Long-Term Results from the IDEAL-CRT Phase 1/2 Trial of Isotoxically Dose-Escalated Radiation Therapy and Concurrent Chemotherapy for Stage II/III Non-small Cell Lung Cancer.

PURPOSE: The IDEAL-CRT phase 1/2 multicenter trial of isotoxically dose-escalated concurrent chemoradiation for stage II/III non-small cell lung cancer investigated two 30-fraction schedules of 5 and 6 weeks' duration. We report toxicity, tumor response, progression-free survival (PFS), and overall survival (OS) for both schedules, with long-term follow-up for the 6-week schedule. METHODS AND MATERIALS: Patients received isotoxically individualized tumor radiation doses of 63 to 71 Gy in 5 weeks or 63 to 73 Gy in 6 weeks, delivered concurrently with 2 cycles of cisplatin and vinorelbine. Eligibility criteria were the same for both schedules. RESULTS: One-hundred twenty patients (6% stage IIB, 68% IIIA, 26% IIIB, 1% IV) were recruited from 9 UK centers, 118 starting treatment. Median prescribed doses were 64.5 and 67.6 Gy for the 36 and 82 patients treated using the 5- and 6-week schedules. Grade ≥3 pneumonitis and early esophagitis rates were 3.4% and 5.9% overall and similar for each schedule individually. Late grade 2 esophageal toxicity occurred in 11.1% and 17.1% of 5- and 6-week patients. Grade ≥4 adverse events occurred in 17 (20.7%) 6-week patients but no 5-week patients. Four adverse events were grade 5, with 2 considered radiation therapy related. After median follow-up of 51.8 and 26.4 months for the 6- and 5-week schedules, median OS was 41.2 and 22.1 months, respectively, and median PFS was 21.1 and 8.0 months. In exploratory analyses, OS was significantly associated with schedule (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.32-0.98; P = .04) and fractional clinical/internal target volume receiving ≥95% of the prescribed dose (HR, 0.88; 95% CI, 0.77-1.00; P = .05). PFS was also significantly associated with schedule (HR, 0.53; 95% CI, 0.33-0.86; P = .01). CONCLUSIONS: Toxicity in IDEAL-CRT was acceptable. Survival was promising for 6-week patients and significantly longer than for 5-week patients. Survival might be further lengthened by following the 6-week schedule with an immune agent, motivating further study of such combined optimized treatments.

Magnetic Resonance Imaging (MRI) of Intratumoral Voxel Heterogeneity as a Potential Response Biomarker: Assessment in a HER2+ Esophageal Adenocarcinoma Xenograft Following Trastuzumab and/or Cisplatin Therapy.

We evaluated magnetic resonance imaging (MRI) voxel heterogeneity following trastuzumab and/or cisplatin in a HER2+ esophageal xenograft (OE19) as a potential response biomarker. OE19 xenografts treated with saline (controls), monotherapy, or combined cisplatin and trastuzumab underwent 9.4-T MRI. Tumor MRI parametric maps of T1 relaxation time (pre/post contrast), T2 relaxation time, T2* relaxation rate (R2*), and apparent diffusion coefficient obtained before (TIME0), after 24hours (TIME1), and after 2weeks of treatment (TIME2) were analyzed. Voxel histogram and fractal parameters (from the whole tumor, rim and center, and as a ratio of rim-to-center) were derived. Tumors were stained for immunohistochemical markers of hypoxia (CA-IX), angiogenesis (CD34), and proliferation (Ki-67). Combination therapy reduced xenograft growth rate (relative change, ∆ +0.58±0.43 versus controls, ∆ +4.1±1.0; P=0.008). More spatially homogeneous voxel distribution between the rim to center was noted after treatment for combination therapy versus controls, respectively, for contrast-enhanced T1 relaxation time (90th percentile: ratio 1.00 versus 0.88, P=0.009), T2 relaxation time (mean: 1.00 versus 0.92, P=0.006; median: 0.98 versus 0.91, P=0.006; 75th percentile: 1.02 versus 0.94, P=0.007), and R2* (10th percentile: 0.99 versus 1.26, P=0.003). We found that combination and trastuzumab monotherapy reduced MRI spatial heterogeneity and growth rate compared to the control or cisplatin groups, the former providing adjunctive tumor response information.

