'Relationship between thermal dose and cell death for "rapid" ablative and "slow" hyperthermic heating'.

AIM: Thermal isoeffective dose (TID) has not been convincingly validated for application to predict biological effects from rapid thermal ablation (e.g., using >55 °C). This study compares the classical method of quantifying TID (derived from hyperthermia data) with a temperature-adjusted method based on the Arrhenius model for predicting cell survival in vitro, after either 'rapid' ablative or 'slow' hyperthermic exposures. METHODS: MTT assay viability data was obtained from two human colon cancer cell lines, (HCT116, HT29), subjected to a range of TIDs (120-720 CEM43) using a thermal cycler for hyperthermic (>2 minutes, <50 °C) treatments, or a novel pre-heated water bath based technique for ablative exposures (<10 seconds, >55 °C). TID was initially estimated using a constant RCEM>43°C=0.5, and subsequently using RCEM(T), derived from temperature dependent cell survival (injury rate) Arrhenius analysis. RESULTS: 'Slow' and 'rapid' exposures resulted in cell survival and significant regrowth (both cell lines) 10 days post-treatment for 240 CEM43 (RCEM>43°C=0.5), while 340-550 CEM43 (RCEM>43°C =0.5) delivered using 'rapid' exposures showed 12 ± 6% viability and 'slow' exposures resulted in undetectable viability. Arrhenius analysis of experimental data (activation energy ΔE = 5.78 ± 0.04 × 105 J mole-1, frequency factor A = 3.27 ± 11 × 1091 sec-1) yielded RCEM=0.42 * e0.0041*T which better-predicted cell survival than using R CEM> 43°C=0.5. CONCLUSIONS: TID calculated using an RCEM(T) informed by Arrhenius kinetic parameters provided a more consistent, heating strategy independent, predictor of cell viability, improving dosimetry of ablative thermal exposures. Cell viability was only undetectable above 305 ± 10 CEM43 using this revised measure.

Low-cost Kinect Version 2 imaging system for breath hold monitoring and gating: Proof of concept study for breast cancer VMAT radiotherapy.

Voluntary inspiration breath hold (VIBH) for left breast cancer patients has been shown to be a safe and effective method of reducing radiation dose to the heart. Currently, VIBH protocol compliance is monitored visually. In this work, we establish whether it is possible to gate the delivery of radiation from an Elekta linac using the Microsoft Kinect version 2 (Kinect v2) depth sensor to measure a patient breathing signal. This would allow contactless monitoring during VMAT treatment, as an alternative to equipment-assisted methods such as active breathing control (ABC). Breathing traces were acquired from six left breast radiotherapy patients during VIBH. We developed a gating interface to an Elekta linac, using the depth signal from a Kinect v2 to control radiation delivery to a programmable motion platform following patient breathing patterns. Radiation dose to a moving phantom with gating was verified using point dose measurements and a Delta4 verification phantom. 60 breathing traces were obtained with an acquisition success rate of 100%. Point dose measurements for gated deliveries to a moving phantom agreed to within 0.5% of ungated delivery to a static phantom using both a conventional and VMAT treatment plan. Dose measurements with the verification phantom showed that there was a median dose difference of better than 0.5% and a mean (3% 3 mm) gamma index of 92.6% for gated deliveries when using static phantom data as a reference. It is possible to use a Kinect v2 device to monitor voluntary breath hold protocol compliance in a cohort of left breast radiotherapy patients. Furthermore, it is possible to use the signal from a Kinect v2 to gate an Elekta linac to deliver radiation only during the peak inhale VIBH phase.

Lung volume reproducibility under ABC control and self-sustained breath-holding.

