Adaptive dose escalated radiotherapy in oropharyngeal cancers: a treatment planning feasibility study.

BACKGROUND: A significant proportion of patients with poor prognosis squamous cell cancer of the oropharynx relapse loco-regionally despite radical (chemo)radiotherapy. If a predictive biomarker for disease control can be identified during treatment then individualised and adaptive treatment strategies may be employed. The aim of this study is to assess the feasibility of adaptive and dose-escalated RT to the gross tumour volume without increasing surrounding planning target volume doses and maintaining clinically acceptable organs at risk doses. MATERIALS AND METHODS: Twenty representative patients with poor prognosis locally advanced OPSCC who were known to have relapsed post RT, were re-planned retrospectively using Eclipse TPS v15.5, RapidPlan™ and multi-criteria optimisation. In our centre, PTV65 is treated with 65 Gy in 30 fractions while areas at risk of containing microscopic disease (PTV54) are treated synchronously to 54 Gy in 30 fractions. The original clinical plans were re-optimised to act as controls (Group I). These plans were split into two plans of 15 fractions each, with the latter 15 fractions used to escalate the dose to the GTV to 73 Gy (Group II) and 82 Gy (Group III). Plan sums were created for the total 30 fractions to record plan evaluation parameters along with assessments of plan deliverability. RESULTS: For all groups, the dose coverage at D98% and D50% for the PTVs were comparable. The D2% dose levels for PTV65-GTV increased. All dose levels associated with PTV54 remained largely unaffected by the dose escalation regimens. Conformity indices for PTV65 and PTVAll (PTV65 plus PTV54) reveal comparable target volume coverage across all three groups. Despite the GTV being escalated by 12.3% and 26.2% in groups II and III, the volume of GTV receiving > 84 Gy was considerably less than 1.75 cc. While OAR doses increased for the escalated groups, these increases were not clinically significant. CONCLUSION: This planning feasibility study exploring RapidPlan™ combined with multi-criteria optimisation has demonstrated that doses to the GTV may be escalated without increasing PTV65-GTV, PTV54 or OAR doses considerably, suggesting an interventional clinical trial using this approach would be feasible.

Analysis of dose using CBCT and synthetic CT during head and neck radiotherapy: A single centre feasibility study.

OBJECTIVES: The study aimed to assess the suitability of deformable image registration (DIR) software to generate synthetic CT (sCT) scans for dose verification during radiotherapy to the head and neck. Planning and synthetic CT dose volume histograms were compared to evaluate dosimetric changes during the treatment course. METHODS: Eligible patients had locally advanced (stage III, IVa and IVb) oropharyngeal cancer treated with primary radiotherapy. Weekly CBCT images were acquired post treatment at fractions 1, 6, 11, 16, 21 and 26 over a 30 fraction treatment course. Each CBCT was deformed with the planning CT to generate a sCT which was used to calculate the dose at that point in the treatment. A repeat planning CT2 was acquired at fraction 16 and deformed with the fraction 16 CBCT to compare differences between the calculations mid-treatment. RESULTS: 20 patients were evaluated generating 138 synthetic CT sets. The single fraction mean dose to PTV_HR between the synthetic and planning CT did not vary, although dose to 95% of PTV_HR was smaller at week 6 compared to planning (difference 2.0%, 95% CI (0.8 to 3.1), p = 0.0). There was no statistically significant difference in PRV_brainstem or PRV_spinal cord maximum dose, although greater variation using the sCT calculations was reported. The mean dose to structures based on the fraction 16 sCT and CT2 scans were similar. CONCLUSIONS: Synthetic CT provides comparable dose calculations to those of a repeat planning CT; however the limitations of DIR must be understood before it is applied within the clinical setting.

Daylight photodynamic therapy in Scotland.

