Population-based survival rates after curative surgical and non-surgical treatment of stage III NSCLC since 2017.

OBJECTIVES: In stage III non-small cell lung cancer (NSCLC), curative treatment approaches used to include neoadjuvant therapy followed by surgery, and definitive chemoradiotherapy followed by consolidation durvalumab (CRT-ICI). Surgical strategies included either neoadjuvant chemotherapy (CTx-surg) or chemoradiotherapy (CRT-surg). We studied the outcomes of these three radical intent strategies in the Netherlands Cancer Registry (NCR) for patients diagnosed from 2017 to 2021. MATERIALS AND METHODS: Patients with clinical stage III NSCLC (TNM edition 8) were identified in the NCR after excluding patients with known driver mutations, ECOG performance status >=2, N3-disease and those undergoing sequential chemoradiotherapy or single modality/palliative treatments. Overall survival (OS) was calculated from date of surgery or start of durvalumab. RESULTS: Treatments delivered were CRT-ICI (n = 1016 patients), CRT-surg (n = 166) and CTx-surg (n = 111). The surgical series comprised 224 lobectomies, 21 bilobectomies and 32 pneumonectomies, with a 90-day postoperative mortality rate of 3.3 %. Use of CRT-surg decreased steeply after 2018, when durvalumab became fully reimbursed, and use of CRT-ICI increased. Three-year OS was better following CRT-surg (78.7 %) compared to CTx-surg (66.7 %) or CRT-ICI (63.2 %). After controlling for age, ECOG performance status and histology, the hazard ratios for CRT-surg and CTx-surg were 0.66 (95 % CI 0.47-0.91) and 0.82 (95 % CI 0.58-1.17), respectively, compared to CRT-ICI. CONCLUSION: Population survivals after curative strategies for clinical stage III NSCLC in The Netherlands exceed those reported historically for both surgical and non-surgical approaches. Use of surgery decreased from 2018 following the formal reimbursement of durvalumab. While variations in case-mix hamper comparison between curative treatment strategies, there is a clear need for randomized studies in subgroups with potentially resectable disease.

Diagnosis and management of pneumonitis following chemoradiotherapy and immunotherapy in stage III non-small cell lung cancer.

BACKGROUND: In inoperable stage III NSCLC, the standard of care is chemoradiotherapy and adjuvant durvalumab (IO) for 12 months. Pneumonitis is the commonest toxicity leading to discontinuation of IO. A failure to distinguish between expected radiation-induced changes, IO pneumonitis and infection can lead to unnecessary durvalumab discontinuation. We investigated the use of a structured multidisciplinary review of CT-scans, radiation dose distributions and clinical symptoms for the diagnosis of IO pneumonitis. METHODS: A retrospective study was conducted at an academic medical center for patients treated for stage III NSCLC with chemoradiotherapy and adjuvant durvalumab between 2018 and 2021. An experienced thoracic radiologist reviewed baseline and follow-up chest CT-scans, systematically scored radiological features suspected for pneumonitis using a published classification system (Veiga C, Radioth Oncol 2018), and had access to screenshots of radiation dose distributions. Next, two experienced thoracic oncologists reviewed each patients' case record, CT-scans and radiation fields. A final consensus diagnosis incorporating views of expert clinicians and the radiologist was made. RESULTS: Among the 45 included patients, 14/45 (31.1%) had a pneumonitis scored in patient records and durvalumab was discontinued in 11/45 cases (24.4%). Review by the radiologist led to a diagnosis of immune-related pneumonitis only in 6/45 patients (13.3%). Review by pulmonary oncologists led to a diagnosis of immune-related pneumonitis in only 4/45 patients (8.9%). In addition a suspicion of an immune-related pneumonitis was rejected in 3 separate patients (6.7%), after the thoracic oncologists had reviewed the patients' radiation fields. CONCLUSIONS: In patients treated using the PACIFIC regimen, multidisciplinary assessment of CT-scans, radiation doses and patient symptoms, resulted in fewer diagnoses of immune-related pneumonitis (8.9%). Our study underscores the challenges in accurately diagnosing either IO-related or radiation pneumonitis in patients undergoing adjuvant immunotherapy after chemoradiotherapy and highlights the need for multidisciplinary review in order to avoid inappropriate cessation of adjuvant IO.

