Absolute calibration of optical power for PDT: report of AAPM TG140.

This report is primarily concerned with methods for optical calibration of laser power for continuous wave (CW) light sources, predominantly used in photodynamic therapy (PDT). Light power calibration is very important for PDT, however, no clear standard has been established for the calibration procedure nor the requirements of power meters suitable for optical power calibration. The purposes of the report are to provide guidance for establishing calibration procedures for thermopile type power meters and establish calibration uncertainties for most commercially available detectors and readout assemblies. The authors have also provided a review of the use of various power meters for CW and pulsed optical sources, and provided recommended temporal frequencies for optical power meter calibrations and guidance for routine quality assurance procedure.

Future radiation therapy: photons, protons and particles.

Radiation therapy plays a critical role in the current management of cancer patients. The most common linear accelerator-based treatment device delivers photons of radiation. In an ever more precise fashion, state-of-the-art technology has recently allowed for both modulation of the radiation beam and imaging for this treatment delivery. This has resulted in better patient outcome with far fewer side effects than were achieved even a decade ago. Recently, a push has begun for proton therapy, which may have clinical advantage in select indications, although significant limitations for these devices have become apparent. In addition, currently, heavy particle therapy has been touted as a potential means to improve cancer patient outcomes. This article will highlight current benefits and drawbacks to modern radiation therapy and speculate on future tools that will likely dramatically improve radiation oncology.

Total error shift patterns for daily CT on rails image-guided radiotherapy to the prostate bed.

BACKGROUND: To evaluate the daily total error shift patterns on post-prostatectomy patients undergoing image guided radiotherapy (IGRT) with a diagnostic quality computer tomography (CT) on rails system. METHODS: A total of 17 consecutive post-prostatectomy patients receiving adjuvant or salvage IMRT using CT-on-rails IGRT were analyzed. The prostate bed's daily total error shifts were evaluated for a total of 661 CT scans. RESULTS: In the right-left, cranial-caudal, and posterior-anterior directions, 11.5%, 9.2%, and 6.5% of the 661 scans required no position adjustments; 75.3%, 66.1%, and 56.8% required a shift of 1 - 5 mm; 11.5%, 20.9%, and 31.2% required a shift of 6 - 10 mm; and 1.7%, 3.8%, and 5.5% required a shift of more than 10 mm, respectively. There was evidence of correlation between the x and y, x and z, and y and z axes in 3, 3, and 3 of 17 patients, respectively. Univariate (ANOVA) analysis showed that the total error pattern was random in the x, y, and z axis for 10, 5, and 2 of 17 patients, respectively, and systematic for the rest. Multivariate (MANOVA) analysis showed that the (x,y), (x,z), (y,z), and (x, y, z) total error pattern was random in 5, 1, 1, and 1 of 17 patients, respectively, and systematic for the rest. CONCLUSIONS: The overall daily total error shift pattern for these 17 patients simulated with an empty bladder, and treated with CT on rails IGRT was predominantly systematic. Despite this, the temporal vector trends showed complex behaviors and unpredictable changes in magnitude and direction. These findings highlight the importance of using daily IGRT in post-prostatectomy patients.

Oncologic photodynamic therapy photosensitizers: a clinical review.

A myriad of naturally occurring and synthetic structures are capable of transferring the energy of light. Few, however, allow for this energy transfer to enable a type II photochemical reaction which, as currently practiced, is a fundamental component of photodynamic therapy. Even fewer of these agents, aptly termed photosensitizers, have found success in the treatment of patients. This review will focus on the oncologic photosensitizers that have come to clinical trial with outcomes published in peer reviewed journals. Based on a clinical orientation the qualities of successful photosensitizers will be examined, how current drugs fare and potential future options explored.

Photodynamic therapy for anal cancer.

Invasive anal cancers are generally successfully treated by combined chemotherapy with radiation therapy (XRT). For those patients who locally fail this intervention many are salvaged by surgery which generally results in permanent colostomy. We examined the treatment and outcome of Photofrin based photodynamic therapy (PDT) in a cohort of patients with anal cancer who failed locally despite chemo-radiation (N=6) and two patients with positive margins of resection after excision of small T(1) squamous cell anal cancers who refused further surgery or chemo-radiation. PDT consisted of outpatient infusion of Photofrin at 1.2mg/kg followed 48 h later by outpatient illumination. Red light (630 nm) illumination was delivered by a 5 cm diffusing fiber, treating transphincterally at 300 J/cm followed by microlens illumination at 200 J/cm(2) to the perianal tumor bed with 2 cm margin. All patients completed PDT without incident and all have maintained local control of disease in the anal region for the length of follow up (18-48 months). PDT may serve as a new means to salvage local failures and perhaps could be employed as a primary treatment modality in select patients with early stage of disease.