IDEAL-CRT: A Phase 1/2 Trial of Isotoxic Dose-Escalated Radiation Therapy and Concurrent Chemotherapy in Patients With Stage II/III Non-Small Cell Lung Cancer.

PURPOSE: To report toxicity and early survival data for IDEAL-CRT, a trial of dose-escalated concurrent chemoradiotherapy (CRT) for non-small cell lung cancer. PATIENTS AND METHODS: Patients received tumor doses of 63 to 73 Gy in 30 once-daily fractions over 6 weeks with 2 concurrent cycles of cisplatin and vinorelbine. They were assigned to 1 of 2 groups according to esophageal dose. In group 1, tumor doses were determined by an experimental constraint on maximum esophageal dose, which was escalated following a 6 + 6 design from 65 Gy through 68 Gy to 71 Gy, allowing an esophageal maximum tolerated dose to be determined from early and late toxicities. Tumor doses for group 2 patients were determined by other tissue constraints, often lung. Overall survival, progression-free survival, tumor response, and toxicity were evaluated for both groups combined. RESULTS: Eight centers recruited 84 patients: 13, 12, and 10, respectively, in the 65-Gy, 68-Gy, and 71-Gy cohorts of group 1; and 49 in group 2. The mean prescribed tumor dose was 67.7 Gy. Five grade 3 esophagitis and 3 grade 3 pneumonitis events were observed across both groups. After 1 fatal esophageal perforation in the 71-Gy cohort, 68 Gy was declared the esophageal maximum tolerated dose. With a median follow-up of 35 months, median overall survival was 36.9 months, and overall survival and progression-free survival were 87.8% and 72.0%, respectively, at 1 year and 68.0% and 48.5% at 2 years. CONCLUSIONS: IDEAL-CRT achieved significant treatment intensification with acceptable toxicity and promising survival. The isotoxic design allowed the esophageal maximum tolerated dose to be identified from relatively few patients.

Imaging Tumor Response and Tumoral Heterogeneity in Non-Small Cell Lung Cancer Treated With Antiangiogenic Therapy: Comparison of the Prognostic Ability of RECIST 1.1, an Alternate Method (Crabb), and Image Heterogeneity Analysis.

PURPOSE: We aimed to assess computed tomography (CT) intratumoral heterogeneity changes, and compared the prognostic ability of the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, an alternate response method (Crabb), and CT heterogeneity in non-small cell lung cancer treated with chemotherapy with and without bevacizumab. MATERIALS AND METHODS: Forty patients treated with chemotherapy (group C) or chemotherapy and bevacizumab (group BC) underwent contrast-enhanced CT at baseline and after 1, 3, and 6 cycles of chemotherapy. Radiologic response was assessed using RECIST 1.1 and an alternate method. CT heterogeneity analysis generating global and locoregional parameters depicting tumor image spatial intensity characteristics was performed. Heterogeneity parameters between the 2 groups were compared using the Mann-Whitney U test. Associations between heterogeneity parameters and radiologic response with overall survival were assessed using Cox regression. RESULTS: Global and locoregional heterogeneity parameters changed with treatment, with increased tumor heterogeneity in group BC. Entropy [group C: median -0.2% (interquartile range -2.2, 1.7) vs. group BC: 0.7% (-0.7, 3.5), P=0.10] and busyness [-27.7% (-62.2, -5.0) vs. -11.5% (-29.1, 92.4), P=0.10] showed a greater reduction in group C, whereas uniformity [1.9% (-8.0, 9.8) vs. -5.0% (-13.9, 5.6), P=0.10] showed a relative increase after 1 cycle but did not reach statistical significance. Two (9%) and 1 (6%) additional responders were identified using the alternate method compared with RECIST in group C and group BC, respectively. Heterogeneity parameters were not significant prognostic factors. CONCLUSIONS: The alternate response method described by Crabb identified more responders compared with RECIST. However, both criteria and baseline imaging heterogeneity parameters were not prognostic of survival.

Molecular imaging of hypoxia in non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) is the commonest cancer worldwide but survival remains poor with a high risk of relapse, particularly after nonsurgical treatment. Hypoxia is present in a variety of solid tumours, including NSCLC. It is associated with treatment resistance and a poor prognosis, although when recognised may be amenable to different treatment strategies. Thus, noninvasive assessment of intratumoral hypoxia could be used to stratify patients for modification of subsequent treatment to improve tumour control. Molecular imaging approaches targeting hypoxic cells have shown some early success in the clinical setting. This review evaluates the evidence for hypoxia imaging using PET in NSCLC and explores its potential clinical utility.