Feasibility of salvage resection following locoregional failure after chemoradiotherapy and consolidation durvalumab for unresectable stage III non-small cell lung cancer.

INTRODUCTION: In patients with unresectable stage III non-small cell lung cancer, high-dose chemoradiotherapy (CRT) followed by consolidation durvalumab improves the 5-year overall survival compared to CRT alone. The feasibility and safety of salvage surgery for such patients who subsequently develop locoregional failure (LRF) is unclear. We evaluated our institutional experience with radical-intent salvage surgery in this patient population. MATERIALS AND METHODS: Details of patients undergoing salvage surgery for locoregional failure after CRT and durvalumab were identified from an institutional surgical database. Each patient's case underwent multidisciplinary discussion at initial disease presentation, and again at time of progression. RESULTS: Ten patients underwent salvage surgery for LRF after prior concurrent (n = 9) or sequential (n = 1) platinum-based high-dose chemo-radiotherapy followed by durvalumab. Consolidation durvalumab was completed in 4 patients, and discontinued in 6, due to either toxicity or disease progression. Median time between end of radiotherapy to detection of LRF was 19 months (range 6-75). Seven patients underwent a lobectomy, 1 a bilobectomy and 2 patients a pneumonectomy. Postoperative morbidity (Clavien-Dindo grade III-V) and 90-day mortality were 10% and 0%, respectively. Median follow-up after surgery was 7 months (range 1-25) during which 2 patients died (both 9 months post-operatively), one due to distant progression, and one of sepsis/bleeding. Eight patients are alive at 1-23 months post-surgery, with 6 showing no evidence of disease. CONCLUSIONS: Our results suggest that salvage pulmonary resection can be performed safely in selected patients with LRF following chemoradiotherapy and durvalumab. This radical-intent treatment option merits consideration by multidisciplinary lung tumor boards.

Long-Term Outcomes After Chemoradiotherapy and Surgery for Superior Sulcus Tumors.

Introduction: Superior sulcus tumors (SSTs) are uncommon, and their anatomical location can make treatment challenging. We analyzed late outcomes of patients with SST treated with concurrent chemoradiotherapy followed by surgical resection (trimodality) in a single tertiary institution. Methods: Patients with non-small cell SSTs, who underwent trimodality therapy between 2002 and 2017, were selected from a prospective institutional surgical database. Patients were uniformly staged with 18F-fluorodeoxyglucose-positron emission tomography, computed tomography scan of the chest and upper abdomen, and brain imaging. Patients undergoing resection of the lung plus chest wall were grouped as limited SST and those needing extensive resections (e.g., including the vertebral body) as extended SST. Kaplan-Meier survival analysis was performed to determine difference in survival. Multivariate Cox regression was used to identify prognostic factors. Results: A total of 123 patients were identified with a median follow-up of 4.9 years (interquartile range: 1.6-8.9 y). The 90-day postoperative mortality and morbidity (Clavien-Dindo grades III-V) were 6.5% and 21.1%, respectively. Patients with a radical resection (R0: 92.7%) had better survival (p = 0.002), as did those who had major pathologic response (73%) (p = 0.001). Ten-year overall survival (OS) and disease-free survival were 48.1% and 42.6%, respectively. There were no differences in 90-day mortality (p = 0.31) and OS (p = 0.79) between extended SST and limited SST patients. Conclusions: In patients with SST, trimodality resulted in a 10-year estimated OS and disease-free survival of 48.1% and 42.6%, respectively, which were improved after radical resection (R0) and major pathologic response. Survival for limited and extended resections was comparable, and distant relapse was the main pattern of failure. Better systemic treatments are therefore needed.

