Stereotactic ablative radiotherapy before resection to avoid delay for early-stage lung cancer or oligometastases during the COVID-19 pandemic: Pathologic outcomes from the SABR-BRIDGE protocol.

BACKGROUND: During coronavirus disease 2019 (COVID-19)-related operating room closures, some multidisciplinary thoracic oncology teams adopted a paradigm of stereotactic ablative radiotherapy (SABR) as a bridge to surgery, an approach called SABR-BRIDGE. This study presents the preliminary surgical and pathological results. METHODS: Eligible participants from four institutions (three in Canada and one in the United States) had early-stage presumed or biopsy-proven lung malignancy that would normally be surgically resected. SABR was delivered using standard institutional guidelines, with surgery >3 months following SABR with standardized pathologic assessment. Pathological complete response (pCR) was defined as absence of viable cancer. Major pathologic response (MPR) was defined as ≤10% viable tissue. RESULTS: Seventy-two patients underwent SABR. Most common SABR regimens were 34 Gy/1 (29%, n = 21), 48 Gy/3-4 (26%, n = 19), and 50/55 Gy/5 (22%, n = 16). SABR was well-tolerated, with one grade 5 toxicity (death 10 days after SABR with COVID-19) and five grade 2-3 toxicities. Following SABR, 26 patients underwent resection thus far (13 pending surgery). Median time-to-surgery was 4.5 months post-SABR (range, 2-17.5 months). Surgery was reported as being more difficult because of SABR in 38% (n = 10) of cases. Thirteen patients (50%) had pCR and 19 (73%) had MPR. Rates of pCR trended higher in patients operated on at earlier time points (75% if within 3 months, 50% if 3-6 months, and 33% if ≥6 months; p = .069). In the exploratory best-case scenario analysis, pCR rate does not exceed 82%. CONCLUSIONS: The SABR-BRIDGE approach allowed for delivery of treatment during a period of operating room closure and was well-tolerated. Even in the best-case scenario, pCR rate does not exceed 82%.

The addition of androgen deprivation therapy and pelvic lymph node treatment to prostate bed salvage radiotherapy (NRG Oncology/RTOG 0534 SPPORT): an international, multicentre, randomised phase 3 trial.