Interstitial diffusion and the relationship between compartment modelling and multi-scale spatial-temporal modelling of (18)F-FLT tumour uptake dynamics.

Tumour cell proliferation can be imaged via positron emission tomography of the radiotracer 3'-deoxy-3'-18F-fluorothymidine (18F-FLT). Conceptually, the number of proliferating cells might be expected to correlate more closely with the kinetics of 18F-FLT uptake than with uptake at a fixed time. Radiotracer uptake kinetics are standardly visualized using parametric maps of compartment model fits to time-activity-curves (TACs) of individual voxels. However the relationship between the underlying spatiotemporal accumulation of FLT and the kinetics described by compartment models has not yet been explored. In this work tumour tracer uptake is simulated using a mechanistic spatial-temporal model based on a convection-diffusion-reaction equation solved via the finite difference method. The model describes a chain of processes: the flow of FLT between the spatially heterogeneous tumour vasculature and interstitium; diffusion and convection of FLT within the interstitium; transport of FLT into cells; and intracellular phosphorylation. Using values of model parameters estimated from the biological literature, simulated FLT TACs are generated with shapes and magnitudes similar to those seen clinically. Results show that the kinetics of the spatial-temporal model can be recovered accurately by fitting a 3-tissue compartment model to FLT TACs simulated for those tumours or tumour sub-volumes that can be viewed as approximately closed, for which tracer diffusion throughout the interstitium makes only a small fractional change to the quantity of FLT they contain. For a single PET voxel of width 2.5-5 mm we show that this condition is roughly equivalent to requiring that the relative difference in tracer uptake between the voxel and its neighbours is much less than one.

18F-FLT uptake kinetics in head and neck squamous cell carcinoma: a PET imaging study.

PURPOSE: To analyze the kinetics of 3(')-deoxy-3(')-[F-18]-fluorothymidine (18F-FLT) uptake by head and neck squamous cell carcinomas and involved nodes imaged using positron emission tomography (PET). METHODS: Two- and three-tissue compartment models were fitted to 12 tumor time-activity-curves (TACs) obtained for 6 structures (tumors or involved nodes) imaged in ten dynamic PET studies of 1 h duration, carried out for five patients. The ability of the models to describe the data was assessed using a runs test, the Akaike information criterion (AIC) and leave-one-out cross-validation. To generate parametric maps the models were also fitted to TACs of individual voxels. Correlations between maps of different parameters were characterized using Pearson'sr coefficient; in particular the phosphorylation rate-constants k3-2tiss and k5 of the two- and three-tissue models were studied alongside the flux parameters KFLT- 2tiss and KFLT of these models, and standardized uptake values (SUV). A methodology based on expectation-maximization clustering and the Bayesian information criterion ("EM-BIC clustering") was used to distil the information from noisy parametric images. RESULTS: Fits of two-tissue models 2C3K and 2C4K and three-tissue models 3C5K and 3C6K comprising three, four, five, and six rate-constants, respectively, pass the runs test for 4, 8, 10, and 11 of 12 tumor TACs. The three-tissue models have lower AIC and cross-validation scores for nine of the 12 tumors. Overall the 3C6K model has the lowest AIC and cross-validation scores and its fitted parameter values are of the same orders of magnitude as literature estimates. Maps of KFLT and KFLT- 2tiss are strongly correlated (r = 0.85) and also correlate closely with SUV maps (r = 0.72 for KFLT- 2tiss, 0.64 for KFLT). Phosphorylation rate-constant maps are moderately correlated with flux maps (r = 0.48 for k3-2tiss vs KFLT- 2tiss and r = 0.68 for k5 vs KFLT); however, neither phosphorylation rate-constant correlates significantly with SUV. EM-BIC clustering reduces the parametric maps to a small number of levels--on average 5.8, 3.5, 3.4, and 1.4 for KFLT- 2tiss, KFLT, k3-2tiss, and k5. This large simplification is potentially useful for radiotherapy dose-painting, but demonstrates the high noise in some maps. Statistical simulations show that voxel level noise degrades TACs generated from the 3C6K model sufficiently that the average AIC score, parameter bias, and total uncertainty of 2C4K model fits are similar to those of 3C6K fits, whereas at the whole tumor level the scores are lower for 3C6K fits. CONCLUSIONS: For the patients studied here, whole tumor FLT uptake time-courses are represented better overall by a three-tissue than by a two-tissue model. EM-BIC clustering simplifies noisy parametric maps, providing the best description of the underlying information they contain and is potentially useful for radiotherapy dose-painting. However, the clustering highlights the large degree of noise present in maps of the phosphorylation rate-constantsk5 and k3-2tiss, which are conceptually tightly linked to cellular proliferation. Methods must be found to make these maps more robust-either by constraining other model parameters or modifying dynamic imaging protocols.