Outcomes with durvalumab after chemoradiotherapy in stage IIIA-N2 non-small-cell lung cancer: an exploratory analysis from the PACIFIC trial.

BACKGROUND: The phase III PACIFIC trial (NCT02125461) established consolidation durvalumab as standard of care for patients with unresectable, stage III non-small-cell lung cancer (NSCLC) and no disease progression following chemoradiotherapy (CRT). In some cases, patients with stage IIIA-N2 NSCLC are considered operable, but the relative benefit of surgery is unclear. We report a post hoc, exploratory analysis of clinical outcomes in the PACIFIC trial, in patients with or without stage IIIA-N2 NSCLC. MATERIALS AND METHODS: Patients with unresectable, stage III NSCLC and no disease progression after ≥2 cycles of platinum-based, concurrent CRT were randomized 2 : 1 to receive durvalumab (10 mg/kg intravenously; once every 2 weeks for up to 12 months) or placebo, 1-42 days after CRT. The primary endpoints were progression-free survival (PFS; assessed by blinded independent central review according to RECIST version 1.1) and overall survival (OS). Treatment effects within subgroups were estimated by hazard ratios (HRs) from unstratified Cox proportional hazards models. RESULTS: Of 713 randomized patients, 287 (40%) had stage IIIA-N2 disease. Baseline characteristics were similar between patients with and without stage IIIA-N2 NSCLC. With a median follow-up of 14.5 months (range: 0.2-29.9 months), PFS was improved with durvalumab versus placebo in both patients with [HR = 0.46; 95% confidence interval (CI), 0.33-0.65] and without (HR = 0.62; 95% CI 0.48-0.80) stage IIIA-N2 disease. Similarly, with a median follow-up of 25.2 months (range: 0.2-43.1 months), OS was improved with durvalumab versus placebo in patients with (HR = 0.56; 95% CI 0.39-0.79) or without (HR = 0.78; 95% CI 0.57-1.06) stage IIIA-N2 disease. Durvalumab had a manageable safety profile irrespective of stage IIIA-N2 status. CONCLUSIONS: Consistent with the intent-to-treat population, treatment benefits with durvalumab were confirmed in patients with stage IIIA-N2, unresectable NSCLC. Prospective studies are needed to determine the optimal treatment approach for patients who are deemed operable.

A nationwide population-based cohort study of surgical care for patients with superior sulcus tumors: Results from the Dutch Lung Cancer Audit for Surgery (DLCA-S).

OBJECTIVES: Data on national patterns of care for patients with superior sulcus tumors (SST) is currently lacking. We investigated the distribution of surgical care and outcome for patients with SST in the Netherlands. MATERIAL AND METHODS: Data was retrieved from the Dutch Lung Cancer Audit for Surgery (DLCA-S) for all patients undergoing resection for clinical stage IIB-IV SST from 2012 to 2019. Because DLCA-S is not linked to survival data, survival for a separate cohort (2015-2017) was obtained from the Netherlands Cancer Registry (NCR). RESULTS: In the study period, 181 patients had SST surgery, representing 1.03% (181/17488) of all lung cancer pulmonary resections. For 2015-2017, the SST resection rate was 14.4% (79/549), and patients with stage IIB/III SST treated with trimodality had a 3-year overall survival of 67.4%. 63.5% of patients were male, and median age was 60 years. Almost 3/4 of tumors were right sided. Surgery was performed in 20 hospitals, with average number of annual resections ranging from ≤ 1 (n = 17) to 9 (n = 1). 39.8% of resections were performed in 1 center and 63.5% in the 3 most active centers. 12.7% of resections were extended (e.g. vertebral resection). 85.1% of resections were complete (R0). Morbidity and 30-day mortality were 51.4% and 3.3% respectively. Despite treating patients with a higher ECOG performance score and more extended resections, the highest volume center had rates of morbidity/mortality, and length of hospital stay that were comparable to those of the medium volume (n = 2) and low-volume centers (n = 1). CONCLUSION: In the Netherlands, surgery for SST accounts for about 1% of all lung cancer pulmonary resections, the number of SST resections/hospital/year varies widely, with most centers performing an average of ≤ 1/year. Morbidity and mortality are acceptable and survival compares favourably with the literature. Although further centralisation is possible, it is unknown whether this will improve outcomes.

