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IntroductionThe majority of stage III patients with non-small cell lung cancer (NSCLC) are unsuitable for concurrent chemoradiotherapy, the non-surgical gold standard of care. As the alternative treatment options of sequential chemoradiotherapy and radiotherapy alone are associated with high local failure rates, various intensification strategies have been employed. There is evidence to suggest that altered fractionation using hyperfractionation, acceleration, dose escalation, and individualisation may be of benefit. The MAASTRO group have pioneered the concept of ‘isotoxic’ radiotherapy allowing for individualised dose escalation using hyperfractionated accelerated radiotherapy based on predefined normal tissue constraints. This study aims to evaluate whether delivering isotoxic radiotherapy using intensity modulated radiotherapy (IMRT) is achievable.Methods and analysisIsotoxic IMRT is a multicentre feasibility study. From June 2014, a total of 35 patients from 7 UK centres, with a proven histological or cytological diagnosis of inoperable NSCLC, unsuitable for concurrent chemoradiotherapy will be recruited. A minimum of 2 cycles of induction chemotherapy is mandated before starting isotoxic radiotherapy. The dose of radiation will be increased until one or more of the organs at risk tolerance or the maximum dose of 79.2 Gy is reached. The primary end point is feasibility, with accrual rates, local control and overall survival our secondary end points. Patients will be followed up for 5 years.Ethics and disseminationThe study has received ethical approval (REC reference: 13/NW/0480) from the National Research Ethics Service (NRES) Committee North West—Greater Manchester South. The trial is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP). The trial results will be published in a peer-reviewed journal and presented internationally.Trial registration numberNCT01836692; Pre-results.

Serial FDG-PET images during CRT show significant increases in SUVpeak for patients in whom RE develops. The changes at week 2 may predict those at risk for the development of grade 3 RE and may be informative for adaptive planning and early intervention.

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

We congratulate Davies et al 1 on the retrospective analysis of 400 patients treated with neoadjuvant chemotherapy followed by surgery at two high-volume London centers over the course of a decade. Rather than examining the prognostic effect of tumor regression, the authors focused on the downstaging effect of neoadjuvant chemotherapy as a predictor of recurrence-free and overall survival. Following adjustment for known clinicopathologic variables, tumor downstaging was associated with a reduction in the risk of recurrence and death, suggesting that major clinical decisions should be based on postchemotherapy staging.As mentioned by the authors, advanced diagnostic staging procedures, such as positron emission tomography-computed tomography (PET-CT), are important for detecting nodal disease and distant metastases. To classify a tumor as downstaged, it is essential to not only accurately define the pathologic stage following surgical resection but also to define the clinical stage before chemotherapy. Although much work has been carried out to standardize the reporting of pathologic stage, the use of clinical staging methodologies has varied over time and between centers. 2,3 Staging that uses PET-CT can detect occult metastatic disease in up to 13% of patients, and in one study, it led to a change in treatment intent in 38% of the patients. 4,5 Considering that the patient cohort in this study was compiled between 2000 and 2010, earlier patients were most likely staged with CT and possibly endoscopic ultrasound, and the authors comment that PET-CT was introduced only "latterly." The authors did not provide a clear breakdown of the proportion of patients staged with PET-CT,asrecommendedbycurrentguidelines. [6][7][8] Whateffectcouldthis have had on the study results? Without clinical staging that incorporates PET-CT,itislikelythatupto13%ofpatientshadoccultmetastaticdisease and so were incurable by surgical resection at presentation. The T3/T4 node-positive patients were used as the reference group in the Kaplan-Meier graphs, and their 3-year survival was unexpectedly low, at approximately 20%, suggesting understaging. In a comparable group of patients with poor prognosis who were clinically staged by using PET-CT and who showed no evidence of a metabolic response to therapy on a repeat PET-CT scan carried out 14 days later, the 3-year survival rate was 35%. 9 The T3/T4 node-positive patients who were not downstaged represented 35% of the patients in the study and the majority of the 56% of patients in the reference group who were used in the multivariable analysis and who were not downstaged. This would lead to an overestimate of the benefit of tumor downstaging because the reference group could contain a subset of patients with resistant metastatic disease. In addition, the R1 resection rate for all patients receiving chemotherapy was 44.8%, markedly above the rate of 31.1% reported in the recent United Kingdom's National Oesophago-GastricCancerAudit,whichemphasizestheimprovementin surgical outcomes over the last...