5-year outcomes after stereotactic ablative body radiotherapy for primary renal cell carcinoma: an individual patient data meta-analysis from IROCK (the International Radiosurgery Consortium of the Kidney).

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is a non-invasive treatment option for primary renal cell carcinoma, for which long-term data are awaited. The primary aim of this study was to report on long-term efficacy and safety of SABR for localised renal cell carcinoma. METHODS: This study was an individual patient data meta-analysis, for which patients undergoing SABR for primary renal cell carcinoma across 12 institutions in five countries (Australia, Canada, Germany, Japan, and the USA) were eligible. Eligible patients had at least 2 years of follow-up, were aged 18 years or older, had any performance status, and had no previous local therapy. Patients with metastatic renal cell carcinoma or upper-tract urothelial carcinoma were excluded. SABR was delivered as a single or multiple fractions of greater than 5 Gy. The primary endpoint was investigator-assessed local failure per the Response Evaluation Criteria in Solid Tumours version 1.1, and was evaluated using cumulative incidence functions. FINDINGS: 190 patients received SABR between March 23, 2007, and Sept 20, 2018. Single-fraction SABR was delivered in 81 (43%) patients and multifraction SABR was delivered in 109 (57%) patients. Median follow-up was 5·0 years (IQR 3·4-6·8). 139 (73%) patients were men, and 51 (27%) were women. Median age was 73·6 years (IQR 66·2-82·0). Median tumour diameter was 4·0 cm (IQR 2·8-4·9). 96 (75%) of 128 patients with available operability details were deemed inoperable by the referring urologist. 56 (29%) of 190 patients had a solitary kidney. Median baseline estimated glomerular filtration rate (eGFR) was 60·0 mL/min per 1·73 m2 (IQR 42·0-76·0) and decreased by 14·2 mL/min per 1·73 m2 (IQR 5·4-22·5) by 5 years post-SABR. Seven (4%) patients required dialysis post-SABR. The cumulative incidence of local failure at 5 years was 5·5% (95% CI 2·8-9·5) overall, with single-fraction SABR yielding fewer local failures than multifraction (Gray's p=0·020). There were no grade 3 toxic effects or treatment-related deaths. One (1%) patient developed an acute grade 4 duodenal ulcer and late grade 4 gastritis. INTERPRETATION: SABR is effective and safe in the long term for patients with primary renal cell carcinoma. Single-fraction SABR might yield less local failure than multifraction, but further evidence from randomised trials is needed to elucidate optimal treatment schedules. These mature data lend further support for renal SABR as a treatment option for patients unwilling or unfit to undergo surgery. FUNDING: None.

An International Consensus on Actions to Improve Lung Cancer Survival: A Modified Delphi Method Among Clinical Experts in the International Cancer Benchmarking Partnership.

BACKGROUND: Research from the International Cancer Benchmarking Partnership (ICBP) demonstrates that international variation in lung cancer survival persists, particularly within early stage disease. There is a lack of international consensus on the critical contributing components to variation in lung cancer outcomes and the steps needed to optimise lung cancer services. These are needed to improve the quality of options for and equitable access to treatment, and ultimately improve survival. METHODS: Semi-structured interviews were conducted with 9 key informants from ICBP countries. An international clinical network representing 6 ICBP countries (Australia, Canada, Denmark, England, Ireland, New Zealand, Northern Ireland, Scotland & Wales) was established to share local clinical insights and examples of best practice. Using a modified Delphi consensus model, network members suggested and rated recommendations to optimise the management of lung cancer. Calls to Action were developed via Delphi voting as the most crucial recommendations, with Good Practice Points included to support their implementation. RESULTS: Five Calls to Action and thirteen Good Practice Points applicable to high income, comparable countries were developed and achieved 100% consensus. Calls to Action include (1) Implement cost-effective, clinically efficacious, and equitable lung cancer screening initiatives; (2) Ensure diagnosis of lung cancer within 30 days of referral; (3) Develop Thoracic Centres of Excellence; (4) Undertake an international audit of lung cancer care; and (5) Recognise improvements in lung cancer care and outcomes as a priority in cancer policy. CONCLUSION: The recommendations presented are the voice of an expert international lung cancer clinical network, and signpost key considerations for policymakers in countries within the ICBP but also in other comparable high-income countries. These define a roadmap to help align and focus efforts in improving outcomes and management of lung cancer patients globally.