Neoadjuvant immune checkpoint inhibitors in resectable non-small-cell lung cancer: a systematic review.

BACKGROUND: The neoadjuvant use of immune checkpoint inhibitors (ICIs) in resectable non-small-cell lung cancer (NSCLC) is currently an area of active ongoing research. The place of neoadjuvant ICIs in the treatment guidelines needs to be determined. We carried out a systematic review of published data on neoadjuvant ICIs in resectable NSCLC to study its efficacy and safety. PATIENTS AND METHODS: A literature search was carried out using the MEDLINE (PubMed) and Embase databases to retrieve articles and conference abstracts of clinical trials measuring the efficacy [major pathological response (MPR) and pathological complete response (pCR)] and safety (failure to undergo resection, surgical delay, treatment-related adverse events (trAEs) grade ≥3) of neoadjuvant immunotherapy in resectable NSCLC until July 2021. RESULTS: Nineteen studies with a total of 1066 patients were included in this systematic review. Neoadjuvant immunotherapy was associated with improved pathological response rates, especially in combination with chemotherapy. Using mono ICI, dual therapy-ICI, chemoradiation-ICI, radiotherapy-ICI, and chemo-ICI, the MPR rates were 0%-45%, 50%, 73%, 53%, and 27%-86%, respectively. Regarding pCR, the rates were 7%-16%, 33%-38%, 27%, 27%, and 9%-63%, respectively. Safety endpoints using monotherapy-ICI, dual therapy-ICI, chemoradiation-ICI, radiotherapy-ICI, and chemo-ICI showed a failure to undergo resection in 0%-17%, 19%-33%, 8%, 13%, and 0%-46%, respectively. The trAEs grade ≥3 rates were 0%-20%, 10%-33%, 7%, 23%, and 0%-67%, respectively. CONCLUSION: In patients with resectable NSCLC stage, neoadjuvant immunotherapy can improve pathological response rates with acceptable toxicity. Further research is needed to identify patients who may benefit most from this approach, and adequately powered trials to establish clinically meaningful benefits are awaited.

The development and external validation of an overall survival nomogram in medically inoperable centrally located early-stage non-small cell lung carcinoma.

BACKGROUND AND PURPOSE: Current nomograms predicting survival prognosis after stereotactic body radiation therapy (SBRT) in non-small cell lung cancer (NSCLC) are based on peripherally located tumors. However, patients with a central lung tumor tend to be older, the tumor is often larger and fraction-schedules are risk-adapted. Therefore, we developed and externally validated a nomogram to predict overall survival (OS) in patients having centrally located early-stage NSCLC treated with SBRT. MATERIALS AND METHODS: Patients who underwent SBRT for centrally located NSCLC were identified and baseline characteristics were obtained. A nomogram was built to predict 6-month, 1-, 2- and 3-year OS using Cox proportional hazards model. The model building procedure was validated using bootstrap sampling. To determine generalizability, external validation was performed on a cohort of patients with central NSCLC treated with SBRT from another center. Discriminatory ability was measured with the concordance index (C-index) and calibration plots were used to compare Kaplan-Meier-estimated and nomogram-predicted OS. RESULTS: The nomogram was built on data of 220 patients and consisted of the following variables: PTV, age, WHO performance status, tumor lobe location and ultracentral location. The C-index of the nomogram (corrected for optimism) was moderate at 0.64 (95% confidence interval (CI) 0.59-0.69). Calibration plots showed favorable predictive accuracy. The external validation showed acceptable validity with a C-index of 0.62 (95% CI 0.61-0.64). DISCUSSION: We developed and externally validated the first nomogram to estimate the OS-probability in patients with centrally located NSCLC treated with SBRT. This nomogram is based on 5 patient and tumor characteristics and gives an individualized survival prediction.

