Optimal management of radiation pneumonitis: Findings of an international Delphi consensus study.

PURPOSE: Radiation pneumonitis (RP) is a dose-limiting toxicity for patients undergoing radiotherapy (RT) for lung cancer, however, the optimal practice for diagnosis, management, and follow-up for RP remains unclear. We thus sought to establish expert consensus recommendations through a Delphi Consensus study. METHODS: In Round 1, open questions were distributed to 31 expert clinicians treating thoracic malignancies. In Round 2, participants rated agreement/disagreement with statements derived from Round 1 answers using a 5-point Likert scale. Consensus was defined as ≥ 75 % agreement. Statements that did not achieve consensus were modified and re-tested in Round 3. RESULTS: Response rate was 74 % in Round 1 (n = 23/31; 17 oncologists, 6 pulmonologists); 82 % in Round 2 (n = 19/23; 15 oncologists, 4 pulmonologists); and 100 % in Round 3 (n = 19/19). Thirty-nine of 65 Round 2 statements achieved consensus; a further 10 of 26 statements achieved consensus in Round 3. In Round 2, there was agreement that risk stratification/mitigation includes patient factors; optimal treatment planning; the basis for diagnosis of RP; and that oncologists and pulmonologists should be involved in treatment. For uncomplicated radiation pneumonitis, an equivalent to 60 mg oral prednisone per day, with consideration of gastroprotection, is a typical initial regimen. However, in this study, no consensus was achieved for dosing recommendation. Initial steroid dose should be administered for a duration of 2 weeks, followed by a gradual, weekly taper (equivalent to 10 mg prednisone decrease per week). For severe pneumonitis, IV methylprednisolone is recommended for 3 days prior to initiating oral corticosteroids. Final consensus statements included that the treatment of RP should be multidisciplinary, the uncertainty of whether pneumonitis is drug versus radiation-induced, and the importance risk stratification, especially in the scenario of interstitial lung disease. CONCLUSIONS: This Delphi study achieved consensus recommendations and provides practical guidance on diagnosis and management of RP.

Systematic review of the efficacy of stereotactic ablative radiotherapy for oligoprogressive disease in metastatic cancer.

BACKGROUND: Stereotactic Ablative Radiotherapy (SABR) for the treatment of oligometastatic disease can improve survival and delay the requirement for systemic therapy. The benefits of SABR in oligoprogressive disease are less well-defined. Here, we evaluate the available evidence investigating the efficacy of SABR in the treatment of oligoprogressive disease. METHODS: A systematic review was carried out following PRISMA guidelines. Medline and Embase databases were searched using the terms "stereotactic radiotherapy" OR "SABR" OR "Stereotactic Ablative Body Radiotherapy" OR "SBRT" OR "SRT" AND "oligoprogression" in May 2022, June 2023, and February 2024. Studies were excluded where: SABR was used as a radical treatment, a specific oligoprogressive cohort could not be identified, publication was as a conference abstract or where fewer than 10 patients were recruited. Studies treating only brain metastases were also excluded. The site of primary tumour, oligoprogressive sites, rates of overall survival (OS), progression free survival (PFS), local control (LC) and time to next systemic therapy were collected. RESULTS: Thirty-three full text studies were included. These consisted of single centre and multi-institutional observational studies, case series and phase II trials. Twenty-two studies were related to a specific tumour type: 12 urological cancer (9 prostate, 3 renal cancer), 6 non-small cell lung cancer, 2 colorectal cancer, 2 breast cancer and 11 were studies covering multiple tumour sites (5 studies involving SABR to a single organ and 6 studies involving SABR to multi-organ). Median PFS was >6 months in patients with oligoprogressive prostate, non-small cell lung cancer and renal cancer patients. CONCLUSIONS: SABR appears to have clinical benefit in oligoprogresssive prostate, lung, and renal patients. However, the optimal management of patients with oligoprogressive disease is still somewhat uncertain due to lack of prospective data. This will hopefully become clearer in the near future with the publication of further randomised trials.

Stereotactic Radiation Therapy in Early Non-Small Cell Lung Cancer and Interstitial Lung Disease: A Nonrandomized Clinical Trial.