Lung SBRT credentialing in the Canadian OCOG-LUSTRE randomized trial.

Purpose: To report on the Stereotactic Body Radiation Therapy (SBRT) credentialing experience during the Phase III Ontario Clinical Oncology Group (OCOG) LUSTRE trial for stage I non-small cell lung cancer. Methods: Three credentialing requirements were required in this process: (a) An institutional technical survey; (b) IROC (Imaging and Radiation Oncology Core) thoracic phantom end-to-end test; and (c) Contouring and completion of standardized test cases using SBRT for one central and one peripheral lung cancer, compared against the host institution as the standard. The main hypotheses were that unacceptable variation would exist particularly in OAR definition across all centres, and that institutions with limited experience in SBRT would be more likely to violate per-protocol guidelines. Results: Fifteen Canadian centres participated of which 8 were new, and 7 were previously established (≥2 years SBRT experience), and all successfully completed surveys and IROC phantom testing. Of 30 SBRT test plans, 10 required replanning due to major deviations, with no differences in violations between new and established centres (p = 0.61). Mean contouring errors were highest for brachial plexus in the central (C) case (12.55 ± 6.62 mm), and vessels in the peripheral (P) case (13.01 ± 12.55 mm), with the proximal bronchial tree (PBT) (2.82 ± 0.78 C, 3.27 ± 1.06 P) as another variable structure. Mean dice coefficients were lowest for plexus (0.37 ± 0.2 C, 0.37 ± 0.14 P), PBT (0.77 ± 0.06 C, 0.75 ± 0.09 P), vessels (0.69 ± 0.29 C, 0.64 ± 0.31 P), and esophagus (0.74 ± 0.04 C, 0.76 ± 0.04 P). All plans passed per-protocol planning target volume (PTV) coverage and maximum/volumetric organs-at-risk constraints, although variations existed in dose gradients within and outside the target. Conclusions: Clear differences exist in both contouring and planning with lung SBRT, regardless of centre experience. Such an exercise is important for studies that rely on high precision radiotherapy, and to ensure that implications on trial quality and outcomes are as optimal as possible.

Outcomes of Radiation Therapy Plus Immunotherapy in Metastatic Renal Cell Carcinoma: Results From the Canadian Kidney Cancer Information System.

Purpose: With the integration of immunotherapy (IO) agents in the management of metastatic renal cell carcinoma (mRCC), there has been interest in the combined use with radiation therapy (RT). However, real world data are limited. The purpose of this study was to evaluate outcomes in patients with mRCC receiving both RT and IO compared with IO alone. Methods and Materials: Data were collected from Canadian Kidney Cancer Information System from January 2011 to September 2019 across 14 academic centers. Patients with mRCC who received IO as first- or second-line therapy were included. RT was categorized as radical dose or palliative dose. Kaplan-Meier estimates were reported for overall survival (OS) and time to treatment failure. Cox proportional hazard models were used adjusted for age and International Metastatic RCC Database Consortium risk categories. Results: In total, 505 patients were included in the study: 179 received RT + IO and 326 received IO alone. Two-year OS for the RT + IO group was 55.0% compared with 66.4% in the IO alone cohort (adjusted hazard ratio [aHR], 1.38; P = .07). At 2 years, 12.2% of the RT + IO patients remained on therapy versus 30.9% in the IO alone group (aHR, 1.30; P = .02). For patients receiving first-line therapy, 2-year OS in the RT + IO group was 56.4% versus 78.4% in the IO alone arm, though this difference was not statistically significant (aHR, 1.23; P = .56). For patients receiving radical dose and palliative dose, 2-year OS was 57.0% and 53.9%, respectively (aHR, 0.86; P = .63). Conclusions: In this descriptive analysis, more than one-third of patients with mRCC received RT and demonstrated inferior outcomes compared with IO alone. Potential explanations include greater presence of adverse metastatic sites in those receiving RT. Prospective clinical trials evaluating potential benefits of RT in an IO era remain an important need.

Stereotactic Radiation for the Comprehensive Treatment of Oligometastases (SABR-COMET): Extended Long-Term Outcomes.

