Associations between cardiac irradiation and survival in patients with non-small cell lung cancer: Validation and new discoveries in an independent dataset.

INTRODUCTION: In 'IDEAL-6' patients (N = 78) treated for locally-advanced non-small-cell lung cancer using isotoxically dose-escalated radiotherapy, overall survival (OS) was associated more strongly with VLAwall-64-73-EQD2, the left atrial (LA) wall volume receiving 64-73 Gy equivalent dose in 2 Gy fractions (EQD2), than with whole-heart irradiation measures. Here we test this in an independent cohort 'OX-RT' (N = 64) treated routinely. METHODS: Using Cox regression analysis we assessed how strongly OS was associated with VLAwall-64-73-EQD2, with whole-heart volumes receiving 64-73 Gy EQD2 or doses above 10-to-70 Gy thresholds, and with principal components of whole-heart dose-distributions. Additionally, we tested associations between OS and volumes of cardiac substructures receiving dose-ranges described by whole-heart principal components significantly associated with OS. RESULTS: In univariable analyses of OX-RT, OS was associated more strongly with VLAwall-64-73-EQD2 than with whole-heart irradiation measures, but more strongly still with VAortV-29-38-EQD2, the volume of the aortic valve region receiving 29-38 Gy EQD2. The best multivariable OS model included LA wall and aortic valve region mean doses, and the aortic valve volume receiving ≥38 Gy EQD2, VAortV-38-EQD2. In a subsidiary analysis of IDEAL-6, the best multivariable model included VLAwall-64-73-EQD2, VAortV-29-38-EQD2, VAortV-38-EQD2 and mean aortic valve dose. CONCLUSION: We propose reducing heart mean doses to the lowest levels possible while meeting protocol dose-limits for lung, oesophagus, proximal bronchial tree, cord and brachial plexus. This in turn achieves large reductions in VAortV-29-38-EQD2 and VLAwall-64-73-EQD2, and we plan to closely monitor patients with values of these measures still >0% (their median value in OX-RT) following reduction.

Buparlisib with thoracic radiotherapy and its effect on tumour hypoxia: A phase I study in patients with advanced non-small cell lung carcinoma.

BACKGROUND: Pre-clinically, phosphoinositide 3-kinase (PI3K) inhibition radiosensitises tumours by increasing intrinsic radiosensitivity and by reducing tumour hypoxia. We assessed whether buparlisib, a class 1 PI3K inhibitor, can be safely combined with radiotherapy in patients with non-small cell lung carcinoma (NSCLC) and investigated its effect on tumour hypoxia. METHODS: This was a 3 + 3 dose escalation and dose expansion phase I trial in patients with advanced NSCLC. Buparlisib dose levels were 50 mg, 80 mg and 100 mg once daily orally for 2 weeks, with palliative thoracic radiotherapy (20 Gy in 5 fractions) delivered during week 2. Tumour hypoxic volume (HV) was measured using 18F-fluoromisonidazole positron-emission tomography-computed tomography at baseline and following 1 week of buparlisib. RESULTS: Twenty-one patients were recruited with 9 patients evaluable for maximum tolerated dose (MTD) analysis. No dose-limiting toxicity was reported; therefore, 100 mg was declared the MTD, and 10 patients received this dose in the expansion phase. Ninety-four percent of treatment-related adverse events were ≤grade 2 with fatigue (67%), nausea (24%) and decreased appetite (19%) most common per patient. One serious adverse event (grade 3 hypoalbuminaemia) was possibly related to buparlisib. No unexpected radiotherapy toxicity was reported. Ten (67%) of 15 patients evaluable for imaging analysis were responders with 20% median reduction in HV at the MTD. CONCLUSION: This is the first clinical trial to combine a PI3K inhibitor with radiotherapy in NSCLC and investigate the effects of PI3K inhibition on tumour hypoxia. This combination was well tolerated and PI3K inhibition reduced hypoxia, warranting investigation into whether this novel class of radiosensitisers can improve radiotherapy outcomes.