Outcomes with durvalumab by tumour PD-L1 expression in unresectable, stage III non-small-cell lung cancer in the PACIFIC trial.

BACKGROUND: In the PACIFIC trial, durvalumab significantly improved progression-free and overall survival (PFS/OS) versus placebo, with manageable safety, in unresectable, stage III non-small-cell lung cancer (NSCLC) patients without progression after chemoradiotherapy (CRT). We report exploratory analyses of outcomes by tumour cell (TC) programmed death-ligand 1 (PD-L1) expression. PATIENTS AND METHODS: Patients were randomly assigned (2:1) to intravenous durvalumab 10 mg/kg every 2 weeks or placebo ≤12 months, stratified by age, sex, and smoking history, but not PD-L1 status. Where available, pre-CRT samples were tested for PD-L1 expression (immunohistochemistry) and scored at pre-specified (25%) and post hoc (1%) TC cut-offs. Treatment-effect hazard ratios (HRs) were estimated from unstratified Cox proportional hazards models (Kaplan-Meier-estimated medians). RESULTS: In total, 713 patients were randomly assigned, 709 of whom received at least 1 dose of study treatment durvalumab (n = 473) or placebo (n = 236). Some 451 (63%) were PD-L1-assessable: 35%, 65%, 67%, 33%, and 32% had TC ≥25%, <25%, ≥1%, <1%, and 1%-24%, respectively. As of 31 January 2019, median follow-up was 33.3 months. Durvalumab improved PFS versus placebo (primary-analysis data cut-off, 13 February 2017) across all subgroups [HR, 95% confidence interval (CI); medians]: TC ≥25% (0.41, 0.26-0.65; 17.8 versus 3.7 months), <25% (0.59, 0.43-0.82; 16.9 versus 6.9 months), ≥1% (0.46, 0.33-0.64; 17.8 versus 5.6 months), <1% (0.73, 0.48-1.11; 10.7 versus 5.6 months), 1%-24% [0.49, 0.30-0.80; not reached (NR) versus 9.0 months], and unknown (0.59, 0.42-0.83; 14.0 versus 6.4 months). Durvalumab improved OS across most subgroups (31 January 2019 data cut-off; HR, 95% CI; medians): TC ≥ 25% (0.50, 0.30-0.83; NR versus 21.1 months), <25% (0.89, 0.63-1.25; 39.7 versus 37.4 months), ≥1% (0.59, 0.41-0.83; NR versus 29.6 months), 1%-24% (0.67, 0.41-1.10; 43.3 versus 30.5 months), and unknown (0.60, 0.43-0.84; 44.2 versus 23.5 months), but not <1% (1.14, 0.71-1.84; 33.1 versus 45.6 months). Safety was similar across subgroups. CONCLUSIONS: PFS benefit with durvalumab was observed across all subgroups, and OS benefit across all but TC <1%, for which limitations and wide HR CI preclude robust conclusions.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with locally-advanced unresectable non-small-cell lung cancer: a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of early and locally-advanced non-small-cell lung cancer (NSCLC) was published in 2017, and covered the diagnosis, staging, management and treatment of both early stage I and II disease and locally-advanced stage III disease. At the ESMO Asia Meeting in November 2018, it was decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special face-to-face guidelines meeting in 2019 in Seoul. The aim was to adapt the ESMO 2017 guidelines to take into account potential differences related to ethnicity, cancer biology and standard practices associated with the treatment of locally-advanced, unresectable NSCLC in Asian patients. These guidelines represent the consensus opinions reached by those experts in the treatment of patients with lung cancer who represented the oncology societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and it was independent of both local current treatment practices and the treatment availability and reimbursement situations in the individual participating Asian countries.