Future of oncologic photodynamic therapy.

Photodynamic therapy (PDT) is a tumor-ablative and function-sparing oncologic intervention. The relative simplicity of photosensitizer application followed by light activation resulting in the cytotoxic and vasculartoxic photodynamic reaction has allowed PDT to reach a worldwide audience. With several commercially available photosensitizing agents now on the market, numerous well designed clinical trials have demonstrated the efficacy of PDT on various cutaneous and deep tissue tumors. However, current photosensitizers and light sources still have a number of limitations. Future PDT will build on those findings to allow development and refinement of more optimal therapeutic agents and illumination devices. This article reviews the current state of the art and limitations of PDT, and highlight the progress being made towards the future of oncologic PDT.

Results of combined photodynamic therapy (PDT) and high dose rate brachytherapy (HDR) in treatment of obstructive endobronchial non-small cell lung cancer (NSCLC).

INTRODUCTION: We reviewed the outcome of combined photodynamic therapy (PDT) and high dose rate brachytherapy (HDR) for patients with symptomatic obstruction from endobronchial non-small cell lung cancer. METHODS: Nine patients who received combined PDT and HDR for endobronchial cancers were identified and their charts reviewed. The patients were eight males and one female aged 52-73 at diagnosis, initially presenting with various stages of disease: stage IA (N=1), stage IIA (N=1), stage III (N=6), and stage IV (N=1). Intervention was with HDR (500 cGy to 5 mm once weekly for 3 weeks) and PDT (2 mg/kg Photofrin, followed by 200 J/cm(2) illumination 48 h post-infusion). Treatment group 1 (TG-1, N=7) received HDR first; Treatment group 2 (TG-2, N=2) received PDT first. Patients were followed by regular bronchoscopies. RESULTS: Treatments were well tolerated, all patients completed therapy, and none were lost to follow-up. In TG-1, local tumor control was achieved in six of seven patients for: 3 months (until death), 15 months, 2+ years (until death), 2+ years (ongoing), and 5+ years (ongoing, N=2). In TG-2, local control was achieved in only one patient, for 84 days. Morbidities included: soft-tissue contraction and/or other reversible benign local tissue reactions (N=8) and photosensitivity reactions (N=2). CONCLUSIONS: Combined HDR/PDT treatment for endobronchial tumors is well tolerated and can achieve prolonged local control with acceptable morbidity when PDT follows HDR and when the spacing between treatments is 1 month or less. This treatment regimen should be studied in a larger patient population.

Cholangiocarcinoma: an emerging indication for photodynamic therapy.

Cholangiocarcinoma (CC) is emerging as an important treatment indication for photodynamic therapy. CCs are generally unresectable locally invasive tumors that occlude the biliary tree leading to fatal cholangitis and liver failure. Biliary decompression via stenting offers symptomatic relief but does not control tumor growth. Founded on an initial case study followed by ever more sophisticated clinical research, including randomized trials, photodynamic therapy has garnered enough momentum to be considered as part of the standard of care for these patients. Further, preliminary clinical data show the potential for benefit of the use of PDT in a neoadjuvant and adjuvant fashion to the minority of patients currently considered resectable or of border line resectability. PDT also impacts interleukin-6 levels and may form the basis for a targeted therapy approach to this disease. We review the clinical rationale, current studies and potential future directions of PDT for patients with CC.

Simulação computacional de um feixe de fótons de 6 MV em diferentes meios heterogêneos utilizando o código PENELOPE / Computer simulation of a 6 MV photon beam in different heterogeneous media utilizing the PENELOPE code

OBJETIVO: Utilizar o código PENELOPE e desenvolver geometrias onde estão presentes heterogeneidades para simular o comportamento do feixe de fótons nessas condições. MATERIAIS E MÉTODOS: Foram feitas simulações do comportamento da radiação ionizante para o caso homogêneo, apenas água, e para os casos heterogêneos, com diferentes materiais. Consideraram-se geometrias cúbicas para os fantomas e geometrias em forma de paralelepípedos para as heterogeneidades com a seguinte composição: tecido simulador de osso e pulmão, seguindo recomendações da International Commission on Radiological Protection, e titânio, alumínio e prata. Definiram-se, como parâmetros de entrada: a energia e o tipo de partícula da fonte, 6 MV de fótons; a distância fonte-superfície de 100 cm; e o campo de radiação de 10x 10 cm². RESULTADOS: Obtiveram-se curvas de percentual de dose em profundidade para todos os casos. Observou-se que em materiais com densidade eletrônica alta, como a prata, a dose absorvida é maior em relação à dose absorvida no fantoma homogêneo, enquanto no tecido simulador de pulmão a dose é menor. CONCLUSÃO: Os resultados obtidos demonstram a importância de se considerar heterogeneidades nos algoritmos dos sistemas de planejamento usados no cálculo da distribuição de dose nos pacientes, evitando-se sub ou superdosagem dos tecidos próximos às heterogeneidades.