BACKGROUND: In men with a detectable prostate-specific antigen (PSA) level after prostatectomy for prostate cancer, salvage prostate bed radiotherapy (PBRT) results in about 70% of patients being free of progression at 5 years. A three-group randomised trial was designed to determine whether incremental gains in patient outcomes can be achieved by adding either 4-6 months of short-term androgen deprivation therapy (ADT) to PBRT, or both short-term ADT and pelvic lymph node radiotherapy (PLNRT) to PBRT. METHODS: The international, multicentre, randomised, controlled SPPORT trial was done at 283 radiation oncology cancer treatment centres in the USA, Canada, and Israel. Eligible patients (aged ≥18 years) were those who after prostatectomy for adenocarcinoma of the prostate had a persistently detectable or an initially undetectable and rising PSA of between 0·1 and 2·0 ng/mL. Patients with and without lymphadenectomy (N0/Nx) were eligible if there was no clinical or pathological evidence of lymph node involvement. Other eligibility criteria included pT2 or pT3 disease, prostatectomy Gleason score of 9 or less, and a Zubrod performance status of 0-1. Eligible patients were randomly assigned to receive PBRT alone at a dose of 64·8-70·2 Gy at 1·8 Gy per fraction daily (group 1), PBRT plus short-term ADT (group 2), or PLNRT (45 Gy at 1·8 Gy per fraction, and then a volume reduction made to the planning target volume for the remaining 19·8-25 ·2 Gy) plus PBRT plus short-term ADT (group 3). The primary endpoint was freedom from progression, in which progression was defined as biochemical failure according to the Phoenix definition (PSA ≥2 ng/mL over the nadir PSA), clinical failure (local, regional, or distant), or death from any cause. A planned interim analysis of 1191 patents with minimum potential follow-up time of 5 years applied a Haybittle-Peto boundary of p<0·001 (one sided) for comparison of 5-year freedom from progression rates between the treatment groups. This trial is registered with ClinicalTrials.gov, NCT00567580. The primary objectives of the trial have been completed, although long-term follow-up is continuing. FINDINGS: Between March 31, 2008, and March 30, 2015, 1792 eligible patients were enrolled and randomly assigned to the three treatment groups (592 to group 1 [PBRT alone], 602 to group 2 [PBRT plus short-term ADT], and 598 to group 3 [PLNRT plus PBRT plus short-term ADT]). 76 patients subsequently found to be ineligible were excluded from the analyses; thus, the evaluable patient population comprised 1716 patients. At the interim analysis (n=1191 patients; data cutoff May 23, 2018), the Haybittle-Peto boundary for 5-year freedom from progression was exceeded when group 1 was compared with group 3 (difference 17·9%, SE 2·9%; p<0·0001). The difference between groups 2 and 3 did not exceed the boundary (p=0·0063). With additional follow-up beyond the interim analysis (the final planned analysis; data cutoff May 26, 2021), at a median follow-up among survivors of 8·2 years (IQR 6·6-9·4), the 5-year freedom from progression rates in all 1716 eligible patients were 70·9% (95% CI 67·0-74·9) in group 1, 81·3% (78·0-84·6) in group 2, and 87·4% (84·7-90·2) in group 3. Per protocol criteria, freedom from progression in group 3 was superior to groups 1 and 2. Acute (≤3 months after radiotherapy) grade 2 or worse adverse events were significantly more common in group 3 (246 [44%] of 563 patients) than in group 2 (201 [36%] of 563; p=0·0034), which, in turn, were more common than in group 1 (98 [18%] of 547; p<0·0001). Similar findings were observed for grade 3 or worse adverse events. However, late toxicity (>3 months after radiotherapy) did not differ significantly between the groups, apart from more late grade 2 or worse blood or bone marrow events in group 3 versus group 2 (one-sided p=0·0060) attributable to the addition of PLNRT in this group. INTERPRETATION: The results of this randomised trial establish the benefit of adding short-term ADT to PBRT to prevent progression in prostate cancer. To our knowledge, these are the first such findings to show that extending salvage radiotherapy to treat the pelvic lymph nodes when combined with short-term ADT results in meaningful reductions in progression after prostatectomy in patients with prostate cancer. FUNDING: National Cancer Institute.

Radiation Oncologist Consultations Prior to Radical Prostatectomy: Disparities and Opportunities.

PURPOSE: In 2015, men undergoing radical prostatectomy in Ontario, Canada were recommended to undergo multidisciplinary care by seeing a radiation oncologist or discussion at multidisciplinary rounds before surgery. The a priori target rate was ≥76%. We used population-based data to explore factors associated with not receiving multidisciplinary care prior to radical prostatectomy. MATERIALS AND METHODS: Men who underwent radical prostatectomy for localized prostate cancer in Ontario between 2007 and 2017 were identified using administrative data. Physician billings identified patients who received multidisciplinary care. Multivariable logistic regression was used to predict receipt of multidisciplinary care. RESULTS: A total of 31,485 men underwent radical prostatectomy between 2007 and 2017. Of these patients 28.7% saw a radiation oncologist, 1.2% underwent multidisciplinary discussion and 1.9% had both before surgery. Multidisciplinary care receipt increased from 17.8% in 2007 to 47.8% in 2017 (p <0.001). The odds ratio between the highest and lowest geographic regions was 7.93 (95% CI 6.17-10.18, p <0.001). Lower odds of multidisciplinary care receipt were observed for men further from the nearest cancer center (OR 0.74 per 50 km, 95% CI 0.71-0.78, p <0.001) and higher odds for the highest versus lowest income quintile (OR 1.41, 95% CI 1.29-1.54, p <0.001). Of 128 urologists who performed ≥10 radical prostatectomies between 2016 and 2017, 29 (22.7%) met the target of having ≥76% of men seen for multidisciplinary care prior to surgery. CONCLUSIONS: Despite increasing utilization, many men do not receive multidisciplinary care prior to radical prostatectomy. While geography and the urologist appear to be the greatest factors predicting multidisciplinary care receipt, these factors are closely intertwined.

Circulating tumor cells detected in follow-up predict survival outcomes in tri-modality management of advanced non-metastatic esophageal cancer: a secondary analysis of the QUINTETT randomized trial.