Stereotactic ablative radiotherapy (SABR) for early-stage central lung tumors: New insights and approaches.

The use of stereotactic ablative radiotherapy (SABR) for central lung tumors is increasing. Centrally located lung tumors can be subdivided into two categories, namely the 'moderately central' tumors where the planning target volume is located within 2 cm of the proximal bronchial tree, and the 'ultracentral' tumors where a planning target volume (PTV) overlaps the trachea or main stem bronchi. The toxicity of SABR appears acceptable when 'moderately central' tumors are treated using techniques that comply with organs at risk tolerance doses used for prospective trials and in recent publications. A high toxicity is seen when ultracentral tumors are treated using SABR, and conventional radiotherapy appears more appropriate in such tumors as the true normal organ tolerance doses remain unknown. When ultracentral tumors are treated with non-SABR hypofractionated radiotherapy, a homogenous dose distribution in the planning target volume and limitation of both normal organ maximum point doses and volumes receiving high doses seems to be needed.

Esophagus toxicity after stereotactic and hypofractionated radiotherapy for central lung tumors: Normal tissue complication probability modeling.

PURPOSE: To correlate esophagus toxicity and dose-volume histogram (DVH) parameters in order to assess risks, and derive a Normal Tissue Complication Probability (NTCP) model. METHODS AND MATERIALS: Patients with a central lung tumor from 2 centers, who underwent stereotactic or hypofractionated radiotherapy (≤12 fractions), were analyzed. Doses were recalculated to an equivalent dose of 2 Gy with an α/ß ratio of 10 (EQD210). The esophagus was manually delineated and DVH-parameters (Dmax,EQD2, D1cc,EQD2, D2cc,EQD2, D5cc,EQD2) were analyzed and used for NTCP modeling based on logistic regression analysis. RESULTS: Two-hundred-and-thirty-one patients with 252 tumors were eligible. No acute or late grade 3-5 esophageal toxicity was reported. Acute grade 1-2 esophagus toxicity was recorded in 38 patients (17%). All DVH-parameters were significantly higher in patients with toxicity. NTCP models showed a 50% probability of acute grade 1-2 toxicity at a Dmax of 67 Gy EQD210 and D1cc of 42 Gy EQD210. No difference in overall survival was observed between patients with and without toxicity (p = 0.428). CONCLUSION: As no grade 3-5 esophageal toxicity was observed in our cohort, a Dmax of 56 Gy EQD210 and a D5cc of 35.5 Gy EQD210 could be delivered without high risks of severe toxicity. The NTCP models of this study might be used as practical guidelines for the treatment of central lung tumors with stereotactic radiotherapy.

Normal Tissue Complication Probability Modeling of Pulmonary Toxicity After Stereotactic and Hypofractionated Radiation Therapy for Central Lung Tumors.