Chronic sun-induced dysplastic skin changes (actinic keratoses) are extremely common in fair-skinned people in Scotland. These changes are a major cause of morbidity and may develop into skin cancer. Actinic keratoses are often extensive and pose a therapeutic challenge as field-directed treatment is required for chronic disease management. One such treatment approach is hospital-based photodynamic therapy, which is a well-established treatment in Scotland for actinic keratoses, using a photosensitiser pro-drug and red LED light irradiation. However, photodynamic therapy using daylight as the activating light source is increasingly and effectively used in continental Europe, but had not been explored in Scotland until we initiated this in 2013. We report our experience of daylight photodynamic therapy in 64 patient-treatment courses and demonstrate that this can be an effective, well-tolerated treatment, which is liked by patients. Our most recent data show that most patients (73%) achieved clearance or at least a good response to treatment and had high levels of satisfaction with daylight photodynamic therapy. Daylight exposure measurements indicated that treatment is feasible in Scotland between April to September. Daylight photodynamic therapy is an important advancement in treatment options for Scottish patients with extensive pre-cancerous field changes and provides opportunities for home-based treatment and increased efficiency of photodynamic therapy services.

A consensus on the use of daylight photodynamic therapy in the UK.

BACKGROUND: Actinic keratoses (AKs) are a consequence of chronic exposure to ultraviolet radiation. Treatment of chronically photo-damaged skin and AKs is driven by risk of progression to squamous cell carcinoma, as well as for symptomatic relief. Conventional photodynamic therapy (c-PDT) is indicated when AKs are multiple or confluent and if patients respond poorly or are unable to tolerate other therapies. c-PDT is limited by the field size that can be treated in single sessions and can cause significant discomfort. OBJECTIVE: Recent studies investigated daylight illumination to activate protoporphyrin IX and daylight-PDT (d-PDT) is now licensed in the UK for face and scalp AKs. A group of experts met to discuss application of d-PDT with methyl aminolevulinate (MAL) and develop a UK consensus statement, specific to UK weather conditions. METHODS: The UK consensus recommendations were reached among eight experts, who reviewed recent studies on d-PDT, assessed UK meteorological data and discussed personal experiences of d-PDT for AKs. RESULTS: Recommendations from these discussions provide guidance on d-PDT use, specifically regarding patient selection, therapeutic indications, when to treat, skin preparation, MAL application and daylight exposure for patients with AKs. CONCLUSIONS: This UK expert consensus provides practical guidance for UK application of d-PDT.

Development of a handheld fluorescence imaging device to investigate the characteristics of protoporphyrin IX fluorescence in healthy and diseased skin.

BACKGROUND: Topical Photodynamic therapy (PDT) is an effective treatment for superficial non-melanoma skin cancers (NMSC) and dysplasia. During PDT light activates the photosensitiser (PpIX), metabolised from a topical pro-drug. A combination of PpIX, light and molecular oxygen results in inflammation and cell death. However, the outcomes of the treatment could be better. Insufficient biosynthesis of PpIX may be one of the causes of incomplete response or recurrence. Measuring surface fluorescence is usually employed as a means of studying PpIX formation. The aim of this work was to develop a device and a method for convenient fluorescence imaging in clinical settings to gather information on PpIX metabolism in healthy skin and NMSC with a view to improving PDT regimes. METHODS: A handheld fluorescence camera and a time course imaging method was developed and used in healthy volunteers and patients diagnosed with basal cell carcinoma (BCC) and actinic keratosis (AK). The photosensitiser (precursor) creams used were 5-aminolaevulinic acid (ALA; Ameluz(®)) and methyl aminolevulinate (MAL; Metvix(®)). Pain was assessed using a visual analogue score immediately after the PDT. RESULTS: Fluorescence due to PpIX increases over three hours incubation in healthy skin and in lesional BCC and AK. Distribution of PpIX fluorescence varies between the lesion types and between subjects. There was no significant correlation between PpIX fluorescence characteristics and pro-drug, diagnosis or pain experienced. However, there was a clear dependence on body site. CONCLUSION: The device and the method developed can be used to assess the characteristics of PpIX fluorescence, quantitative analysis and time course. Our findings show that body site influences PpIX fluorescence which we suggest may be due to the difference in skin temperature at different body sites.