BACKGROUND: Our aim was to establish if presence of circulating tumor cells (CTCs) predicted worse outcome in patients with non-metastatic esophageal cancer undergoing tri-modality therapy. METHODS: We prospectively collected CTC data from patients with operable non-metastatic esophageal cancer from April 2009 to November 2016 enrolled in our QUINTETT esophageal cancer randomized trial (NCT00907543). Patients were randomized to receive either neoadjuvant cisplatin and 5-fluorouracil (5-FU) plus radiotherapy followed by surgical resection (Neoadjuvant) or adjuvant cisplatin, 5-FU, and epirubicin chemotherapy with concurrent extended volume radiotherapy following surgical resection (Adjuvant). CTCs were identified with the CellSearch® system before the initiation of any treatment (surgery or chemoradiotherapy) as well as at 6-, 12-, and 24-months post-treatment. The threshold for CTC positivity was one and the findings were correlated with patient prognosis. RESULTS: CTC data were available for 74 of 96 patients and identified in 27 patients (36.5%) at a median follow-up of 13.1months (interquartile range:6.8-24.1 months). Detection of CTCs at any follow-up visit was significantly predictive of worse disease-free survival (DFS;hazard ratio [HR]: 2.44; 95% confidence interval [CI]: 1.41-4.24; p=0.002), regional control (HR: 6.18; 95% CI: 1.18-32.35; p=0.031), distant control (HR: 2.93; 95% CI: 1.52-5.65;p=0.001) and overall survival (OS;HR: 2.02; 95% CI: 1.16-3.51; p=0.013). After adjusting for receiving neoadjuvant vs. adjuvant chemoradiotherapy, the presence of CTCs at any follow-up visit remained significantly predictive of worse OS ([HR]:2.02;95% [Cl]:1.16-3.51; p=0.013) and DFS (HR: 2.49;95% Cl: 1.43-4.33; p=0.001). Similarly, any observed increase in CTCs was significantly predictive of worse OS (HR: 3.14; 95% CI: 1.56-6.34; p=0.001) and DFS (HR: 3.34; 95% CI: 1.67-6.69; p<0.001). CONCLUSION: The presence of CTCs in patients during follow-up after tri-modality therapy was associated with significantly poorer DFS and OS regardless of timing of chemoradiotherapy.

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.

Is hypofractionated whole pelvis radiotherapy (WPRT) as well tolerated as conventionally fractionated WPRT in prostate cancer patients? The HOPE trial.

BACKGROUND: Patients with high-risk prostate cancer are at increased risk of lymph node metastasis and are thought to benefit from whole pelvis radiotherapy (WPRT). There has been recent interest in the use of hypofractionated radiotherapy in treating prostate cancer. However, toxicity and cancer outcomes associated with hypofractionated WPRT are unclear at this time. This phase II study aims to investigate the impact in quality of life associated with hypofractionated WPRT compared to conventionally fractionated WPRT. METHODS: Fifty-eight patients with unfavourable intermediate-, high- or very high-risk prostate cancer will be randomized in a 1:1 ratio between high-dose-rate brachytherapy (HDR-BT) + conventionally fractionated (45 Gy in 25 fractions) WPRT vs. HDR-BT + hypofractionated (25 Gy in 5 fractions) WPRT. Randomization will be performed with a permuted block design without stratification. The primary endpoint is late bowel toxicity and the secondary endpoints include acute and late urinary and sexual toxicity, acute bowel toxicity, biochemical failure-, androgen deprivation therapy-, metastasis- and prostate cancer-free survival of the hypofractionated arm compared to the conventionally fractionated arm. DISCUSSION: To our knowledge, this is the first study to compare hypofractionated WPRT to conventionally fractionated WPRT with HDR-BT boost. Hypofractionated WPRT is a more attractive and convenient treatment approach, and may become the new standard of care if demonstrated to be well-tolerated and effective. TRIAL REGISTRATION: This trial was prospectively registered in ClinicalTrials.gov as NCT04197141 on December 12, 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.

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.

Identification and survival outcomes of a cohort of patients with cancer of unknown primary in Ontario, Canada.