Prophylactic radiotherapy for the prevention of procedure-tract metastases after surgical and large-bore pleural procedures in malignant pleural mesothelioma (SMART): a multicentre, open-label, phase 3, randomised controlled trial.

BACKGROUND: The use of prophylactic radiotherapy to prevent procedure-tract metastases (PTMs) in malignant pleural mesothelioma remains controversial, and clinical practice varies worldwide. We aimed to compare prophylactic radiotherapy with deferred radiotherapy (given only when a PTM developed) in a suitably powered trial. METHODS: We did a multicentre, open-label, phase 3, randomised controlled trial in 22 UK hospitals of patients with histocytologically proven mesothelioma who had undergone large-bore pleural interventions in the 35 days prior to recruitment. Eligible patients were randomised (1:1), using a computer-generated sequence, to receive immediate radiotherapy (21 Gy in three fractions within 42 days of the pleural intervention) or deferred radiotherapy (same dose given within 35 days of PTM diagnosis). Randomisation was minimised by histological subtype, surgical versus non-surgical procedure, and pleural procedure (indwelling pleural catheter vs other). The primary outcome was the incidence of PTM within 7 cm of the site of pleural intervention within 12 months from randomisation, assessed in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN72767336. FINDINGS: Between Dec 23, 2011, and Aug 4, 2014, we randomised 203 patients to receive immediate radiotherapy (n=102) or deferred radiotherapy (n=101). The patients were well matched at baseline. No significant difference was seen in PTM incidence in the immediate and deferred radiotherapy groups (nine [9%] vs 16 [16%]; odds ratio 0·51 [95% CI 0·19-1·32]; p=0·14). The only serious adverse event related to a PTM or radiotherapy was development of a painful PTM within the radiotherapy field that required hospital admission for symptom control in one patient who received immediate radiotherapy. Common adverse events of immediate radiotherapy were skin toxicity (grade 1 in 50 [54%] and grade 2 in four [4%] of 92 patients vs grade 1 in three [60%] and grade 2 in two [40%] of five patients in the deferred radiotherapy group who received radiotherapy for a PTM) and tiredness or lethargy (36 [39%] in the immediate radiotherapy group vs two [40%] in the deferred radiotherapy group) within 3 months of receiving radiotherapy. INTERPRETATION: Routine use of prophylactic radiotherapy in all patients with mesothelioma after large-bore thoracic interventions is not justified. FUNDING: Research for Patient Benefit Programme from the UK National Institute for Health Research.

Protocol for the surgical and large bore procedures in malignant pleural mesothelioma and radiotherapy trial (SMART Trial): an RCT evaluating whether prophylactic radiotherapy reduces the incidence of procedure tract metastases.

INTRODUCTION: Patients with malignant pleural mesothelioma (MPM) may develop painful 'procedure tract metastasis' (PTM) at the site of previous pleural interventions. Prophylactic radiotherapy has been used to minimise this complication; however, three small randomised trials have shown conflicting results regarding its effectiveness. The surgical and large bore procedures in malignant pleural mesothelioma and radiotherapy trial (SMART Trial) is a suitably powered, multicentre, randomised controlled trial, designed to evaluate the efficacy of prophylactic radiotherapy within 42 days of pleural instrumentation in preventing the development of PTM in MPM. METHODS AND ANALYSIS: 203 patients with a histocytologically proven diagnosis of MPM, who have undergone a large bore pleural intervention (thoracic surgery, large bore chest drain, indwelling pleural catheter or local anaesthetic thoracoscopy) in the previous 35 days, will be recruited from UK hospitals. Patients will be randomised (1:1) to receive immediate radiotherapy (21 Gy in 3 fractions over 3 working days within 42 days of the pleural intervention) or deferred radiotherapy (21 Gy in 3 fractions over 3 working days given if a PTM develops). Patients will be followed up for 12 months. The primary outcome measure is the rate of PTM until death or 12 months (whichever is sooner), as defined by the presence of a clinically palpable nodule of at least 1 cm diameter felt within 7 cm of the margins of the procedure site as confirmed by two assessors. Secondary outcome measures include chest pain, quality of life, analgaesic requirements, healthcare utilisation and safety (including radiotherapy toxicity). ETHICS AND DISSEMINATION: The trial has received ethical approval from the Southampton B Research Ethics Committee (11/SC/0408). There is a Trial Steering Committee, including independent members and a patient and public representative. The trial results will be published in a peer-reviewed journal and presented at international conferences. TRIAL REGISTRATION NUMBER: ISRCTN72767336.