Laser-induced autofluorescence spectroscopy: can it be of importance in detection of bladder lesions?

BACKGROUND: Non-muscle invasive bladder cancer can be missed during white light endoscopy in up to 50% of cases. We aimed to test whether or not we could find a difference between benign and cancerous tissue wavelengths using laser induced autofluorescence spectroscopy can increase cancer detection. MATERIALS AND METHODS: We analysed 67 tissue samples using spectral analysis. The WavSTAT (Spectra Science) optical biopsy device was used to record fluorescence spectra from biopsied tissue enabling calculation of an AUC for each spectrum, a measure of the mean spectral wavelength (λ¯ (nm)) and a dimensionless fluorescence ratio. Mann-Whitney test was used to compare the two groups. RESULTS: We found that 49.3% (33/67) of the tissue was benign, 44.8% (30/67) was CIS/cancerous tissue, and the remaining 4/67 samples were atypia (2) and dysplasia (2). The median AUC for the benign tissue was 19.53 (interquartile range [IQR]: 5.35-30.39) and that for CIS/cancerous tissue was 7.05 (IQR: 2.89-14.24) (P=0.002). The median wavelengths for the benign tissue and malignant tissue were 502.4nm (IQR: 500.3-504.3nm) and 505.2nm (IQR: 502.1-513.2nm), respectively (P=0.003). The median fluorescence ratio was 0.080 (IQR: 0.070-0.088) for benign tissue and 0.096 (IQR: 0.079-0.221) for CIS/cancerous tissue (P=0.002). CONCLUSIONS: We found statistical differences between the median AUC calculations and median wavelengths for the benign and cancerous tissue. We also found a statistical difference between the fluorescence ratios between the two tissue types. There seems to be a role for optical spectroscopy in verifying bladder lesions.

The effect of 222-nm UVC phototesting on healthy volunteer skin: a pilot study.

BACKGROUND: Frequent topical antiseptic use to hands is now common in healthcare and other work environments. Inevitably, the use of such antiseptics will present an occupational risk for irritancy and allergic dermatitis. New, less irritant and even non-chemical antimicrobial approaches are under investigation. METHODS: A Sterilray disinfectant source (222 nm) conventionally used to sterilize equipment and work surfaces was assessed for tolerability in human skin. Using an escalating dosage study methodology, four skin phototype I and II healthy volunteers had their minimal erythema dose (MED) determined. Punch biopsies of irradiated sites were stained for cyclobutane pyrimidine dimers (CPD). The degree of CPD was compared with that in biopsies from unexposed skin and from areas exposed to UVB (280-315 nm) radiation. RESULTS: Calibrated spectral measurements revealed emission at a peak wavelength of 222 nm with 97% emission at wavelengths less than 250 nm. At low doses below the threshold bacteriostatic effect, the source was capable of inducing both erythema and CPD formation in human skin. In two individuals, cells in the basal layer were not shielded by the overlying tissue as indicated by the presence of CPD. CONCLUSION: The source showed an erythemogenic or CPD potential at lower doses than those required to reach the reported threshold bacteriostatic effect.

Comparison of intraoperative fluorescence and MRI image guided neuronavigation in malignant brain tumours, a prospective controlled study.