BACKGROUND: Cancer of unknown primary origin (CUP) is defined by the presence of pathologically identified metastatic disease without clinical or radiological evidence of a primary tumour. Our objective was to identify incident cases of CUP in Ontario, Canada, and determine the influence of histology and sites of metastases on overall survival (OS). MATERIAL AND METHODS: We used the Ontario Cancer Registry (OCR) and the Same-Day Surgery and Discharge Abstract Database (SDS/DAD) to identify patients diagnosed with CUP in Ontario between 1 January 2000, and 31 December 2005. Patient diagnostic information, including histology and survival data, was obtained from the OCR. We cross-validated CUP diagnosis and obtained additional information about metastasis through data linkage with the SDS/DAD database. OS was assessed using Cox regression models adjusting for histology and sites of metastases. RESULTS: We identified 3564 patients diagnosed with CUP. Patients without histologically confirmed disease (n = 1821) had a one-year OS of 10.9%, whereas patients with confirmed histology (n = 1743) had a one-year OS of 15.6%. The most common metastatic sites were in the respiratory or digestive systems (n = 1603), and the most common histology was adenocarcinoma (n = 939). Three-year survival rates were 3.5%, 5.3%, 41.6% and 3.6% among adenocarcinoma, unspecified carcinoma, squamous cell carcinoma and undifferentiated histology, respectively. Three-year survival rates were 40%, 2.4%, 8.0% and 4.6% among patients with metastases localised to lymph nodes, the respiratory or digestive systems, other specified sites, and unspecified sites, respectively. CONCLUSION: CUP patients in Ontario have a poor prognosis. Some subgroups may have better survival rates, such as patients with metastases localised to lymph nodes and patients with squamous cell histology.

Impact of target volume segmentation accuracy and variability on treatment planning for 4D-CT-based non-small cell lung cancer radiotherapy.

BACKGROUND: Accurate target volume segmentation is crucial for success in image-guided radiotherapy. However, variability in anatomical segmentation is one of the most significant contributors to uncertainty in radiotherapy treatment planning. This is especially true for lung cancer where target volumes are subject to varying magnitudes of respiratory motion. MATERIAL AND METHODS: This study aims to analyze multiple observer target volume segmentations and subsequent intensity-modulated radiotherapy (IMRT) treatment plans defined by those segmentations against a reference standard for lung cancer patients imaged with four-dimensional computed tomography (4D-CT). Target volume segmentations of 10 patients were performed manually by six physicians, allowing for the calculation of ground truth estimate segmentations via the simultaneous truth and performance level estimation (STAPLE) algorithm. Segmentation variability was assessed in terms of distance- and volume-based metrics. Treatment plans defined by these segmentations were then subject to dosimetric evaluation consisting of both physical and radiobiological analysis of optimized 3D dose distributions. RESULTS: Significant differences were noticed amongst observers in comparison to STAPLE segmentations and this variability directly extended into the treatment planning stages in the context of all dosimetric parameters used in this study. Mean primary tumor control probability (TCP) ranged from (22.6±11.9)% to (33.7±0.6)%, with standard deviation ranging from 0.5% to 11.9%. However, mean normal tissue complication probabilities (NTCP) based on treatment plans for each physician-derived target volume well as the NTCP derived from STAPLE-based treatment plans demonstrated no discernible trends and variability appeared to be patient-specific. This type of variability demonstrated the large-scale impact that target volume segmentation uncertainty can play in IMRT treatment planning. CONCLUSIONS: Significant target volume segmentation and dosimetric variability exists in IMRT treatment planning amongst experts in the presence of a reference standard for 4D-CT-based lung cancer radiotherapy. Future work is needed to mitigate this uncertainty and ensure highly accurate and effective radiotherapy for lung cancer patients.

Measuring the population impact of introducing stereotactic ablative radiotherapy for stage I non-small cell lung cancer in Canada.

