Jason R. Pantarotto

Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): An open-label, phase 3, randomised, superiority trial

Summary Background Concurrent chemoradiotherapy is the standard of care in limited-stage small-cell lung cancer, but the optimal radiotherapy schedule and dose remains controversial. The aim of this study was to establish a standard chemoradiotherapy treatment regimen in limited-stage small-cell lung cancer. Methods The CONVERT trial was an open-label, phase 3, randomised superiority trial. We enrolled adult patients (aged ≥18 years) who had cytologically or histologically confirmed limited-stage small-cell lung cancer, Eastern Cooperative Oncology Group performance status of 0–2, and adequate pulmonary function. Patients were recruited from 73 centres in eight countries. Patients were randomly assigned to receive either 45 Gy radiotherapy in 30 twice-daily fractions of 1·5 Gy over 19 days, or 66 Gy in 33 once-daily fractions of 2 Gy over 45 days, starting on day 22 after commencing cisplatin–etoposide chemotherapy (given as four to six cycles every 3 weeks in both groups). The allocation method used was minimisation with a random element, stratified by institution, planned number of chemotherapy cycles, and performance status. Treatment group assignments were not masked. The primary endpoint was overall survival, defined as time from randomisation until death from any cause, analysed by modified intention-to-treat. A 12% higher overall survival at 2 years in the once-daily group versus the twice-daily group was considered to be clinically significant to show superiority of the once-daily regimen. The study is registered with ClinicalTrials.gov (NCT00433563) and is currently in follow-up. Findings Between April 7, 2008, and Nov 29, 2013, 547 patients were enrolled and randomly assigned to receive twice-daily concurrent chemoradiotherapy (274 patients) or once-daily concurrent chemoradiotherapy (273 patients). Four patients (one in the twice-daily group and three in the once-daily group) did not return their case report forms and were lost to follow-up; these patients were not included in our analyses. At a median follow-up of 45 months (IQR 35–58), median overall survival was 30 months (95% CI 24–34) in the twice-daily group versus 25 months (21–31) in the once-daily group (hazard ratio for death in the once daily group 1·18 [95% CI 0·95–1·45]; p=0·14). 2-year overall survival was 56% (95% CI 50–62) in the twice-daily group and 51% (45–57) in the once-daily group (absolute difference between the treatment groups 5·3% [95% CI −3·2% to 13·7%]). The most common grade 3–4 adverse event in patients evaluated for chemotherapy toxicity was neutropenia (197 [74%] of 266 patients in the twice-daily group vs 170 [65%] of 263 in the once-daily group). Most toxicities were similar between the groups, except there was significantly more grade 4 neutropenia with twice-daily radiotherapy (129 [49%] vs 101 [38%]; p=0·05). In patients assessed for radiotherapy toxicity, was no difference in grade 3–4 oesophagitis between the groups (47 [19%] of 254 patients in the twice-daily group vs 47 [19%] of 246 in the once-daily group; p=0·85) and grade 3–4 radiation pneumonitis (4 [3%] of 254 vs 4 [2%] of 246; p=0·70). 11 patients died from treatment-related causes (three in the twice-daily group and eight in the once-daily group). Interpretation Survival outcomes did not differ between twice-daily and once-daily concurrent chemoradiotherapy in patients with limited-stage small-cell lung cancer, and toxicity was similar and lower than expected with both regimens. Since the trial was designed to show superiority of once-daily radiotherapy and was not powered to show equivalence, the implication is that twice-daily radiotherapy should continue to be considered the standard of care in this setting. Funding Cancer Research UK (Clinical Trials Awards and Advisory Committee), French Ministry of Health, Canadian Cancer Society Research Institute, European Organisation for Research and Treatment of Cancer (Cancer Research Fund, Lung Cancer, and Radiation Oncology Groups).

Upper abdominal normal organ contouring guidelines and atlas: A Radiation Therapy Oncology Group consensus

PURPOSE To standardize upper abdominal normal organ contouring guidelines for Radiation Therapy Oncology Group (RTOG) trials. METHODS AND MATERIALS Twelve expert radiation oncologists contoured the liver, esophagus, gastroesophageal junction (GEJ), stomach, duodenum, and common bile duct (CBD), and reviewed and edited 33 additional normal organ and blood vessel contours on an anonymized patient computed tomography (CT) dataset. Contours were overlaid and compared for agreement using MATLAB (MathWorks, Natick, MA). S95 contours, defined as the binomial distribution to generate 95% group consensus contours, and normal organ contouring definitions were generated and reviewed by the panel. RESULTS There was excellent consistency and agreement of the liver, duodenal, and stomach contours, with substantial consistency for the esophagus contour, and moderate consistency for the GEJ and CBD contours using a Kappa statistic. Consensus definitions, detailed normal organ contouring recommendations and high-resolution images were developed. CONCLUSIONS Consensus contouring guidelines and a CT image atlas should improve contouring uniformity in radiation oncology clinical planning and RTOG trials.