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.

The use of the Active Breathing Coordinator throughout radical non-small-cell lung cancer (NSCLC) radiotherapy.

PURPOSE: To assess feasibility and reproducibility of an Active Breathing Coordinator (ABC) used throughout radical radiotherapy for non-small-cell lung cancer, and compare lung dosimetric parameters between free-breathing and ABC plans. METHODS AND MATERIALS: A total of 18 patients, recruited into an approved study, had free-breathing and ABC breath-hold treatment plans generated. Lung volume, the percentage volume of lung treated to a dose of ≥20 Gy (V(20)), and mean lung dose (MLD) were compared. Treatment (64 Gy in 32 fractions, 5 days/week) was delivered in breath-hold. Repeat breath-hold computed tomography scans were used to assess change in gross tumor volume (GTV) size and position. Setup error was also measured and potential GTV-planning target volume (PTV) margins calculated. RESULTS: Seventeen of 18 patients completed radiotherapy using ABC daily. Intrafraction tumor position was consistent, but interfraction variation had mean (range) values of 5.1 (0-25), 3.6 (0-9.7), and 3.5 (0-16.6) mm in the superoinferior (SI), right-left (RL), and anteroposterior (AP) directions, respectively. Tumor moved partially outside the PTV in 5 patients. Mean reduction in GTV from planning to end of treatment was 25% (p = 0.003). Potentially required PTV margins were 18.1, 11.9, and 11.9 mm in SI, RL, and AP directions. ABC reduced V(20) by 13% (p = 0.0001), V(13) by 12% (p = 0.001), and MLD by 13% (p < 0.001) compared with free-breathing; lung volume increased by 41% (p < 0.001). CONCLUSIONS: Clinically significant movements of GTV were seen during radiotherapy for non-small-cell lung cancer using ABC. Image guidance is recommended with ABC. The use of ABC can reduce dose volume parameters determining lung toxicity, and might allow for equitoxic radiotherapy dose escalation.

Feasibility of the use of the Active Breathing Co ordinator (ABC) in patients receiving radical radiotherapy for non-small cell lung cancer (NSCLC).

INTRODUCTION: One method to overcome the problem of lung tumour movement in patients treated with radiotherapy is to restrict tumour motion with an active breathing control (ABC) device. This study evaluated the feasibility of using ABC in patients receiving radical radiotherapy for non-small cell lung cancer. METHODS: Eighteen patients, median (range) age of 66 (44-82) years, consented to the study. A training session was conducted to establish the patient's breath hold level and breath hold time. Three planning scans were acquired using the ABC device. Reproducibility of breath hold was assessed by comparing lung volumes measured from the planning scans and the volume recorded by ABC. Patients were treated with a 3-field coplanar beam arrangement and treatment time (patient on and off the bed) and number of breath holds recorded. The tolerability of the device was assessed by weekly questionnaire. Quality assurance was performed on the two ABC devices used. RESULTS: 17/18 patients completed 32 fractions of radiotherapy using ABC. All patients tolerated a maximum breath hold time >15s. The mean (SD) patient training time was 13.8 (4.8)min and no patient found the ABC very uncomfortable. Six to thirteen breath holds of 10-14 s were required per session. The mean treatment time was 15.8 min (5.8 min). The breath hold volumes were reproducible during treatment and also between the two ABC devices. CONCLUSION: The use of ABC in patients receiving radical radiotherapy for NSCLC is feasible. It was not possible to predict a patient's ability to hold breath. A minimum tolerated breath hold time of 15 s is recommended prior to commencing treatment.

Improvement in tumour control probability with active breathing control and dose escalation: a modelling study.