PURPOSE: To evaluate clinical pulmonary and radiographic bronchial toxicity after stereotactic ablative radiation therapy and hypofractionated radiation therapy for central lung tumors, and perform normal tissue complication probability modeling and multivariable analyses to identify predictors for toxicity. METHODS AND MATERIALS: A pooled analysis was performed of patients with a central lung tumor treated using ≤12 fractions at 2 centers between 2006 and 2015. Airways were manually contoured on planning computed tomography scans, and doses were recalculated to an equivalent dose of 2 Gy per fraction with an α/ß ratio of 3. Grade ≥3 (≥G3) clinical pulmonary toxicity was evaluated by 2 or more physicians. Radiographic toxicity was defined as a stenosis or an occlusion with or without atelectasis using follow-up computed tomography scans. Logistic regression analyses were used for statistical analyses. RESULTS: A total of 585 bronchial structures were studied in 195 patients who were mainly treated using 5 or 8 fractions (60%). Median patient survival was 27.9 months (95% confidence interval 22.3-33.6 months). Clinical ≥G3 toxicity was observed in 24 patients (12%) and radiographic bronchial toxicity in 55 patients (28%), both mainly manifesting ≤12 months after treatment. All analyzed dosimetric parameters correlated with clinical and lobar bronchial radiographic toxicity, with V130Gy,EQD having the highest odds ratio. Normal tissue complication probability modeling showed a volume dependency for the development of both clinical and radiographic toxicity. On multivariate analyses, significant predictors for ≥G3 toxicity were a planning target volume overlapping the trachea or main stem bronchus (P = .005), chronic obstructive pulmonary disease (P = .034), and the total V130Gy,EQD (P = .012). Radiographic bronchial toxicity did not significantly correlate with clinical toxicity (P = .663). CONCLUSIONS: We identified patient and dosimetric factors associated with clinical and radiographic toxicity after high-dose radiation therapy for central lung tumors. Additional data from prospective studies are needed to validate these findings.

Population-based Results of Chemoradiotherapy for Limited Stage Small Cell Lung Cancer in The Netherlands.

AIMS: Treatment guidelines for limited stage small cell lung cancer (LS-SCLC) favour early concurrent chemoradiotherapy (CRT). Little is known about contemporary, real-world treatment patterns and outcome. We evaluated population-based practice patterns of CRT and corresponding survival in the Netherlands, focusing on the impact of the 2011 national guidelines recommending use of twice-daily (BID) radiotherapy, and treatment outcomes in elderly patients. MATERIALS AND METHODS: Data for 1635 patients with LS-SCLC treated with CRT from 2010 to 2014 were retrieved from the Netherlands Cancer Registry. The type of CRT was designated as either concurrent BID, concurrent once-daily (OD), concurrent atypical or sequential. Overall survival was the primary end point and prognostic factors were evaluated with multivariable Cox regression and represented by hazard ratios and 95% confidence intervals. RESULTS: The most common form of CRT used was sequential (41%). The proportion of patients treated BID increased from 13% in 2010-2011 to 36% in 2013-2014 (P < 0.001). The median survival was 21 months and did not improve with time (P = 0.58). Five year survival was 16% for sequential, 31% for BID (hazard ratio = 0.67, confidence interval 0.57-0.79) and 28% for OD (hazard ratio = 0.73, confidence interval 0.63-0.85). In patients aged 70 years and older, concurrent CRT was less often used than in younger patients (45% versus 66%) and 5 year survival after concurrent CRT was less favourable; 18% versus 32%, respectively. CONCLUSIONS: Outcome data at the population level for LS-SCLC are equivalent to those reported in clinical trials. The increased use of BID schemes since 2011 did not improve survival.

Incidence of High-Risk Radiologic Features in Patients Without Local Recurrence After Stereotactic Ablative Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer.

PURPOSE: To investigate, in the setting of stereotactic ablative radiation therapy (SABR) for early-stage non-small cell lung cancer, the incidence and patterns of change in high-risk radiologic features (HRFs) in patients known to have no local recurrence. METHODS AND MATERIALS: Computed tomography (CT) scans of patients treated using volumetric modulated arc therapy SABR between 2008 and 2013 were eligible if follow-up scans were available for 2 years and no local recurrences were diagnosed. All scans were reviewed at a workstation using an add-on tool for ClearCanvas (Synaptive Medical). Five clinicians who were blinded to clinical outcomes scored the presence of HRFs: enlarging opacity (EO), sequential enlarging opacity, enlarging opacity after 12 months (EO12), bulging margin, loss of linear margins, cranio-caudal growth, and loss of air bronchogram. After each review, clinicians recommended follow-up procedures based on published recommendations. RESULTS: A total of 88 patients (747 CT scans) were evaluated. The HRFs most frequently recorded by ≥3 observers on at least 1 follow-up scan were EO (64.8%), EO12 (50.0%), and sequential enlarging opacity (13.6%). Fifty-six patients developed EO within the first year after SABR, and of these, 46 also developed subsequent EO (EO12). In 76 patients who developed EO after 1 year of follow-up, 30 had not manifested EO previously. Three or more HRFs have been associated with recurrences, and this was observed on CT scan in 22.7% of patients. In their routine care, 6 patients had undergone a positron emission tomography scan because of a suspected local recurrence, and 4 underwent an attempt at biopsy. CONCLUSIONS: More than 50% of patients without a local recurrence after SABR develop HRFs. Because ≥3 HRFs were present in nearly 25% of patients, further refinement of follow-up recommendations are necessary.