OBJECTIVE: The PENELOPE code was utilized to simulate irradiation geometries where heterogeneities are present and to simulate a photon beam behavior under these conditions. MATERIALS AND METHODS: For the homogeneous case, the ionizing radiation behavior was simulated only with water, and different materials were introduced to simulate heterogeneous conditions. Cubic geometries were utilized for the homogeneous phantoms, and parallelepiped-shaped geometries for the heterogeneities with the following composition: bone and lung tissue simulators, as recommended by the International Commission on Radiological Protection, and titanium, aluminum and silver. Input parameters were defined as follows: energy and type of source, 6 MV photons; source-surface distance=100 cm; and radiation field of 10x 10 cm². RESULTS: Percentage depth-dose curves were obtained for all the cases. As result, it was observed that for high electronic density materials, such as silver, the absorbed dose is higher than the absorbed dose in the homogeneous phantom, and for the lung tissue simulator, it is lower. CONCLUSION: Results clearly demonstrate the relevant role of heterogeneities in the treatment planning system algorithms utilized in the calculation of dose distribution in patients, increasing the accuracy of the dose delivered to the tumor and avoiding unnecessary irradiation of healthy tissues.

Differences in mRNA and microRNA microarray expression profiles in human colon adenocarcinoma HT-29 cells treated with either Intensity-modulated Radiation Therapy (IMRT), or Conventional Radiation Therapy (RT).

We carried out this in vitro molecular study to investigate the effect of two clinical X-irradiation modalities (a two-dimensional external beam radiotherapy referred to in this article as conventional RT, and a three dimensional conformal intensity-modulated radiation therapy (IMRT) on a colon adenocarcinoma HT-29 cell line. Cells were synchronized by serum deprivation 48 h before irradiation so that >90% of them were in the G(0)/G(1) phase of the cell cycle. Cells were allowed to recover 3 h after irradiation before total RNA extraction. Two types of arrays, namely Affymetrix Human HG U133A 2.0 oligonucleotide microarrays and Ambion mirVana bioarrays, were employed to study mRNA and microRNA expressions, respectively. Three flasks were used per irradiation dose, and an additional three unirradiated flasks served as control. Microarray data were validated by reverse transcriptase quantitative polymerase chain reaction, and proteins of some expressed genes were determined by Western blots. Results showed the existence of differences in expression profiles between the two irradiation modalities. IMRT appeared to influence expression of some DNA repair genes, whereas in conventional RT, some DNA repair and cell cycle-related genes that initially seemed to be preferentially expressed dwindled to normal levels. Earlier in vitro experiments using cell survival to study sublethal damage repair support our conclusions. Bioinformatic investigation revealed a correlation of gene expression with derepression effects of microRNA molecules. We have presented opinions as to how microRNAs might influence gene expression during radiation-induced stress and have suggested future avenues for research.

Nutrition and orthomolecular supplementation in lung cancer patients.

This article reviews updates and provides some data related to nutritional and orthomolecular supplementation in oncology patients with an emphasis on lung cancer, a commonly diagnosed tumor with significant nutritional disturbances. Cancer and its treatment play a significant role in nutritional imbalance which likely has negative impact on the patient both in terms of quality and quantity of life. Nutritional supplementation may correct these imbalances with significant clinical benefit both physiologically and psychologically. This review will help assist in providing clinically useful data to assess the cancer patient's nutritional status and to guide nutritional intervention to assist these patients' recovery.

Isodose-based methodology for minimizing the morbidity and mortality of thoracic hypofractionated radiotherapy.