Pretreatment [18F]-fluoro-2-deoxy-glucose Positron Emission Tomography Maximum Standardized Uptake Value as Predictor of Distant Metastasis in Early-Stage Non-Small Cell Lung Cancer Treated With Definitive Radiation Therapy: Rethinking the Role of Positron Emission Tomography in Personalizing Treatment Based on Risk Status

PURPOSE The aim of this study was to determine whether the preradiation maximum standardized uptake value (SUVmax) of the primary tumor for [(18)F]-fluoro-2-deoxy-glucose positron emission tomography (FDG-PET) has a prognostic significance in patients with Stage T1 or T2N0 non-small cell lung cancer (NSCLC) treated with curative radiation therapy, whether conventional or stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS Between January 2007 and December 2011, a total of 163 patients (180 tumors) with medically inoperable histologically proven Stage T1 or T2N0 NSCLC and treated with radiation therapy (both conventional and SBRT) were entered in a research ethics board approved database. All patients received pretreatment FDG-PET / computed tomography (CT) at 1 institution with consistent acquisition technique. The medical records and radiologic images of these patients were analyzed. RESULTS The overall survival at 2 years and 3 years for the whole group was 76% and 67%, respectively. The mean and median SUVmax were 8.1 and 7, respectively. Progression-free survival at 2 years with SUVmax <7 was better than that of the patients with tumor SUVmax ≥7 (67% vs 51%; P=.0096). Tumors with SUVmax ≥7 were associated with a worse regional recurrence-free survival and distant metastasis-free survival. In the multivariate analysis, SUVmax ≥7 was an independent prognostic factor for distant metastasis-free survival. CONCLUSION In early-stage NSCLC managed with radiation alone, patients with SUVmax ≥7 on FDG-PET / CT scan have poorer outcomes and high risk of progression, possibly because of aggressive biology. There is a potential role for adjuvant therapies for these high-risk patients with intent to improve outcomes.

Treatment of metastatic liver tumors using stereotactic ablative radiotherapy

The prognosis of patients with metastatic liver disease remains dismal with a median survival of only 6-12 mo. As 80%-90% of patients are not candidates for surgical therapy, there is a need for effective non-surgical therapies that would improve outcomes in these patients. The body of evidence related to the use of stereotactic ablative radiotherapy (SABR) in metastatic liver disease has substantially grown and evolved over the past decade. This review summarizes the current evidence supporting liver SABR with particular attention given to patient selection, target delineation, organ at risk dose volume constraints, response evaluation imaging and the various SABR techniques for delivering ablative radiotherapy to the liver. Even though it is unclear what dose-fractionation scheme, delivery system, concomitant therapy or patient selection strategy yields the optimum liver SABR outcomes, clear and growing evidence is available that SABR is a safe and effective therapy for the treatment of oligometastatic liver disease.

Impact of Patient Selection, Disease Progression, and Adverse Events on Esophageal Cancer Outcomes After Trimodality Therapy

BACKGROUND Neoadjuvant chemoradiation followed by surgery (NeoCRT) has been advocated as standard therapy for resectable esophageal cancer. Our objective was to compare oncologic outcomes between NeoCRT and upfront surgical resection (SURG). METHODS We conducted a single-institution, retrospective review of all potentially resectable esophageal cancer patients treated with NeoCRT or SURG. RESULTS From 2003 to 2010, 151 patients had NeoCRT (n = 48; 31.8%) or SURG (n = 103; 68.1%). Histology was mostly adenocarcinoma (77.5%) or squamous carcinoma (19.2%). Mean radiation dose was 44 ± 0.1 Gy, and 80.8% received platinum-based doublet chemotherapy. There were more women in the SURG group (23.3% vs 4.2%; p < 0.01) and more cardiovascular comorbidity in the NeoCRT group (39.6% vs 21.4%; p = 0.027). There was no difference in age, histology, R0 resection rate, and treatment-related mortality (NeoCRT = 4.2%; SURG = 3.9%; p = 0.15). Failure to undergo resection after NeoCRT (n = 11; 22.9%) was mainly due to disease progression (n = 6) or treatment-related mortality (n = 4). Resection could not be performed in 4 SURG patients (3.9%; p < 0.001; unresectable = 2; occult metastases = 2). NeoCRT did not improve median survival (NeoCRT = 29 ± 6; SURG = 26 ± 3 months; p = 0.376) or recurrence-free interval (NeoCRT = 25.8 ± 5; SURG = 19.4 ± 2 months; p = 0.19). Complete pathologic response (n = 8; 21.6%) was not associated with improved survival. If we exclude from analysis NeoCRT patients who did not undergo surgery, survival was significantly improved after NeoCRT (NeoCRT = 41 ± 15; SURG = 24 ± 8 months; p = 0.0082). CONCLUSIONS Patient selection and early assessment of treatment response may be key factors in identifying the best candidates for trimodality therapy.