Importance: Patients with interstitial lung disease (ILD) and early-stage non-small cell lung cancer (NSCLC) have been reported to be at high risk of toxic effects after stereotactic ablative radiotherapy (SABR), but for many patients, there are limited alternative treatment options. Objective: To prospectively assess the benefits and toxic effects of SABR in this patient population. Design, Setting, and Participants: This prospective cohort study was conducted at 6 academic radiation oncology institutions, 5 in Canada and 1 in Scotland, with accrual between March 7, 2019, and January 12, 2022. Patients aged 18 years or older with fibrotic ILD and a diagnosis of T1-2N0 NSCLC who were not candidates for surgical resection were enrolled. Intervention: Patients were treated with SABR to a dose of 50 Gy in 5 fractions every other day. Main Outcomes and Measures: The study prespecified that SABR would be considered worthwhile if median overall survival-the primary end point-was longer than 1 year, with a grade 3 to 4 risk of toxic effects less than 35% and a grade 5 risk of toxic effects less than 15%. Secondary end points included toxic effects, progression-free survival (PFS), local control (LC), quality-of-life outcomes, and changes in pulmonary function. Intention-to-treat analysis was conducted. Results: Thirty-nine patients enrolled and received SABR. Median age was 78 (IQR, 67-83) years and 59% (n = 23) were male. At baseline, 70% (26 of 37) of patients reported dyspnea, median forced expiratory volume in first second of expiration was 80% (IQR, 66%-90%) predicted, median forced vital capacity was 84% (IQR, 69%-94%) predicted, and median diffusion capacity of the lung for carbon monoxide was 49% (IQR, 38%-61%) predicted. Median follow-up was 19 (IQR, 14-25) months. Overall survival at 1 year was 79% (95%, CI 62%-89%; P < .001 vs the unacceptable rate), and median overall survival was 25 months (95% CI, 14 months to not reached). Median PFS was 19 months (95% CI, 13-28 months), and 2-year LC was 92% (95% CI, 69%-98%). Adverse event rates (highest grade per patient) were grade 1 to 2: n = 12 (31%), grade 3: n = 4 (10%), grade 4: n = 0, and grade 5: n = 3 (7.7%, all due to respiratory deterioration). Conclusions and Relevance: In this trial, use of SABR in patients with fibrotic ILD met the prespecified acceptability thresholds for both toxicity and efficacy, supporting the use of SABR for curative-intent treatment after a careful discussion of risks and benefits. Trial Registration: ClinicalTrials.gov Identifier: NCT03485378.

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.

Optimising recruitment to a lung cancer screening trial: A comparison of general practitioner and community-based recruitment.

OBJECTIVES: Pre-trial focus groups of the Early detection of Cancer of the Lung Scotland (ECLS) trial indicated that those at high risk of lung cancer are more likely to engage with community-based recruitment methods. The current study aimed to understand if general practitioner (GP) and community-based recruitment might attract different groups of people, and to quantitatively explore the demographic and psychosocial differences between people responding to GP or community-based recruitment. DESIGN: Secondary data analysis of ECLS trial baseline data. METHODS: Adults (n = 11,164) aged 50 to 75 years completed a baseline questionnaire as part of their participation in the ECLS trial. The questionnaire assessed smoking behaviour, health state, health anxiety and illness perception. Alongside demographic characteristics, how participants were made aware of the study/participant recruitment method (GP recruitment/community recruitment) was also obtained via trial records. RESULTS: The likelihood of being recruited via community-based methods increased as deprivation level decreased. Those recruited via the community had higher levels of perceived personal control of developing lung cancer and were more likely to understand their own risk of developing lung cancer, compared to those who were recruited to the trial via their GP. Health state and health anxiety did not predict recruitment methods in multivariable analysis. CONCLUSIONS: Community and opportunistic screening invitations were associated with uptake in people from less-deprived backgrounds, and therefore might not be the optimal method to reach those at high risk of lung cancer and living in more deprived areas.

Real-World Impact of SABR on Stage I Non-Small-Cell Lung Cancer Outcomes at a Scottish Cancer Centre.