Optimizing collimator margins for isotoxically dose-escalated conformal radiation therapy of non-small cell lung cancer.

PURPOSE: Isotoxic dose escalation schedules such as IDEAL-CRT [isotoxic dose escalation and acceleration in lung cancer chemoradiation therapy] (ISRCTN12155469) individualize doses prescribed to lung tumors, generating a fixed modeled risk of radiation pneumonitis. Because the beam penumbra is broadened in lung, the choice of collimator margin is an important element of the optimization of isotoxic conformal radiation therapy for lung cancer. METHODS AND MATERIALS: Twelve patients with stage I-III non-small cell lung cancer (NSCLC) were replanned retrospectively using a range of collimator margins. For each plan, the prescribed dose was calculated according to the IDEAL-CRT isotoxic prescription method, and the absolute dose (D99) delivered to 99% of the planning target volume (PTV) was determined. RESULTS: Reducing the multileaf collimator margin from the widely used 7 mm to a value of 2 mm produced gains of 2.1 to 15.6 Gy in absolute PTV D99, with a mean gain ± 1 standard error of the mean of 6.2 ± 1.1 Gy (2-sided P<.001). CONCLUSIONS: For NSCLC patients treated with conformal radiation therapy and an isotoxic dose prescription, absolute doses in the PTV may be increased by using smaller collimator margins, reductions in relative coverage being offset by increases in prescribed dose.

Assessment of sarcopenia and changes in body composition after neoadjuvant chemotherapy and associations with clinical outcomes in oesophageal cancer.

OBJECTIVES: Sarcopenia and changes in body composition following neoadjuvant chemotherapy (NAC) may affect clinical outcome. We assessed the associations between CT body composition changes following NAC and outcomes in oesophageal cancer. METHODS: A total of 35 patients who received NAC followed by oesophagectomy, and underwent CT assessment pre- and post-NAC were included. Fat mass (FM), fat-free mass (FFM), subcutaneous fat to muscle ratio (FMR) and visceral to subcutaneous adipose tissue ratio (VA/SA) were derived from CT. Changes in FM, FFM, FMR, VA/SA and sarcopenia were correlated to chemotherapy dose reductions, postoperative complications, length of hospital stay (LOS), circumferential resection margin (CRM), pathological chemotherapy response, disease-free survival (DFS) and overall survival (OS). RESULTS: Nine (26 %) patients were sarcopenic before NAC and this increased to 15 (43 %) after NAC. Average weight loss was 3.7 % ± 6.4 (SD) in comparison to FM index (-1.2 ± 4.2), FFM index (-4.6 ± 6.8), FMR (-1.2 ± 24.3) and VA/SA (-62.3 ± 12.7). Changes in FM index (p = 0.022), FMR (p = 0.028), VA/SA (p = 0.024) and weight (p = 0.007) were significant univariable factors for CRM status. There was no significant association between changes in body composition and survival. CONCLUSIONS: Loss of FM, differential loss of VA/SA and skeletal muscle were associated with risk of CRM positivity. KEY POINTS: • Changes in CT body composition occur after neoadjuvant chemotherapy in oesophageal cancer. • Sarcopenia was more prevalent after neoadjuvant chemotherapy. • Fat mass, fat-free mass and weight decreased after neoadjuvant chemotherapy. • Changes in body composition were associated with CRM positivity. • Changes in body composition did not affect perioperative complications and survival.

Influence of dose calculation algorithms on isotoxic dose-escalation of non-small cell lung cancer radiotherapy.