Approach to the non-operative management of patients with stage II non-small cell lung cancer (NSCLC): A survey of Canadian medical and radiation oncologists

BACKGROUND AND OBJECTIVES Standard management of stage II non-small cell lung cancer (NSCLC) is surgery, often followed by adjuvant chemotherapy. However, some patients do not undergo surgery for various reasons. The optimal non-surgical management of stage II NSCLC is undefined. We surveyed Canadian oncologists to understand current practices. MATERIALS AND METHODS Canadian oncologists specializing in the management of lung cancer were invited by email to complete an anonymous, online survey developed by the research team. Physician demographics were recorded. Physicians were asked to comment on their practice and make treatment choices in eight clinical scenarios of inoperable stage II NSCLC. RESULTS Responses were received from 81/194 physicians (42% response rate), 57% medical and 42% radiation oncologists. Most physicians (90%) had a practice with at least 25% lung cancer patients and 85% were based at an academic institution. Across eight clinical patient scenarios, radical therapy was selected 79-98% of the time. Radical radiotherapy alone and concurrent chemoradiotherapy were the preferred options for these patients, while sequential chemoradiation was less favoured. Nodal status (N0 vs N1) did not influence choice of therapy (p 0.31), but the reason for patient inoperability did (p<0.0001). There was no significant difference in choice of therapy when comparing responses between medical vs radiation oncologists, academic vs community physicians, and physicians with high vs low proportion of lung cancer patients. CONCLUSION Most lung cancer physicians manage inoperable stage II NSCLC patients with curative intent, but consensus on how to optimally employ radiotherapy and/or chemotherapy is lacking. Future prospective, randomized trials are warranted.

Radical Treatment of Stage II Non–small-cell Lung Cancer With Nonsurgical Approaches: A Multi-institution Report of Outcomes

Introduction Standard management of stage II non–small‐cell lung cancer (NSCLC) is surgery, often followed by adjuvant chemotherapy. However, some patients do not undergo surgery for various reasons. We examined outcomes in this defined patient group. Methods We reviewed the records of patients with stage II NSCLC treated nonsurgically with curative intent from 2002 to 2012 across 3 academic cancer centers. Data collected included demographics, comorbidities, staging, treatments, and survival. The primary endpoint was overall survival (OS). We assessed factors associated with treatment choice and OS. Results A total of 158 patients were included: the median age was 74 years (range, 50‐91 years), 44% were female, and 68% had a performance status of 0 to 1. The stage II groupings of the patients were T2b‐T3 N0 in 55% and N1 in 45%. The most common reasons for inoperability were inadequate pulmonary reserve (27%) and medical comorbidities (24%). All patients received radical radiotherapy (RT) (median, 60 Gy [range, 48‐75 Gy]). Seventy‐three percent received RT alone; 24% received concurrent and 3% sequential chemoradiotherapy (CRT). In multivariate analyses, CRT was less likely in older patients (≥ 70 years) (odds ratio [OR], 0.28; 95% confidence interval [CI], 0.11‐0.70; P = .006) and in patients with higher (> 5) Charlson comorbidity scores (OR, 0.34; 95% CI, 0.13‐0.90; P = .03) or normal (< 10 × 109/L) white blood cell counts (OR, 0.26; 95% CI, 0.09‐0.73; P = .01). At the time of our analysis, 74% have died. The median OS was 22.9 months (range, 17.1‐26.6 months). Patients who had undergone CRT had a significantly longer median OS than those receiving RT alone (39.1 vs. 20.5 months; P = .0019), confirmed in multivariate analysis (hazard ratio, 0.38; 95% CI, 0.21‐0.69; P = .001). Conclusion Nonsurgical approaches to management of stage II NSCLC are varied. Treatment with CRT was associated with significantly longer survival compared with RT alone. A randomized trial may be warranted. Micro‐Abstract The optimal nonoperative management of stage II non–small‐cell lung cancer is undefined, with limited data to guide decision‐making in this setting. We reviewed treatment patterns and outcomes of 158 patients in this defined group. The majority (73%) received radical radiotherapy alone; however, those treated with combined‐modality chemoradiation had significantly longer median survival (39.1 vs. 20.5 months; P = .0019). A randomized trial is warranted.