PURPOSE: Long-term randomized data assessing the effect of ablative therapies in patients with oligometastases are lacking. The Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastases (SABR-COMET) randomized phase 2 trial was originally designed with 5 years of follow-up, but the trial was amended in 2016 to extend follow-up to 10 years. Herein we report oncologic outcomes beyond 5 years. METHODS AND MATERIALS: Patients were eligible if they had a controlled primary tumor and 1 to 5 metastases, with all metastases amenable to SABR. Patients were randomized in a 1:2 ratio between palliative standard-of-care treatment (control arm) versus SABR to all metastases plus standard of care (SABR arm). The primary endpoint was overall survival (OS) and secondary endpoints included progression-free survival (PFS), toxicity, quality of life (using the Functional Assessment of Cancer Therapy: General [FACT-G]), and time to new metastases. RESULTS: Ninety-nine patients were randomized between 2012 and 2016 (n = 33 in arm 1 vs n = 66 in arm 2). Primary tumor sites included lung (n = 18), breast (n = 18), colon (n = 18), prostate (n = 16), and other (n = 29). Eight-year OS was 27.2% in the SABR arm versus 13.6% in the control arm (hazard ratio, 0.50; 95% confidence interval, 0.30-0.84; P = .008). Eight-year PFS estimates were 21.3% versus 0.0%, respectively (hazard ratio, 0.45; 95% confidence interval, 0.28-0.72; P < .001). Rates of grade ≥ 2 acute or late toxic effects were 30.3% versus 9.1% (P = .019), with no new grade 3 to 5 toxic effects. FACT-G quality of life scores declined over time in both arms, but there were no differences in quality of life scores between arms. The use of systemic therapy overall was similar between arms, but patients in the SABR arm were less likely to require cytotoxic chemotherapy (33.3% vs 54.6%, respectively, P = .043). CONCLUSIONS: SABR achieved durable improvements in OS and PFS, with no new major toxicity signals with extended follow-up. A minority of patients randomized to the SABR arm (21.3%) achieved > 5 years of survival without recurrence.

The histologic effects of neoadjuvant stereotactic body radiation therapy (SBRT) followed by pulmonary metastasectomy-rationale and protocol design for the Post SBRT Pulmonary Metastasectomy (PSPM) trial.

Background: For the local management of pulmonary malignancies, surgical resection and stereotactic body radiation therapy (SBRT) are mutually exclusive treatments. This study aims to assess the effectiveness of SBRT on reducing tumor viability at a histologic level in the context of pulmonary metastases. Methods: This protocol describes an open-label unblinded single-arm prospective Phase 2 trial to determine the effects of dual treatment of pulmonary metastasis amenable to curative resection using neoadjuvant SBRT followed by surgical resection, the Post SBRT Pulmonary Metastasectomy (PSPM) trial. Sample size require 39 patients, with an anticipated study duration of 30-36 months. Following completion of SBRT, eligible patients will be assessed at the 4-6-week mark by the treating radiation oncologist and thoracic surgeon with a post-treatment computed tomography (CT) of the chest. Patients with no disease progression will undergo scheduled surgical resection of all metastatic tumors at 8-12 weeks post SBRT. Patients will then be evaluated postoperatively at 30 days, and every 6 months for a total of 36 months with surveillance CT scans. Patients will also undergo sequential serologic evaluation of circulating tumor DNA (ctDNA) levels throughout their respective treatment pathway. The primary outcome of this study is the rate of complete pathologic response (pCR) following SBRT, assess using the International Association for the Study of Lung Cancer (IASLC) multidisciplinary recommendations for pathologic assessment of lung cancer resection specimens after neoadjuvant therapy. Secondary outcomes include overall survival (OS), disease free survival (DFS), local recurrence rates, cancer histology effects on pCR and treatment related complications, and treatment effect on ctDNA levels. Primary and secondary outcomes will be analyzed using Fisher's Exact test and Student's t-test based on data type. Cox-proportional hazard ratios will be used to evaluate OS and DFS, using the log rank test. Discussion: In evaluating the effect of SBRT on pulmonary metastasis at a histologic level, this trial may increase the use of this modality in selected patients who would otherwise only undergo surgery for disease that has already metastasized. Also, the trial provides secondary benefits of evaluating the abscopal effects of radiation on pulmonary metastatic disease, and serves as a platform for more comprehensive large-scale research in this field. Trial Registration: ClinicalTrials.gov identifier: NCT04160143 (HiREB: 7925).