INTRODUCTION: Stereotactic ablative body radiotherapy (SABR) offers patients with stage I non-small-cell lung cancer (NSCLC) a safe, effective radical therapy option. The impact of introducing SABR at a Scottish regional cancer centre was studied. METHODS: The Edinburgh Cancer Centre Lung Cancer Database was assessed. Treatment patterns and outcomes were compared across treatment groups (no radical therapy (NRT), conventional radical radiotherapy (CRRT), SABR and surgery) and across three time periods reflecting the availability of SABR (A, January 2012/2013 (pre-SABR); B, 2014/2016 (introduction of SABR); C, 2017/2019, (SABR established)). RESULTS: 1143 patients with stage I NSCLC were identified. Treatment was NRT in 361 (32%), CRRT in 182 (16%), SABR in 132 (12%) and surgery in 468 (41%) patients. Age, performance status, and comorbidities correlated with treatment choice. The median survival increased from 32.5 months in time period A to 38.8 months in period B to 48.8 months in time period C. The greatest improvement in survival was seen in patients treated with surgery between time periods A and C (HR 0.69 (95% CI 0.56-0.86), p < 0.001). The proportion of patients receiving a radical therapy rose between time periods A and C in younger (age ≤ 65, 65-74 and 75-84 years), fitter (PS 0 and 1), and less comorbid patients (CCI 0 and 1-2), but fell in other patient groups. CONCLUSIONS: The introduction and establishment of SABR for stage I NSCLC has improved survival outcomes in Southeast Scotland. Increasing SABR utilisation appears to have enhanced the selection of surgical patients and increased the proportion of patients receiving a radical therapy.

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.

Determining Planning Priorities for SABR for Oligometastatic Disease: A Secondary Analysis of the SABR-COMET Phase II Randomized Trial.

PURPOSE: SABR may improve survival in patients with oligometastases, but for some lesions, safe delivery of SABR may require a reduction in delivered dose or target coverage. This study assessed the association between target coverage compromise and oncologic and survival outcomes. METHODS AND MATERIALS: Patients with a controlled primary malignancy and 1 to 5 oligometastases were randomized (1:2) between standard of care (SOC) treatment and SOC plus SABR. In patients receiving SABR, the target dose coverage was reduced to meet organ at risk (OAR) constraints, if necessary. The D99 value (minimum dose received by the hottest 99% of the planning target volume [PTV]) was used as a measure of PTV coverage for each treatment plan, and the relationship between the coverage compromise index (CCI, defined as D99/prescription dose) and patient outcomes was assessed. RESULTS: Sixty-two patients in the SABR arm had dosimetric information available and a total of 109 lesions were evaluated. The mean CCI per lesion was 0.96 (95% CI, 0.56-1.61). Of the 109 lesions evaluated, 29.4% (n = 32) required coverage compromise (CCI <0.9). Adrenal metastases required coverage compromise in 100% of analyzed lesions (n = 7). CCI was not significantly associated with lesional control, adverse events, overall survival (OS), or progression-free survival (PFS). CONCLUSIONS: Target compromise was required in a substantial minority of cases, but PTV coverage was not associated with OS, progression-free survival, or lesional control. This suggests that OAR constraints used for SABR treatments in the oligometastatic setting should continue to be prioritized during planning.

Hypoalbuminaemia as a Prognostic Biomarker of First-Line Treatment Resistance in Metastatic Non-small Cell Lung Cancer.