INTRODUCTION: MBT carry poor prognosis and more than 80% of MBT recur locally within 2 cm of the resection margin because of inadequate surgical removal. A number of techniques have been implemented in recent years to improve surgical removal of MBT with variable success. We examined two methods commonly used to resect MBT to establish which one offered the best chances of gross total removal; MRI guided technology and ALA-induced fluorescence. PATIENTS AND METHODS: Twenty consecutive patients diagnosed with MBT were included in this study. They were given 20mg ALA per kg body weight 3h before anaesthesia orally mixed in water. Surgery was planned using preoperative enhanced MPR age images. Surgery was executed using the Stealth Station image guidance system and ALA-induced fluorescence microsurgical techniques. During surgery the intensity of fluorescence was graded into red, pink or blue. The intensity of fluorescence was also measured using pulsed 405 nm laser and a compact spectrometer using a touch probe directly placed on the tissue. The extent of tumour invasion was assessed intraoperatively using standard white light, blue light and spectroscopic measurements. Postoperative enhanced MRI was used to assess the extent of resection and the volume of residual tumour was measured. RESULTS: There were six newly diagnosed GBM, eight recurrent GBM, one oligodendroglioma (ODG) and five metastases (MET). On enhanced MRI, the mean diameter of new GBM, recurrent GBM, ODG and MET was 2.3 cm, 2.3 cm, 1.5 cm, and 2.3 cm respectively. Under the blue light, the mean diameter of new GBM, recurrent GBM, ODG and MET was 2.9 cm, 3 cm, 1.5 cm and 2.3 cm respectively. The results of quantitative measurements of fluorescence ratios revealed that red fluorescence corresponded to 5.9-11.6 (solid tumour on histology), and pink fluorescence measured 0.8-1.9 (infiltrating edge of tumour on histology). When we compared the maximum tumour diameter of GBM we found on average it was 10mm wider on spectroscopy compared to standard white light microscopy and 6mm wider than what the enhanced MRI demonstrated. CONCLUSIONS: Fluorescence technology revealed that GBMs are wider than the enhanced MRI had demonstrated, while MET enhanced MRI was similar in size to fluorescence. Furthermore, solid tumour can be identified intraoperatively and can be measured using fluorescence and spectroscopy techniques and it can be removed safely. Infiltrating tumour can also be identified intraoperatively using this technology and can be removed in non-eloquent areas to maximise surgical resection.

Modelling fluorescence in clinical photodynamic therapy.

Understanding the interactions of non-ionizing radiation with living organisms has been the focus of much research over recent decades. The complex nature of these interactions warrants development of theoretical and experimental studies to gain an insight into predicting and monitoring the success of photodynamic therapy (PDT) protocols. There is a major impetus towards evidence-based recommendations for patient diagnosis, treatment and management. Knowledge of the biophysical aspects of PDT is important for improving dosimetry protocols. Fluorescence in clinical PDT may be used to detect and diagnose pre-malignant and malignant conditions, while photobleaching can monitor changes in fluorescence during treatment. Combining empirical fluorescence photobleaching clinical data with computational modelling enables clinical PDT dosimetry protocols to be investigated with a view to optimising treatment regimes. We will discuss how Monte Carlo radiation transfer (MCRT) modelling has been intercalated in the field of fluorescence detection and PDT. In this paper we highlight important aspects of basic research in PDT by reporting on the current utilisation of fluorescence in clinical PDT from both a clinical and theoretical perspective. Understanding and knowledge of light propagation in biological tissue from these perspectives should have a positive impact on treatment planning.

Mathematical modeling of the optimum pulse structure for safe and effective photo epilation using broadband pulsed light.

The objective of this work is the investigation of intense pulsed light (IPL) photoepilation using Monte Carlo simulation to model the effect of the output dosimetry with millisecond exposure used by typical commercial IPL systems. The temporal pulse shape is an important parameter, which may affect the biological tissue response in terms of efficacy and adverse reactions. This study investigates the effect that IPL pulse structures, namely free discharge, square pulse, close, and spaced pulse stacking, has on hair removal. The relationship between radiant exposure distribution during the IPL pulse and chromophore heating is explored and modeled for hair follicles and the epidermis using a custom Monte Carlo computer simulation. Consistent square pulse and close pulse stacking delivery of radiant exposure across the IPL pulse is shown to generate the most efficient specific heating of the target chromophore, whilst sparing the epidermis, compared to free discharge and pulse stacking pulse delivery. Free discharge systems produced the highest epidermal temperature in the model. This study presents modeled thermal data of a hair follicle in situ, indicating that square pulse IPL technology may be the most efficient and the safest method for photoepilation. The investigation also suggests that the square pulse system design is the most efficient, as energy is not wasted during pulse exposure or lost through interpulse delay times of stacked pulses.