An Active Breathing Coordinator (ABC) can be employed to induce breath-holds during CT imaging and radiotherapy of lung, breast and liver cancer, and recently during lung cancer MRI. The apparatus measures and controls respiratory volume, hence subject lung volume reproducibility is its principal measure of effectiveness. To assess ABC control quality, the intra-session reproducibility of ABC-induced lung volumes was evaluated and compared with that reached by applying the clinical standard of operator-guided self-sustained breath-holds on healthy volunteers during MRI. Inter-session reproducibility was investigated by repeating ABC-controlled breath-holds on a second visit. Additionally, lung volume agreement with ABC devices used with different imaging modalities in the same institution (MR, CT), or for a breast trial treatment, was assessed. Lung volumes were derived from three-dimensional (3D) T1-weighted MRI datasets by three observers employing semiautomatic lung delineation on a radiotherapy treatment planning system. Inter-observer variability was less than 6% of the delineated lung volumes. Lung volume agreement between the different conditions over all subjects was investigated using descriptive statistics. The ABC equipment dedicated for MR application exhibited good intra-session and inter-session lung volume reproducibility (1.8% and 3% lung volume variability on average, respectively). MR-assessed lung volumes were similar using different ABC equipment dedicated to MR, CT, or breast radiotherapy. Overall, lung volumes controlled by the same or different ABC devices agreed better than with self-controlled breath-holds, as suggested by the average ABC variation of 1.8% of the measured lung volumes (99 mL), compared to the 4.1% (226 mL) variability observed on average with self-sustained breath-holding.

An experimental system for the study of ultrasound exposure of isolated blood vessels.

An experimental system designed for the study of the effects of diagnostic or therapeutic ultrasound exposure on isolated blood vessels in the presence or absence of intraluminal contrast agent is described. The system comprised several components. A microscope was used to monitor vessel size (and thus vessel functionality), and potential leakage of intraluminal 70 kDa FITC-dextran fluorescence marker. A vessel chamber allowed the mounting of an isolated vessel whilst maintaining its viability, with pressure regulation for the control of intraluminal pressure and induction of flow for the infusion of contrast microbubbles. A fibre-optic hydrophone sensor mounted on the vessel chamber using a micromanipulator allowed pre-exposure targeting of the vessel to within 150 µm, and monitoring of acoustic cavitation emissions during exposures. Acoustic cavitation was also detected using changes in the ultrasound drive voltage and by detection of audible emissions using a submerged microphone. The suitability of this system for studying effects in the isolated vessel model has been demonstrated using a pilot study of 6 sham exposed and 18 high intensity focused ultrasound exposed vessels, with or without intraluminal contrast agent (SonoVue) within the vessels.

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.

Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy.

BACKGROUND: Radiation dose distributions created by two dimensional (2D) treatment planning are responsible for partial volumes receiving >107% of the prescribed dose in a proportion of patients prescribed whole breast radiotherapy after tumour excision of early breast cancer. These may contribute to clinically significant late radiation adverse effects. AIM: To test three dimensional (3D) intensity modulated radiotherapy (IMRT) against 2D dosimetry using standard wedge compensators in terms of late adverse effects after whole breast radiotherapy. METHODS: Three hundred and six women prescribed whole breast radiotherapy after tumour excision for early stage cancer were randomised to 3D IMRT (test arm) or 2D radiotherapy delivered using standard wedge compensators (control arm). All patients were treated with 6 or 10MV photons to a dose of 50Gy in 25 fractions to 100% in 5 weeks followed by an electron boost to the tumour bed of 11.1Gy in 5 fractions to 100%. The primary endpoint was change in breast appearance scored from serial photographs taken before radiotherapy and at 1, 2 and 5 years follow up. Secondary endpoints included patient self-assessments of breast discomfort, breast hardness, quality of life and physician assessments of breast induration. Analysis was by intention to treat. RESULTS: 240 (79%) patients with 5-year photographs were available for analysis. Change in breast appearance was identified in 71/122 (58%) allocated standard 2D treatment compared to only 47/118 (40%) patients allocated 3D IMRT. The control arm patients were 1.7 times more likely to have a change in breast appearance than the IMRT arm patients after adjustment for year of photographic assessment (95% confidence interval 1.2-2.5, p=0.008). Significantly fewer patients in the 3D IMRT group developed palpable induration assessed clinically in the centre of the breast, pectoral fold, infra-mammary fold and at the boost site. No significant differences between treatment groups were found in patient reported breast discomfort, breast hardness or quality of life. CONCLUSION: This analysis suggests that minimisation of unwanted radiation dose inhomogeneity in the breast reduces late adverse effects. Incidence of change in breast appearance was statistically significantly higher in patients in the standard 2D treatment arm compared with the IMRT arm. A beneficial effect on quality of life remains to be demonstrated.