BACKGROUND: The Cancer Risk Management Model (CRMM) was used to estimate the health and economic impact of introducing stereotactic ablative radiotherapy (SABR) for stage I non-small cell lung cancer (NSCLC) in Canada. METHODS: The CRMM uses Monte Carlo microsimulation representative of all Canadians. Lung cancer outputs were previously validated internally (Statistics Canada) and externally (Canadian Cancer Registry). We updated costs using the Ontario schedule of fees and benefits or the consumer price index to calculate 2013 Canadian dollars, discounted at a 3% rate. The reference model assumed that for stage I NSCLC, 75% of patients undergo surgery (lobectomy, sublobar resection, or pneumonectomy), 12.5% undergo radiotherapy (RT), and 12.5% undergo best supportive care (BSC). SABR was introduced in 2008 as an alternative to sublobar resection, RT, and BSC at rates reflective of the literature. Incremental cost effectiveness ratios (ICERs) were calculated; a willingness-to-pay threshold of $100,000 (all amounts are in Canadian dollars) per quality-adjusted life-year (QALY) was used from the health care payer perspective. RESULTS: The total cost for 25,085 new cases of lung cancer in 2013 was calculated to be $608,002,599. Mean upfront costs for the 4,318 stage I cases were $7,646.98 for RT, $8,815.55 for SABR, $12,161.17 for sublobar resection, $16,266.12 for lobectomy, $22,940.59 for pneumonectomy, and $14,582.87 for BSC. SABR dominated (higher QALY, lower cost) RT, sublobar resection, and BSC. RT had lower initial costs than SABR that were offset by subsequent costs associated with recurrence. Lobectomy was cost effective when compared with SABR, with an ICER of $55,909.06. CONCLUSION: The use of SABR for NSCLC in Canada is projected to result in significant cost savings and survival gains.

Functional lung avoidance for individualized radiotherapy (FLAIR): study protocol for a randomized, double-blind clinical trial.

BACKGROUND: Although radiotherapy is a key component of curative-intent treatment for locally advanced, unresectable non-small cell lung cancer (NSCLC), it can be associated with substantial pulmonary toxicity in some patients. Current radiotherapy planning techniques aim to minimize the radiation dose to the lungs, without accounting for regional variations in lung function. Many patients, particularly smokers, can have substantial regional differences in pulmonary ventilation patterns, and it has been hypothesized that preferential avoidance of functional lung during radiotherapy may reduce toxicity. Although several investigators have shown that functional lung can be identified using advanced imaging techniques and/or demonstrated the feasibility and theoretical advantages of avoiding functional lung during radiotherapy, to our knowledge this premise has never been tested via a prospective randomized clinical trial. METHODS/DESIGN: Eligible patients will have Stage III NSCLC with intent to receive concurrent chemoradiotherapy (CRT). Every patient will undergo a pre-treatment functional lung imaging study using hyperpolarized 3He MRI in order to identify the spatial distribution of normally-ventilated lung. Before randomization, two clinically-approved radiotherapy plans will be devised for all patients on trial, termed standard and avoidance. The standard plan will be designed without reference to the functional state of the lung, while the avoidance plan will be optimized such that dose to functional lung is as low as reasonably achievable. Patients will then be randomized in a 1:1 ratio to receive either the standard or the avoidance plan, with both the physician and the patient blinded to the randomization results. This study aims to accrue a total of 64 patients within two years. The primary endpoint will be a pulmonary quality of life (QOL) assessment at 3 months post-treatment, measured using the functional assessment of cancer therapy-lung cancer subscale. Secondary endpoints include: pulmonary QOL at other time-points, provider-reported toxicity, overall survival, progression-free survival, and quality-adjusted survival. DISCUSSION: This randomized, double-blind trial will comprehensively assess the impact of functional lung avoidance on pulmonary toxicity and quality of life in patients receiving concurrent CRT for locally advanced NSCLC. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02002052.

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.

What is the predictive value of RECIST criteria following stereotactic lung radiation?

PURPOSE: Response EvaluationCriteriain Solid Tumors (RECIST) is commonly used to assess response to anti-cancer therapies. However, its application after lung stereotactic ablative radiotherapy (SABR) is complicated by radiation-induced lung changes. This study assesses the frequency of progressive disease (PD) by RECIST following lung SABR and correlates this with actual treatment outcomes as determined by longitudinal follow-up. METHODS AND MATERIALS: We reviewed patients treated with lung SABR for primary lung tumors or oligometastases between 2010 and 2015. Patients were treated with SABR doses of 54-60 Gy in 3-8 fractions. All follow-up scans were assessed and the treated lesion was serially measured over time, with the maximum diameter on axial CT slices used for RECIST calculations. Lesions demonstrating PD by RECIST criteria were identified and subsequently followed for long-term outcomes. The final 'gold-standard' assessment of response was based on size changes after PD and, as available, positron emission tomography scan and/or biopsy. RESULTS: Eighty-eight lesions met inclusion criteria. Seventy-five were lung primaries and thirteen were lung metastases. Median follow-up was 52 months (interquartile range: 33-68). Two-thirds (66 %, 58/88) of treated lesions met RECIST criteria for PD; however, local recurrence was only confirmed in 16 % (9/58) of cases. Most lesions that triggered PD by RECIST (47/58, 81 %) were ultimately found not to represent recurrence, while a minority (2/58, 3 %) had an uncertain response. The positive predictive value [PPV] of a RECIST defined PD event was 0.16. If PD was triggered within 12-months post-treatment, PPV was 0.08, compared to 0.21 for lesions triggering PD after 12-months. CONCLUSION: Using RECIST criteria, two-thirds of patients treated with lung SABR met criteria for PD. However, only a minority had recurrence, leading to a poor PPV of RECIST. This highlights the limitations of RECIST in this setting and provides context for physicians when interpreting post-lung SABR imaging.