BACKGROUND AND PURPOSE: Help identify and define potential normal tissue dose constraints to minimize the mortality and morbidity of hypofractionated lung radiotherapy. MATERIALS AND METHODS: A method to generate isodose-based constraints and visually evaluate treatment plans, based on the published peer reviewed literature and the linear quadratic model, is presented. The radiobiological analysis assumes that the linear quadratic model is valid up to 28 Gy per fraction, the alpha/beta ratio is 2 for the spinal cord and brachial plexus, 4 for pneumonitis, 4 or 10 for acute skin reactions depending on treatment length, and 3 for late complications in other normal tissues. A review of the literature was necessary to identify possible endpoints and normal tissue constraints for thoracic hypofractionated lung radiotherapy. RESULTS: Preliminary normal tissue constraints to reduce mortality and morbidity were defined for organs at risk based upon hypofractionated lung radiotherapy publications. A modified dose nomenclature was introduced to facilitate the comparison of hypofractionated doses. Potential side effects from hypofractionated lung radiotherapy such as aortic dissection, neuropathy, and fatal organ perforation rarely seen in conventional treatments were identified. The isodose-based method for treatment plan analysis and normal tissue dose constraint simplification was illustrated. CONCLUSIONS: The radiobiological analysis based on the LQ method, biologically equivalent dose nomenclature, and isodose-based method proposed in this study simplifies normal tissue dose constraints and treatment plan evaluation. This may also be applied to extrathoracic hypofractionated radiotherapy. Prospective validation of these preliminary thoracic normal tissue dose constraints for hypofractionated lung radiotherapy is necessary.

Enhanced response of the fricke solution doped with hematoporphyrin under X-rays irradiation

The vials filled with Fricke solutions were doped with increasing concentrations of Photogem®, used in photodynamic therapy. These vials were then irradiated with low-energy X-rays with doses ranging from 5 to 20 Gy. The conventional Fricke solution was also irradiated with the same doses. The concentration of ferric ions for the Fricke and doped-Fricke irradiated solutions were measured in a spectrophotometer at 220 to 340 nm. The results showed that there was an enhancement in the response of the doped-Fricke solution, which was proportional to the concentration of the photosensitizer. The use of such procedure for studying the radiosensitizing property of photosensitizers based on the production of free radicals is also discussed.

Tubos de ensaio foram preenchidos com a solução Fricke dopada com Fotogem® em concentrações crescentes; essa hemotoporfirina é utilizada na terapia fotodinâmica. Esses tubos foram irradiados com doses de 5 a 20 Gy. A solução Fricke convencional também foi irradiada com as mesmas doses. As concentrações de íons férricos nas soluções Fricke convencional e dopadas irradiadas foram medidas num espectrofotômetro com comprimento de onda entre 220 e 340 nm. Os resultados mostraram que quando comparado o Fricke convencional com o Fricke dopado irradiado, as amostras dopadas demonstraram um aumento na resposta da dose absorvida que é proporcional a concentração do Photogem® na solução Fricke. Concluímos que esse procedimento pode ser utilizado para propósitos de dosimetria na terapia com radiossensibilizadores.

Photofrin photodynamic therapy: 2.0 mg/kg or not 2.0 mg/kg that is the question.

Photodynamic therapy (PDT) is an innovative minimally invasive therapy that has great potential for both tumor ablation and normal tissue preservation. However, while in recent years the standards of surgery, radiation and chemotherapy have dramatically improved in terms of outcomes and morbidity, the same cannot be said of PDT in general and Photofrin((R))-based PDT in particular. As currently practiced PDT dosimetry has not really improved tumor ablation and diminished side effects over reports from two decades ago. We critically examine the clinical variables available for PDT dosimetry and conclude that the simple maneuver of diminishing drug dose, with an appropriate increase in light dose, can enhance disease control with a significantly lower risk of morbidity. This conclusion should also be applicable to most systemically introduced photosensitizer.

Photodiagnosis for cutaneous malignancy: a brief clinical and technical review.

Photodiagnosis (PD) for cutaneous malignancy attempts to differentiate between normal and diseased skin without the need for histological evaluation. This technique exploits natural or induced differences in fluorescent signatures between these tissues. The technique may be as simple as using ultraviolet light in combination with clinical exam to as complex as optical tomography. While the need is great due to the enormous number of skin lesions currently requiring physical biopsy, the results so far generated are not as specific or sensitive as is required in the clinic. This brief review outlines the value of PD, its potential applications and shortcomings as well as a short primer on the most common technique employed in clinical practice.

Image-guided radiation therapy: current and future directions.