Identifying barriers to accrual in radiation oncology randomized trials.

BACKGROUND: Data about factors driving accrual to radiation oncology trials are limited. In oncology, 30%-40% of trials are considered unsuccessful, many because of poor accrual. The goal of the present study was to inform the design of future trials by evaluating the effects of institutional, clinician, and patient factors on accrual rates to a randomized radiation oncology trial. METHODS: Investigators participating in sabr-comet (NCT01446744), a randomized phase ii trial open in Canada, Europe, and Australia that is evaluating the role of stereotactic ablative radiotherapy (sabr) in oligometastatic disease, were invited to complete a survey about factors affecting accrual. Institutional ethics approval was obtained. The primary endpoint was the annual accrual rate per institution. Univariable and multivariable linear regression analyses were used to identify factors predictive of annual accrual rates. RESULTS: On univariable linear regression analysis, off-trial availability of sabr (p = 0.014) and equipoise of the referring physician (p = 0.014) were found to be predictive of annual accrual rates. The annual accrual rates were lower when centres offered sabr for oligometastases off-trial (median: 3.7 patients vs. 8.4 patients enrolled) and when referring physicians felt that, compared with having equipoise, sabr was beneficial (median: 4.8 patients vs. 8.4 patients enrolled). Multivariable analysis identified perceived level of equipoise of the referring physician to be predictive of the annual accrual rate (p = 0.023). CONCLUSIONS: The level of equipoise of referring physicians might play a key role in accrual to radiation oncology randomized controlled trials. Efforts to communicate with and educate referring physicians might therefore be beneficial for improving trial accrual rates.

Fast and robust online adaptive planning in stereotactic MR-guided adaptive radiation therapy (SMART) for pancreatic cancer.

BACKGROUND AND PURPOSE: To implement a robust and fast stereotactic MR-guided adaptive radiation therapy (SMART) online strategy in locally advanced pancreatic cancer (LAPC). MATERIAL AND METHODS: SMART strategy for plan adaptation was implemented with the MRIdian system (ViewRay Inc.). At each fraction, OAR (re-)contouring is done within a distance of 3cm from the PTV surface. Online plan re-optimization is based on robust prediction of OAR dose and optimization objectives, obtained by building an artificial neural network (ANN). Proposed limited re-contouring strategy for plan adaptation (SMART3CM) is evaluated by comparing 50 previously delivered fractions against a standard (re-)planning method using full-scale OAR (re-)contouring (FULLOAR). Plan quality was assessed using PTV coverage (V95%, Dmean, D1cc) and institutional OAR constraints (e.g. V33Gy). RESULTS: SMART3CM required a significant lower number of optimizations than FULLOAR (4 vs 18 on average) to generate a plan meeting all objectives and institutional OAR constraints. PTV coverage with both strategies was identical (mean V95%=89%). Adaptive plans with SMART3CM exhibited significant lower intermediate and high doses to all OARs than FULLOAR, which also failed in 36% of the cases to adhere to the V33Gy dose constraint. CONCLUSIONS: SMART3CM approach for LAPC allows good OAR sparing and adequate target coverage while requiring only limited online (re-)contouring from clinicians.