Quantitative texture analysis on pre-treatment computed tomography predicts local recurrence in stage I non-small cell lung cancer following stereotactic radiation therapy

Background The prediction of local recurrence (LR) of stage I non-small cell lung cancer (NSCLC) after definitive stereotactic body radiotherapy (SBRT) remains elusive. The purpose of this study was to assess whether quantitative imaging features on pre-treatment computed tomography (CT) can predict LR beyond 18 (18F) fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT maximum standard uptake value (SUVmax). Methods This retrospective study evaluated 36 patients with 37 stage I NSCLC who had local tumor control (LC; n=19) and (LR; n=18). Textural features were extracted on pre-treatment CT. Mann-Whitney U tests were used to compare LC and LR groups. Receiver-operating characteristic (ROC) curves were constructed and the area under the curve (AUC) calculated with LR as outcome. Results Gray-level correlation and sum variance were greater in the LR group, compared with the LC group (P=0.02 and P=0.04, respectively). Gray-level difference variance was lower in the LR group (P=0.004). The logistic regression model generated using gray-level correlation and difference variance features resulted in AUC (SE) 0.77 (0.08) (P=0.0007). The addition of 18F-FDG PET/CT SUVmax did not improve the AUC (P=0.75). Conclusions CT textural features were found to be predictors of LR of early stage NSCLC on baseline CT prior to SBRT.

Regional process redesign of lung cancer care: a learning health system pilot project

Background The Ottawa Hospital (toh) defined delay to timely lung cancer care as a system design problem. Recognizing the patient need for an integrated journey and the need for dynamic alignment of providers, toh used a learning health system (lhs) vision to redesign regional diagnostic processes. A lhs is driven by feedback utilizing operational and clinical information to drive system optimization and innovation. An essential component of a lhs is a collaborative platform that provides connectivity across silos, organizations, and professions. Methods To operationalize a lhs, we developed the Ottawa Health Transformation Model (ohtm) as a consensus approach that addresses process barriers, resistance to change, and conflicting priorities. A regional Community of Practice (cop) was established to engage stakeholders, and a dedicated transformation team supported process improvements and implementation. Results The project operationalized the lung cancer diagnostic pathway and optimized patient flow from referral to initiation of treatment. Twelve major processes in referral, review, diagnostics, assessment, triage, and consult were redesigned. The Ottawa Hospital now provides a diagnosis to 80% of referrals within the provincial target of 28 days. The median patient journey from referral to initial treatment decreased by 48% from 92 to 47 days. Conclusions The initiative optimized regional integration from referral to initial treatment. Use of a lhs lens enabled the creation of a system that is standardized to best practice and open to ongoing innovation. Continued transformation initiatives across the continuum of care are needed to incorporate best practice and optimize delivery systems for regional populations.

Age-not Charlson Co-morbidity Index-predicts for mortality after stereotactic ablative radiotherapy for medically inoperable stage I non-small cell lung cancer

Purpose In this single institution retrospective study of patients with stage I medically inoperable non-small cell lung cancer (NSCLC) treated with stereotactic ablative radiotherapy (SABR) we attempt to model overall survival (OS) using initial prognostic variables with specific attention on the Charlson co-morbidity index (CCI). Methods Between 2008 and 2013, 335 patients with medically inoperable stage I NSCLC were treated with SABR or hypofractionated radiotherapy (50–60 Gy in at least 5 Gy or 4 Gy fractions respectively) at our institution. Medical comorbidities and Charlson scores were determined by individual chart review. Patients were stratified into 3 groups based on the CCI score (0–1, 2–3, 4–9) and again based on the age-adjusted Charlson Comorbidity score (aCCI). Cumulative survival for each stratum was determined using the Kaplan-Meier method. Non-significant and confounding variables were identified and discounted from survival modeling. 3 sex stratified Cox regression models were tested: (1) aCCI with age and comorbidity combined; (2) age and CCI; (3) age alone, comorbidity removed. Results The median survival was 4.4 years and the median follow up 4.7 years. The median CCI and aCCI scores were 2 and 5 respectively. Patients with aCCI 7–12 had an increased hazard of death on univariate analysis HR 2.45 (1.15–5.22 95%CI, p = 0.02) and -excluding age as a competing variable- on multivariate analysis HR 2.25 (1.04–4.84 95%CI, p = 0.04). Patients with CCI 4-9 had an increased hazard of death on univariate analysis HR 1.57(1.30–2.90) but not on multivariate analysis. On formalized testing – with either continuous or categorical variables- all three survival models yielded similar coefficients of effect. Conclusion We identify male gender, weight loss greater than 10% and age as independent prognostic factors for patients treated with medically inoperable NSCLC treated with SABR or hypofractionated radiotherapy. Based on our survival models, age alone can be used interchangeably with aCCI or CCI plus age with the same prognostic value. Age is more reliably recorded, less prone to error and therefore a more useful metric than Charlson score in this group of patients.