Introduction: Despite significant advances in systemic anticancer therapy (SACT) for non-small cell lung cancer (NSCLC), many patients still fail to respond to treatment or develop treatment resistance. Albumin, a biomarker of systemic inflammation and malnutrition, predicts survival in many cancers. We evaluated the prognostic significance of albumin in patients receiving first-line targeted therapy or immunotherapy-based SACT for metastatic NSCLC. Methods: All patients treated with first-line targeted therapy or immunotherapy-based SACT for metastatic NSCLC at a regional Scottish cancer centre were identified. Serum albumin at pre-treatment, after 12-weeks of treatment, and at the time of progressive disease were recorded. The relationship between albumin (≥ 35g/L v <35g/L) and overall survival (OS) was examined. Results: Data were available for 389 patients of both targeted therapy cohort (n = 159) and immunotherapy-based therapy cohort (n = 230). Pre-treatment albumin was predictive of OS in each cohort at HR1.82 (95%CI 1.23-2.7) (p =0.003) and HR2.55 (95%CI 1.78-3.65) (p < 0.001), respectively. Pre-treatment albumin <35 g/L was associated with a significantly higher relative risk of death within 12 weeks in each cohort at RR9.58 (95%CI 2.20-41.72, p = 0.003) and RR3.60 (95%CI 1.74-6.57, p < 0.001), respectively. The 12-week albumin was predictive of OS in each cohort at HR1.88 (95%CI 1.86-4.46) (p < 0.001) and HR2.67 (95%CI 1.74-4.08) (p < 0.001), respectively. 46 out of 133 (35%) evaluable patients treated with targeted therapy and 43 out of 169 (25%) treated with immunotherapy-based therapy crossed over albumin prognostic groups between pre-treatment and 12-week. The prognostic value of 12-week albumin was independent of pre-treatment albumin status. A majority of patients had albumin <35g/L at the time of progressive disease when it was also predictive of survival following progressive disease at HR2.48 (95%CI 1.61-3.82) (p < 0.001) and HR2.87 (95%CI 1.91-4.31) (p < 0.001) respectively). Conclusions: Albumin is a reliable prognostic factor in patients with metastatic NSCLC, predicting survival independent of the class of drug treatment at various time points during the patient journey. Tracking albumin concentrations during systemic therapy may indicate disease activity or treatment response over time.

An International Expert Survey on the Indications and Practice of Radical Thoracic Reirradiation for Non-Small Cell Lung Cancer.

PURPOSE: Thoracic reirradiation for non-small cell lung cancer with curative intent is potentially associated with severe toxicity. There are limited prospective data on the best method to deliver this treatment. We sought to develop expert consensus guidance on the safe practice of treating non-small cell lung cancer with radiation therapy in the setting of prior thoracic irradiation. METHODS AND MATERIALS: Twenty-one thoracic radiation oncologists were invited to participate in an international Delphi consensus process. Guideline statements were developed and refined during 4 rounds on the definition of reirradiation, selection of appropriate patients, pretreatment assessments, planning of radiation therapy, and cumulative dose constraints. Consensus was achieved once ≥75% of respondents agreed with a statement. Statements that did not reach consensus in the initial survey rounds were revised based on respondents' comments and re-presented in subsequent rounds. RESULTS: Fifteen radiation oncologists participated in the 4 surveys between September 2019 and March 2020. The first 3 rounds had a 100% response rate, and the final round was completed by 93% of participants. Thirty-three out of 77 statements across all rounds achieved consensus. Key recommendations are as follows: (1) appropriate patients should have a good performance status and can have locally relapsed disease or second primary cancers, and there are no absolute lung function values that preclude reirradiation; (2) a full diagnostic workup should be performed in patients with suspected local recurrence and; (3) any reirradiation should be delivered using optimal image guidance and highly conformal techniques. In addition, consensus cumulative dose for the organs at risk in the thorax are described. CONCLUSIONS: These consensus statements provide practical guidance on appropriate patient selection for reirradiation, appropriate radiation therapy techniques, and cumulative dose constraints.

Is SABR Cost-Effective in Oligometastatic Cancer? An Economic Analysis of the SABR-COMET Randomized Trial.