INTRODUCTION: The prognosis from non-small cell lung cancer remains poor, even in those patients suitable for radical radiotherapy. The ability of radiotherapy to achieve local control is hampered by the sensitivity of normal structures to irradiation at the high tumour doses needed. This study aimed to look at the potential gain in tumour control probability from dose escalation facilitated by moderate deep inspiration breath-hold. METHOD: The data from 28 patients, recruited into two separate studies were used. These patients underwent planning with and without the use of moderate deep inspiration breath-hold with an active breathing control (ABC) device. Whilst maintaining the mean lung dose (MLD) at the level of the conventional plan, the ABC plan dose was theoretically escalated to a maximum of 84 Gy, constrained by usual normal tissue tolerances. Calculations were performed using data for both lungs and for the ipsilateral lung only. Resulting local progression-free survival at 30 months was calculated using a standard logistic model. RESULTS: The prescription dose could be escalated from 64 Gy to a mean of 73.7+/-6.5 Gy without margin reduction, which represents a statistically significant increase in tumour control probability from 0.15+/-0.01 to 0.29+/-0.11 (p<0.0001). The results were not statistically different whether both lungs or just the ipsilateral lung was used for calculations. CONCLUSION: A near-doubling of tumour control probability is possible with modest dose escalation, which can be achieved with no extra increase in lung dose if deep inspiration breath-hold techniques are used.

Defining the margins in the radical radiotherapy of non-small cell lung cancer (NSCLC) with active breathing control (ABC) and the effect on physical lung parameters.

BACKGROUND: The effectiveness of ABC has been traditionally measured as the reduction in internal margin (IM) within the planning target volume (PTV). Not to overestimate the benefit of ABC, the effect of patient movement during treatment also needs to be taken into account. We determined the IM and set-up error with ABC and the effect on physical lung parameters compared to standard margins used with free breathing. We also assessed interfraction oesophageal movement to determine a planning organ at risk volume (PRV). MATERIALS AND METHODS: Two sequential studies were performed using ABC in NSCLC patients suitable for radical radiotherapy (RT). Twelve out of 14 patients in Study 1 had tumours visible fluoroscopically and had intrafraction tumour movement assessed with and without ABC. Sixteen patients were recruited to Study 2 and had interfraction tumour movement measured using ABC in a moderate deep inspiration breath-hold, of these 7 patients also had interfraction oesophageal movement recorded. Interfraction movement was assessed by CT scan prior to and in the middle and final week of RT. Displacement of the tumour centre of mass and oesophageal borders relative to the first scan provided a measure of movement. Set-up error was measured in 9 patients treated with an in-house lung board adapted for the ABC device. Combining movement and set-up errors determined PTV and PRV margins with ABC. The effect of ABC on mean lung dose (MLD), lung V20 and V13 was calculated. RESULTS: ABC in a moderate deep inspiration breath-hold was tolerated in 25 out of 30 patients (83%) in Study 1 and 2. The random contribution of periodic tumour motion was reduced by 90% in the y direction with ABC compared to free-breathing. The magnitude of motion reduction was less in the x and z direction. Combining the systematic and random set-up error in quadrature with the systematic and random intrafraction and interfraction tumour variations with ABC results in a PTV margin of 8.3mm in the x direction, 12.0mm in the y direction and 9.8mm in the z direction. There was a relative mean reduction in MLD, lung V20 and V13 of 25%, 21% and 18% with the ABC PTV compared to a free-breathing PTV. Oesophageal movement combined with set-up error resulted in an isotropic PRV of 4.7 mm. CONCLUSIONS: The reduction in PTV size with ABC resulted in an 18-25% relative reduction in physical lung parameters. PTV margin reduction has the potential to spare normal lung and allow dose-escalation if coupled with image-guided RT. The oesophageal PRV needs to be considered when irradiating central disease and is of increasing importance with altered RT fractionation and concomitant chemoradiation schedules. Further reductions in PTV and PRV may be possible if patient set-up error was minimised, confirming that attention to patient immobilisation is as important as attempts to control tumour motion.