Since its discovery, ionizing radiation has been a cornerstone of cancer treatment. In step with technological advances, radiation therapy has strived to increase its therapeutic ratio. With the advent of 3D and cross-sectional imaging, and the ability to modulate the radiation beam, the current age of radiation oncology was initiated, promising better tumor control rates with fewer side effects. However, these ever more precise and conformal treatments have also revealed the importance of accounting for organ and tumor motion. Efforts to understand and compensate for the uncertainties caused by movement are required to ensure accurate conformal radiation therapy. This review will explore the current and future directions of image-guided radiation therapy, whose goal is to increase the accuracy of radiotherapy.

Inhibition of the CaM-kinases augments cell death in response to oxygen radicals and oxygen radical inducing cancer therapies in MCF-7 human breast cancer cells.

Many cancer treatments induce cell death through lethal oxidative stress. Oxidative stress also induces the activation of the calcium/calmodulin-dependent kinases (CaM-Ks), CaM-KII and CaM-KIV. In turn, the CaM-Ks are known to induce the activation of antiapoptotic signaling pathways, such as Akt, ERK, and NF-kappaB in many different cell types. The aim of this study was to determine the role of CaM-Kinases in resistance to hydrogen peroxide and three oxidative stress-inducing cancer therapies in MCF-7 breast cancer cells. We found that oxidative stress induced CaM-Kinase activity in MCF-7 breast cancer cells and that CaM-K inhibition increased hydrogen peroxide-induced cell death in MCF-7 human breast cancer cells. When MCF-7 cells were treated with doxorubicin, ionizing radiation, or photodynamic therapy in the presence of a CaM-K inhibitor a greater level of cell killing was observed than when cells were treated with doxorubicin, ionizing radiation, or photodynamic therapy alone. In support of this finding, CaM-K inhibition increased hydrogen peroxide-induced apoptosis in MCF-7 cells, as determined by increased number of apoptotic cells, DNA fragmentation, and PARP cleavage. Pharmacological and molecular inhibition indicated that CaM-KII was participating in hydrogen peroxide-induced ERK phosphorylation in breast cancer cells indicating a potential mechanism by which this sensitization occurs. This is the first time that CaM-K inhibition is reported to sensitize cancer cells to reactive oxygen intermediate inducing cancer treatments.

The future of photodynamic therapy in oncology.

The medicinal properties of light-based therapies have been appreciated for millennia. Yet, only in this century have we witnessed the birth of photodynamic therapy (PDT), which over the last few decades has emerged to prominence based on its promising results and clinical simplicity. The fundamental and distinguishing characteristics of PDT are based on the interaction of a photosensitizing agent, which, when activated by light, transfers its energy into an oxygen-dependent reaction. Clinically, this photodynamic reaction is cytotoxic and vasculotoxic. While the current age of PDT is based on oncological therapy, the future of PDT will probably show a significant expansion to non-oncological indications. This harks back to much of the original work from a century ago. Therefore, this paper will attempt to predict the future of PDT, based in part on a review of its origin.

A clinical review of PDT for cutaneous malignancies.

More critical than for most other anatomy, intervention to cutaneous malignancy must not only be therapeutically successful but also achieve excellent cosmetic and functional outcome. As it can achieve those ends, PDT has moved to the forefront in the management of skin cancer. A number of well designed clinical trials and large patient series have reported outstanding outcomes for many histologies. This paper will review the rationale and outcomes of cutaneous PDT to malignancy using both topical and systemic photosensitizers. The benefits and drawbacks of cutaneous PDT are also examined.

Modeling of a type II photofrin-mediated photodynamic therapy process in a heterogeneous tissue phantom.

We present a quantitative framework to model a Type II photodynamic therapy (PDT) process in the time domain in which a set of rate equations are solved to describe molecular reactions. Calculation of steady-state light distributions using a Monte Carlo method in a heterogeneous tissue phantom model demonstrates that the photon density differs significantly in a superficial tumor of only 3 mm thickness. The time dependences of the photosensitizer, oxygen and intracellular unoxidized receptor concentrations were obtained and monotonic decreases in the concentrations of the ground-state photosensitizer and receptor were observed. By defining respective decay times, we quantitatively studied the effects of photon density, drug dose and oxygen concentration on photobleaching and cytotoxicity of a photofrin-mediated PDT process. Comparison of the dependences of the receptor decay time on photon density and drug dose at different concentrations of oxygen clearly shows an oxygen threshold under which the receptor concentration remains constant or PDT exhibits no cytotoxicity. Furthermore, the dependence of the photosensitizer and receptor decay times on the drug dose and photon density suggests the possibility of PDT improvement by maximizing cytotoxicity in a tumor with optimized light and drug doses. We also discuss the utility of this model toward the understanding of clinical PDT treatment of chest wall recurrence of breast carcinoma.