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.

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.

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.

Evaluation of the depth-ratio and backscattering-factor methods in quality control measurements of electron beam energies.

Sensitivities of two different methods for evaluating electron beam energy have been investigated. One of them uses the ratio of ionization at two depths corresponding to two different points on the depth curve of ionization. The other one uses the magnitude of backscattering by lead as a measure of the electron beam energy. The depth-ratio method was found to be sensitive and practical for a routine quality control program. The sensitivity of the backscattering effect was found to be insufficient for electron energies higher than 12 MeV.

AAPM TG-43 formalism for brachytherapy dose calculation of a 137Cs tube source.

We present a development of the use of the AAPM TG-43 dose formalism applied to 137Cs gynecological implant sources. The geometry factor, radial dose function, and anisotropy function of a 137Cs source modeled after the Nuclear Associates 67-809 series stainless steel jacketed tube source were derived following the AAPM TG-43 formalism. The dose rate distribution through the center of the source using the AAPM TG-43 dose formalism is calculated and compared with the calculations obtained using the Sievert summation and Monte Carlo simulation. The three methods resulted in an agreement within less than 5%, or an isodose rate line agreement within 2 mm. We demonstrate that the AAPM TG-43 formalism can be applied to 137Cs linear sources and is capable of serving as a 137Cs dose calculation algorithm that can be used for treatment planning purpose.

Photosensitizers in clinical PDT.

Photosensitizers in photodynamic therapy allow for the transfer and translation of light energy into a type II chemical reaction. In clinical practice, photosensitizers arise from three families-porphyrins, chlorophylls, and dyes. All clinically successful photosensitizers have the ability to a greater or lesser degree, to target specific tissues or their vasculature to achieve ablation. Each photosensitizer needs to reliably activate at a high enough light wavelength useful for therapy. Their ability to fluoresce and visualize the lesion is a bonus. Photosensitizers developed from each family have unique properties that have so far been minimally clinically exploited. This review looks at the potential benefits and consequences of each major photosensitizer that has been tried in a clinical setting.

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.

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.

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.

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.

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.

Avaliaçäo de proteçäo ocular em feixes de elétrons / Evaluation of eye shield for electron beams

Nos tratamentos por radiaçäo, nos quais a regiäo ocular é exposta ao campo de tratamento, uma proteçäo é colocada entre a pálpebra e o globo ocular para proteger as estruturas oculares mais sensíveis à radiaçäo. Isto é importante, pois uma dose de 500 cGy na córnea pode provocar catarata. A efetividade de uma proteçäo ocular construida em chumbo e uma outra proteçäo comercial (Ace Medical Supply Co., New York) foi avaliada para feixes de elétrons de 5,4 MeV e 3,7 MeV. Na avaliaçäo do efeito de concavidade, verificou-se que o formato côncavo desse tipo de proteçäo permite que o dobro de radiaçäo seja transmitida, comparada a uma proteçäo plana. A proteçäo comercial testada apresentou proteçäo suficiente para o feixe de 3,7 MeV/ entretanto, para o feixe de 5,4 MeV a dose na interface proteçäo-material absorvedor foi 56 por cento da dose na profundidade de dose máxima, dmax, sem a proteçäo. A espessura encontrada para uma dose transmitida de aproximadamente 5 por cento da dose em dmax`, para uma proteçäo desse tipo, para este último feixe, foi de 3mm em chumbo. Um aumento significativo da dose na interface externa da proteçäo ocorre devido ao efeito de retroespalhamento dos elétrons. Para que este efeito seja reduzido a um nível de dose próximo à dose em dmax, espessura mínima de 3mm de poliestireno é necessária para ambos os feixes testados