PURPOSE: The phase 2 randomized study SABR-COMET demonstrated that in patients with controlled primary tumors and 1 to 5 oligometastatic lesions, SABR was associated with improved progression-free survival (PFS) compared with standard of care (SoC), but with higher costs and treatment-related toxicities. The aim of this study was to assess the cost-effectiveness of SABR versus SoC in this setting. METHODS AND MATERIALS: A Markov model was constructed to perform a cost-utility analysis from the Canadian health care system perspective. Utility values and transition probabilities were derived from individual-level data from the SABR-COMET trial. One-way, 2-way, and probabilistic sensitivity analyses were performed. Costs were expressed in 2018 CAD. A separate analysis based on US payer's perspective was performed. An incremental cost-effectiveness ratio (ICER) at a willingness-to-pay threshold of $100,000 per quality-adjusted life year (QALY) was used. RESULTS: In the base case scenario, SABR was cost-effective at an ICER of $37,157 per QALY gained. This finding was most sensitive to the number of metastatic lesions treated with SABR (ICER: $28,066 per QALY for 2, increasing to $64,429 per QALY for 5), difference in chemotherapy use (ICER: $27,173-$53,738 per QALY), and PFS hazard ratio (HR) between strategies (ICER: $31,548-$53,273 per QALY). Probabilistic sensitivity analysis revealed that SABR was cost-effective in 97% of all iterations. Two-way sensitivity analysis demonstrated a nonlinear relationship between the number of lesions and the PFS HR. To maintain cost-effectiveness for each additional metastasis, the HR must decrease by approximately 0.047. The US cost analysis yielded similar results, with an ICER of $54,564 (2018 USD per QALY) for SABR. CONCLUSIONS: SABR is cost-effective for patients with 1 to 5 oligometastatic lesions compared with SoC.

Isotoxic Intensity Modulated Radiation Therapy in Stage III Non-Small Cell Lung Cancer: A Feasibility Study.

PURPOSE: Not all patients with stage III non-small cell lung cancer (NSCLC) are suitable for concurrent chemoradiation therapy (CRT). Local failure rate is high for sequential concurrent CRT. As such, there is a rationale for treatment intensification. METHODS AND MATERIALS: Isotoxic intensity modulated radiation therapy (IMRT) is a multicenter feasibility study that combines different intensification strategies including hyperfractionation, acceleration, and dose escalation facilitated by IMRT. Patients with unresectable stage III NSCLC, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, and unsuitable for concurrent CRT were recruited. A minimum of 2 cycles of platinum-based chemotherapy was compulsory before starting radiation therapy (RT). Radiation dose was increased until a maximum dose of 79.2 Gy was reached or 1 or more of the organs at risk met predefined constraints. RT was delivered in 1.8-Gy fractions twice daily, and an RT quality assurance program was implemented. The primary objective was the delivery of isotoxic IMRT to a dose >60 Gy equivalent dose in 2-Gy fractions (EQD2 assuming an α/ß ratio of 10 Gy for acute reacting tissues). RESULTS: Thirty-seven patients were recruited from 7 UK centers. Median age was 69.9 years (range, 46-86 years). The male-to-female ratio was 17:18. ECOG PS was 0 to 5 in 14.2% of patients; PS was 1 to 27 in 77.1% of patients; PS was 2 to 3 in 8.6% of patients. Stage IIIA:IIIB ratio was 22:13 (62.9%:37.1%). Of 37 patients, 2 (5.4%) failed to achieve EQD2 > 60 Gy. Median prescribed tumor dose was 77.4 Gy (range, 61.2-79.2 Gy). A maximum dose of 79.2Gy was achieved in 14 patients (37.8%). Grade 3 esophagitis was reported in 2 patients, and no patients developed grade 3 to 4 pneumonitis. There were 3 grade 5 events: acute radiation pneumonitis, bronchopulmonary hemorrhage, and acute lung infection. Median follow-up at time of analysis was 25.4 months (range, 8.0-44.2) months for 11 of 35 survivors. The median survival was 18.1 months (95% confidence interval [CI], 13.9-30.6), 2-year overall survival was 33.6% (95% CI, 17.9-50.1), and progression-free survival was 23.9% (95% CI, 11.3-39.1). CONCLUSIONS: Isotoxic IMRT is a well-tolerated and feasible approach to treatment intensification.

CONCORDE: A phase I platform study of novel agents in combination with conventional radiotherapy in non-small-cell lung cancer.

Lung cancer is the leading cause of cancer mortality worldwide and most patients are unsuitable for 'gold standard' treatment, which is concurrent chemoradiotherapy. CONCORDE is a platform study seeking to establish the toxicity profiles of multiple novel radiosensitisers targeting DNA repair proteins in patients treated with sequential chemoradiotherapy. Time-to-event continual reassessment will facilitate efficient dose-finding.

Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial.

PURPOSE: The oligometastatic paradigm hypothesizes that patients with a limited number of metastases may achieve long-term disease control, or even cure, if all sites of disease can be ablated. However, long-term randomized data that test this paradigm are lacking. METHODS: We enrolled patients with a controlled primary malignancy and 1-5 metastatic lesions, with all metastases amenable to stereotactic ablative radiotherapy (SABR). We stratified by the number of metastases (1-3 v 4-5) and randomized in a 1:2 ratio between palliative standard-of-care (SOC) treatments (arm 1) and SOC plus SABR (arm 2). We used a randomized phase II screening design with a primary end point of overall survival (OS), using an α of .20 (wherein P < .20 indicates a positive trial). Secondary end points included progression-free survival (PFS), toxicity, and quality of life (QOL). Herein, we present long-term outcomes from the trial. RESULTS: Between 2012 and 2016, 99 patients were randomly assigned at 10 centers internationally. The most common primary tumor types were breast (n = 18), lung (n = 18), colorectal (n = 18), and prostate (n = 16). Median follow-up was 51 months. The 5-year OS rate was 17.7% in arm 1 (95% CI, 6% to 34%) versus 42.3% in arm 2 (95% CI, 28% to 56%; stratified log-rank P = .006). The 5-year PFS rate was not reached in arm 1 (3.2%; 95% CI, 0% to 14% at 4 years with last patient censored) and 17.3% in arm 2 (95% CI, 8% to 30%; P = .001). There were no new grade 2-5 adverse events and no differences in QOL between arms. CONCLUSION: With extended follow-up, the impact of SABR on OS was larger in magnitude than in the initial analysis and durable over time. There were no new safety signals, and SABR had no detrimental impact on QOL.

Stereotactic ablative radiotherapy for the comprehensive treatment of 1-3 Oligometastatic tumors (SABR-COMET-3): study protocol for a randomized phase III trial.

BACKGROUND: A recent randomized phase II trial evaluated stereotactic ablative radiotherapy (SABR) in a group of patients with a small burden of oligometastatic disease (mostly with 1-3 metastatic lesions), and found that SABR was associated with a significant improvement in progression-free survival and a trend to an overall survival benefit, supporting progression to phase III randomized trials. METHODS: Two hundred and ninety-seven patients will be randomized in a 1:2 ratio between the control arm (consisting of standard of care [SOC] palliative-intent treatments), and the SABR arm (consisting of SOC treatment + SABR to all sites of known disease). Randomization will be stratified by two factors: histology (prostate, breast, or renal vs. all others), and disease-free interval (defined as time from diagnosis of primary tumor until first detection of the metastases being treated on this trial; divided as ≤2 vs. > 2 years). The primary endpoint is overall survival, and secondary endpoints include progression-free survival, cost effectiveness, time to development of new metastatic lesions, quality of life (QoL), and toxicity. Translational endpoints include assessment of circulating tumor cells, cell-free DNA, and tumor tissue as prognostic and predictive markers, including assessment of immunological predictors of response and long-term survival. DISCUSSION: This study will provide an assessment of the impact of SABR on survival, QoL, and cost effectiveness to determine if long-term survival can be achieved for selected patients with 1-3 oligometastatic lesions. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03862911. Date of registration: March 5, 2019.