Is the pain of topical photodynamic therapy with methyl aminolevulinate any different from that with 5-aminolaevulinic acid?

Topical photodynamic therapy (PDT) using 5-aminolaevulinic acid (ALA) or methyl aminolevulinate (MAL) is widely used in dermatology. It is commonly stated that MAL PDT is less painful than ALA PDT, although published data are conflicting. We report our experience of the use of ALA (4-6 h) (n = 20) and MAL (3 h) (n = 20) in 40 consecutive patients with Bowen's disease or superficial basal cell carcinoma, treated with PDT using an identical irradiation regime. Although there was a trend to higher pain scores with ALA PDT [visual analogue scale (VAS)score, median 4.50], this was not significantly different from that of MAL PDT (VAS score, median 3.55; P = 0.98), nor considered to be clinically important. Importantly, both ALA and MAL PDT regimes were fairly well tolerated in this patient cohort, supporting the use of these prodrugs in dermatological PDT.

Monte Carlo modeling of in vivo protoporphyrin IX fluorescence and singlet oxygen production during photodynamic therapy for patients presenting with superficial basal cell carcinomas.

We present protoporphyrin IX (PpIX) fluorescence measurements acquired from patients presenting with superficial basal cell carcinoma during photodynamic therapy (PDT) treatment, facilitating in vivo photobleaching to be monitored. Monte Carlo (MC) simulations, taking into account photobleaching, are performed on a three-dimensional cube grid, which represents the treatment geometry. Consequently, it is possible to determine the spatial and temporal changes to the origin of collected fluorescence and generated singlet oxygen. From our clinical results, an in vivo photobleaching dose constant, ß of 5-aminolaevulinic acid-induced PpIX fluorescence is found to be 14 ± 1 J/cm(2). Results from our MC simulations suggest that an increase from our typical administered treatment light dose of 75-150 J/cm(2) could increase the effective PDT treatment initially achieved at a depth of 2.7-3.3 mm in the tumor, respectively. Moreover, this increase reduces the surface PpIX fluorescence from 0.00012 to 0.000003 of the maximum value recorded before treatment. The recommendation of administrating a larger light dose, which advocates an increase in the treatment time after surface PpIX fluorescence has diminished, remains valid for different sets of optical properties and therefore should have a beneficial outcome on the total treatment effect.

A quantitative comparison of 5-aminolaevulinic acid- and methyl aminolevulinate-induced fluorescence, photobleaching and pain during photodynamic therapy.

The characteristics of protoporphyrin IX (PPIX) fluorescence in superficial basal cell carcinoma (sBCC) and carcinoma in situ (Bowen's Disease, BD) following application of 5-aminolaevulinic acid (5-ALA) and its methyl ester (methyl aminolevulinate [MAL]) before, during and after photodynamic therapy (PDT) were investigated in 40 patients. Photosensitizer prodrug penetration can limit PDT efficacy and understanding the characteristics of PPIX fluorescence through fluorescence spectroscopy, may improve knowledge of photosensitizer delivery. Fluorescence intensity was assessed quantitatively, and the rate of photobleaching was determined by fitting an exponential decay. As a secondary end-point, PDT-induced pain was also measured continuously during treatment using a novel hand-held device, known as a pain logger. In vivo PPIX fluorescence was shown to decrease during irradiation, allowing the in vivo photobleaching of PPIX to be monitored. No significant difference was found between ALA- or MAL-induced PPIX fluorescence in lesions of sBCC and BD (P>0.05), indicating no detectable difference in PPIX kinetics for the two prodrugs as assessed by these measures. Pain, as assessed by the logger device, showed high interindividual variability and pain levels tended to be higher initially, decreasing during treatment. No difference was seen in pain experienced during ALA-or MAL-PDT (P>0.05).