Measuring the Integration of Stereotactic Ablative Radiotherapy Plus Surgery for Early-Stage Non-Small Cell Lung Cancer (MISSILE): Long-Term Clinical Outcomes.

INTRODUCTION: For early-stage non-small cell lung cancer (NSCLC), surgery is the preferred approach in operable patients, whereas stereotactic ablative radiotherapy (SABR) is preferred for medically inoperable patients. The combination of neoadjuvant SABR followed by surgery was tested in the MISSILE phase II trial. We report long-term outcomes, beyond 5 years of follow-up. METHODS: Patients diagnosed with T1-2N0M0 NSCLC with good performance status and adequate lung function were enrolled. Patients underwent neoadjuvant SABR followed by lobectomy/wedge resection. Forty enrolled patients received SABR, of which 36 patients proceeded to surgery. RESULTS: The pathologic and major complete response rates were 60% and 63%, respectively. Median follow-up was 6.6 years following surgery. Five-year overall, disease-free and cancer-specific survival were 66.7% (95% CI: 48.8-79.5), 58.3% (95% CI: 40.7-72.4) and 76.4% (95% CI: 58.2-87.4). Five-year local, regional and distant control were 93.5% (95% CI: 76.3-98.4), 80.1% (95% CI: 62.7-90.0) and 82.4% (95% CI: 64.9-91.7). After SABR and surgery, 16.7% (n=6) of patients experienced related grade ≥ 3 adverse events and there were no grade 5 events. CONCLUSION: The combined approach of SABR and surgery was safe and demonstrated reasonable long-term clinical outcomes, but similar to surgery alone.

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.

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.

Corrigendum to "Androgen Deprivation and Radiotherapy with or Without Docetaxel for Localized High-risk Prostat Cancer: Long-term Follow-up from the Randomized NRG Oncology RTOG 0521 Trial" [Eur. Eurol. 84(2) (2023) 156-163].

BACKGROUND: Intensification of therapy may improve outcomes for patients with high-risk localized prostate cancer. OBJECTIVE: To provide long-term follow-up data from phase III RTOG 0521, which compared a combination of androgen deprivation therapy (ADT) + external beam radiation therapy (EBRT) + docetaxel with ADT + EBRT. DESIGN, SETTING, AND PARTICIPANTS: High-risk localized prostate cancer patients (>50% of patients had Gleason 9-10 disease) were prospectively randomized to 2 yr of ADT + EBRT or ADT + EBRT + six cycles of docetaxel. A total of 612 patients were accrued, and 563 were eligible and included in the modified intent-to-treat analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was overall survival (OS). Analyses with Cox proportional hazards were performed as prespecified in the protocol; however, there was evidence of nonproportional hazards. Thus, a post hoc analysis was performed using the restricted mean survival time (RMST). The secondary endpoints included biochemical failure, distant metastasis (DM) as detected by conventional imaging, and disease-free survival (DFS). RESULTS AND LIMITATIONS: After 10.4 yr of median follow-up among survivors, the hazard ratio (HR) for OS was 0.89 (90% confidence interval [CI] 0.70-1.14; one-sided log-rank p = 0.22). Survival at 10 yr was 64% for ADT + EBRT and 69% for ADT + EBRT + docetaxel. The RMST at 12 yr was 0.45 yr and not statistically significant (one-sided p = 0.053). No differences were detected in the incidence of DFS (HR = 0.92, 95% CI 0.73-1.14), DM (HR = 0.84, 95% CI 0.73-1.14), or prostate-specific antigen recurrence risk (HR = 0.97, 95% CI 0.74-1.29). Two patients had grade 5 toxicity in the chemotherapy arm and zero patients in the control arm. CONCLUSIONS: After a median follow-up of 10.4 yr among surviving patients, no significant differences are observed in clinical outcomes between the experimental and control arms. These data suggest that docetaxel should not be used for high-risk localized prostate cancer. Additional research may be warranted using novel predictive biomarkers. PATIENT SUMMARY: No significant differences in survival were noted after long-term follow-up for high-risk localized prostate cancer patients in a large prospective trial where patients were treated with androgen deprivation therapy + radiation to the prostate ± docetaxel.