Assessment of precision irradiation in early non-small cell lung cancer and interstitial lung disease (ASPIRE-ILD): study protocol for a phase II trial.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) has become an established treatment option for medically-inoperable early-stage (Stage I-IIA) non-small cell lung cancer (ES-NSCLC). SABR is able to obtain high rates of local control with low rates of symptomatic toxicity in this patient population. However, in a subset of patients with fibrotic interstitial lung disease (ILD), elevated rates of SABR-related toxicity and mortality have been described. The Assessment of Precision Irradiation in Early Non-Small Cell Lung Cancer and Interstitial Lung Disease (ASPIRE-ILD) study will conduct a thorough prospective evaluation of the clinical outcomes, toxicity, changes in diagnostic test parameters and patient-related outcomes following SABR for ES-NSCLC for patients with fibrotic ILD. METHODS: ASPIRE-ILD is a single-arm Phase II prospective study. The accrual target is 39 adult patients with T1-2N0M0 non-small cell lung cancer with co-existing ILD who are not candidates for surgical excision. Pathological confirmation of diagnosis is strongly recommended but not strictly required. Enrolled patients will be stratified by ILD-related mortality risk. The starting SABR dose will be 50 Gy in 5 fractions every other day (biologically effective dose: 100 Gy10 or 217 Gy3), but the radiation dose can be de-escalated up to two times to 50 Gy in 10 fractions daily (75 Gy10 or 133 Gy3) and 45 Gy in 15 fractions daily (58 Gy10 or 90 Gy3). Dose de-escalation will occur if 2 or more of the first 7 patients in a cohort experiences grade 5 toxicity within 6 months of treatment. Similarly, dose de-escalation can also occur if 2 or more of the first 7 patients with a specific subtype of ILD experiences grade 5 toxicity within 6 months of treatment. The primary endpoint is overall survival. Secondary endpoints include toxicity (CTC-AE 4.0), progression-free survival, local control, patient-reported outcomes (cough severity and quality of life), rates of ILD exacerbation and changes in pulmonary function tests/high-resolution computed tomography findings post-SABR. DISCUSSION: ASPIRE-ILD will be the first prospective study specifically designed to comprehensively evaluate the effectiveness and safety of SABR for ES-NSCLC in patients with co-existing ILD. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03485378. Date of registration: April 2, 2018.

Quality of Life Outcomes After Stereotactic Ablative Radiation Therapy (SABR) Versus Standard of Care Treatments in the Oligometastatic Setting: A Secondary Analysis of the SABR-COMET Randomized Trial.

PURPOSE: Randomized data assessing the longitudinal quality of life (QoL) impact of stereotactic ablative radiation therapy (SABR) in the oligometastatic setting are lacking. METHODS AND MATERIALS: We enrolled patients who had a controlled primary malignancy with 1 to 5 metastatic lesions, with good performance status and life expectancy >6 months. We randomized in a 1:2 ratio between standard of care (SOC) treatment (SOC arm) and SOC plus SABR to all metastatic lesions (SABR arm). QoL was measured using the Functional Assessment of Cancer Therapy-General. QoL changes over time and between groups were assessed with linear mixed modeling. RESULTS: Ninety-nine patients were randomized. Median age was 68 years (range, 43-89), and 60% were male. The most common primary tumor types were breast (n = 18), lung (n = 18), colorectal (n = 18), and prostate (n = 16). Most patients (n = 92) had 1 to 3 metastases. Median follow-up was 26 months. Because of the previously reported inferior survival of the SOC arm, the time for attrition in QoL respondents to <10% of subjects was shorter in the SOC versus SABR arm (30 vs 42 months). In the whole cohort, QoL declined over time after randomization: There were significant declines in total Functional Assessment of Cancer Therapy-General score over time compared with baseline (P < .001) owing to declines in physical and functional subscales (both P < .001), with no declines in social and emotional subscales. However, the magnitudes of decline were small, and clinically meaningful changes were not seen at most time points. Comparison between arms showed no differences in QoL between the SABR and SOC arms in total score (P = .42) or in the physical (P = .98), functional (P = .59), emotional (P = .82), or social (P = .17) subscales. CONCLUSIONS: For patients with oligometastases, average QoL declines slowly over time regardless of treatment approach, although the changes are small in magnitude. The use of SABR, compared with SOC, was not associated with a QoL detriment.