BACKGROUND AND PURPOSE: A series of phase I/II clinical trials are being initiated in several UK centres to explore the use of dose-escalated schedules for the treatment of non-small cell lung cancer (NSCLC). Among them the IDEAL-CRT trial (ISRCTN12155469) will investigate the introduction of individualised "isotoxic" treatment schedules based on the relative mean lung normalised total dose (rNTD(mean)), an estimator related to lung toxicity. Since treatment planning will be performed using different treatment planning systems (TPSs), for the quality assurance of the trial we have carried out work to quantify the influence of dose calculation algorithms based on the determination of rNTD(mean) and on the choice of individualised prescription doses. MATERIAL AND METHODS: Twenty-five patient plans with stage I, II and III NSCLC were calculated, with the same prescription dose, using the Adaptive Convolve (AC) and Collapsed Cone (CC) algorithms of the Pinnacle TPS, the pencil beam convolution (PBC) and AAA algorithms of Eclipse, and the CC and pencil beam (PB) algorithms of Oncentra Masterplan (OMP). For the paired-lungs-GTV structure, dose-volume histograms were obtained and used to calculate the corresponding rNTD(mean) values and results obtained with the different algorithms were compared. RESULTS: For most (19 out of 25) of the patients studied, no algorithm-to-algorithm differences were seen in dose prescription based on rNTD(mean). For the other 6 patients differences were within 2.3 Gy, except in one case where the difference was 4 Gy. CONCLUSIONS: For the IDEAL-CRT trial no corrections need to be applied to the value of rNTD(mean) calculated using any of the more advanced convolution/superposition algorithms studied in this work. For the two pencil beam algorithms analysed, no correction is necessary for the data obtained with the Eclipse-PBC, while for OMP-PB data a small correction needs to be applied, by using a scaling factor, to make prescription doses consistent with the other algorithms investigated.

A continuous 4D motion model from multiple respiratory cycles for use in lung radiotherapy.

Respiratory motion causes errors when planning and delivering radiotherapy treatment to lung cancer patients. To reduce these errors, methods of acquiring and using four-dimensional computed tomography (4DCT) datasets have been developed. We have developed a novel method of constructing computational motion models from 4DCT. The motion models attempt to describe an average respiratory cycle, which reduces the effects of variation between different cycles. They require substantially less memory than a 4DCT dataset, are continuous in space and time, and facilitate automatic target propagation and combining of doses over the respiratory cycle. The motion models are constructed from CT data acquired in cine mode while the patient is free breathing (free breathing CT - FBCT). A "slab" of data is acquired at each couch position, with 3-4 contiguous slabs being acquired per patient. For each slab a sequence of 20 or 30 volumes was acquired over 20 seconds. A respiratory signal is simultaneously recorded in order to calculate the position in the respiratory cycle for each FBCT. Additionally, a high quality reference CT volume is acquired at breath hold. The reference volume is nonrigidly registered to each of the FBCT volumes. A motion model is then constructed for each slab by temporally fitting the nonrigid registration results. The value of each of the registration parameters is related to the position in the respiratory cycle by fitting an approximating B spline to the registration results. As an approximating function is used, and the data is acquired over several respiratory cycles, the function should model an average respiratory cycle. This can then be used to calculate the value of each degree of freedom at any desired position in the respiratory cycle. The resulting nonrigid transformation will deform the reference volume to predict the contents of the slab at the desired position in the respiratory cycle. The slab model predictions are then concatenated to produce a combined prediction over the entire region of interest. We have performed a number of experiments to assess the accuracy of the nonrigid registration results and the motion model predictions. The individual slab models were evaluated by expert visual assessment and the tracking of easily identifiable anatomical points. The combined models were evaluated by calculating the discontinuities between the transformations at the slab boundaries. The experiments were performed on five patients with a total of 18 slabs between them. For the point tracking experiments, the mean distance between where a clinician manually identified a point and where the registration results located the point, the target registration error (TRE), was 1.3 mm. The mean distance between a manually identified point and the models prediction of the point's location, the target model error (TME), was 1.6 mm. The mean discontinuity between model predictions at the slab boundaries, the Continuity Error, was 2.2 mm. The results show that the motion models perform with a level of accuracy comparable to the slice thickness of 1.5 mm.