Ensuring Superior Reporting of Radiation Therapy Noninferiority Trials: A Systematic Review.

Purpose: Although the frequency of noninferiority trials is increasing, the consistency of the reporting of these trials can vary. The aim of this systematic review was to assess the reporting quality of radiation therapy noninferiority trials. Methods and Materials: The PubMed, Embase, and Cochrane databases were queried for randomized controlled radiation therapy trials with noninferiority hypotheses published in English between January 2000 and July 2022, and this was performed by an information scientist. Descriptive statistics were used to summarize data. Results: Of 423 records screened, 59 (14%) were included after full-text review. All were published after 2003 and open label. The most common primary cancer type was breast (n = 15, 25%). Altered radiation fractionation (n = 26, 45%) and radiation de-escalation (n = 11, 19%) were the most common types of interventions. The most common primary endpoints were locoregional control (n = 17, 29%) and progression-free survival (n = 14, 24%). Fifty-three (90%) reported the noninferiority margin, and only 9 (17%) provided statistical justification for the margin. The median absolute noninferiority margin was 9% (interquartile range, 5%-10%), and the median relative margin was 1.51 (interquartile range, 1.33-2.04). Sample size calculations and confidence intervals were reported in 54 studies (92%). Both intention-to-treat and per-protocol analyses were reported in 27 studies (46%). In 31 trials (53%), noninferiority of the primary endpoint was reached. Conclusions: There was variability in the reporting of key components of noninferiority trials. We encourage consideration of additional statistical reasoning such as guidelines or previous trials in the selection of the noninferiority margin, reporting both absolute and relative margins, and the avoidance of statistically vague or misleading language in the reporting of future noninferiority trials.

Planning for the Effect of the SC.24 Trial on Spine Stereotactic Body Radiation Therapy Utilization at a Tertiary Cancer Center.

Purpose: The goal of this study was to assess the potential real-world effect of the recently reported SC.24 trial on spine stereotactic body radiation therapy (SBRT) utilization. We estimated the proportion of patients treated with conventional radiation therapy (CRT) who would have been eligible for spine SBRT per trial inclusion criteria and analyzed the potential estimated increased costs to our institution. Methods and Materials: This was a retrospective review of patients who received spine CRT at our institution between August and October 2020. Data abstracted included demographics, SC.24 eligibility criteria, provider-reported pain response, and survival. A cost analysis and time survey was performed using institutional and provincial data. Results: Of 73 patients reviewed, 24 patients (33%) were eligible. The most common exclusion factors included irradiation of ≥3 consecutive spinal segments (n = 32, 44%), Eastern Cooperative Oncology Group performance status >2 (n = 17, 23%), and symptomatic spinal cord compression (n = 13, 18%). Of eligible patients, the mean age was 68.92 years, median spinal instability in neoplasia score was 8 (interquartile range, 7-9), and median Eastern Cooperative Oncology Group performance status was 2 (interquartile range, 1-2). The most common primary cancer types among eligible patients were lung (n = 10) and breast (n = 4). The median survival of eligible patients was 10 months (95% confidence interval, 4 months to not reached) with 58% surviving longer than 3 months. Of patients who had subjective pain documented after CRT, 54% had at least some response. The cost of spine SBRT was estimated at CA$4764.80 compared with $3589.10 for CRT, and tasks for spine SBRT took roughly 3 times as long as those for CRT. Conclusions: One-third of patients who received palliative spine CRT met eligibility criteria for SC.24. This possible expanded indication for spine SBRT can have a substantial effect on resource utilization. These data may be useful in guiding resource planning at institutions looking to commence a spine SBRT program.