Stereotactic ablative radiotherapy for the comprehensive treatment of 4-10 oligometastatic tumors (SABR-COMET-10): study protocol for a randomized phase III trial.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) has emerged as a new treatment option for patients with oligometastatic disease. SABR delivers precise, high-dose, hypofractionated radiotherapy, and achieves excellent rates of local control for primary tumors or metastases. A recent randomized phase II trial evaluated SABR in a group of patients with a small burden of oligometastatic disease (mostly with 1-3 metastatic lesions), and found that SABR was associated with benefits in progression-free survival and overall survival. The goal of this phase III trial is to assess the impact of SABR in patients with 4-10 metastatic cancer lesions. METHODS: One hundred and fifty-nine patients will be randomized in a 1:2 ratio between the control arm (consisting of standard of care palliative-intent treatments), and the SABR arm (consisting of standard of care treatment + SABR to all sites of known disease). Randomization will be stratified by two factors: histology (Group 1: prostate, breast, or renal; Group 2: all others), and type of pre-specified systemic therapy (Group 1: immunotherapy/targeted; Group 2: cytotoxic; Group 3: observation). SABR is to be completed within 2 weeks, allowing for rapid initiation of systemic therapy. Recommended SABR doses are 20 Gy in 1 fraction, 30 Gy in 3 fractions, or 35 Gy in 5 fractions, chosen to minimize risks of toxicity. The primary endpoint is overall survival, and secondary endpoints include progression-free survival, time to development of new metastatic lesions, quality of life, and toxicity. Translational endpoints include assessment of circulating tumor cells, cell-free DNA, and tumor tissue as prognostic and predictive markers, including assessment of immunological predictors of response and long-term survival. DISCUSSION: This study will provide an assessment of the impact of SABR on clinical outcomes and quality of life, to determine if long-term survival can be achieved for selected patients with 4-10 oligometastatic lesions. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03721341 . Date of registration: October 26, 2018.

Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial.

BACKGROUND: The oligometastatic paradigm suggests that some patients with a limited number of metastases might be cured if all lesions are eradicated. Evidence from randomised controlled trials to support this paradigm is scarce. We aimed to assess the effect of stereotactic ablative radiotherapy (SABR) on survival, oncological outcomes, toxicity, and quality of life in patients with a controlled primary tumour and one to five oligometastatic lesions. METHODS: This randomised, open-label phase 2 study was done at 10 hospitals in Canada, the Netherlands, Scotland, and Australia. Patients aged 18 or older with a controlled primary tumour and one to five metastatic lesions, Eastern Cooperative Oncology Group score of 0-1, and a life expectancy of at least 6 months were eligible. After stratifying by the number of metastases (1-3 vs 4-5), we randomly assigned patients (1:2) to receive either palliative standard of care treatments alone (control group), or standard of care plus SABR to all metastatic lesions (SABR group), using a computer-generated randomisation list with permuted blocks of nine. Neither patients nor physicians were masked to treatment allocation. The primary endpoint was overall survival. We used a randomised phase 2 screening design with a two-sided α of 0·20 (wherein p<0·20 designates a positive trial). All analyses were intention to treat. This study is registered with ClinicalTrials.gov, number NCT01446744. FINDINGS: 99 patients were randomised between Feb 10, 2012, and Aug 30, 2016. Of 99 patients, 33 (33%) were assigned to the control group and 66 (67%) to the SABR group. Two (3%) patients in the SABR group did not receive allocated treatment and withdrew from the trial; two (6%) patients in the control group also withdrew from the trial. Median follow-up was 25 months (IQR 19-54) in the control group versus 26 months (23-37) in the SABR group. Median overall survival was 28 months (95% CI 19-33) in the control group versus 41 months (26-not reached) in the SABR group (hazard ratio 0·57, 95% CI 0·30-1·10; p=0·090). Adverse events of grade 2 or worse occurred in three (9%) of 33 controls and 19 (29%) of 66 patients in the SABR group (p=0·026), an absolute increase of 20% (95% CI 5-34). Treatment-related deaths occurred in three (4·5%) of 66 patients after SABR, compared with none in the control group. INTERPRETATION: SABR was associated with an improvement in overall survival, meeting the primary endpoint of this trial, but three (4·5%) of 66 patients in the SABR group had treatment-related death. Phase 3 trials are needed to conclusively show an overall survival benefit, and to determine the maximum number of metastatic lesions wherein SABR provides a benefit. FUNDING: Ontario Institute for Cancer Research and London Regional Cancer Program Catalyst Grant.