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.

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.

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.

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.

An ultrasonic device for source to skin surface distance measurement in patient setup.

PURPOSE: To develop an ultrasound-based source to skin surface distance (SSD) measurement technique and device for patient setup and test its feasibility and accuracy. METHODS AND MATERIALS: The ultrasonic SSD measurement device (USD) prototype consists of two main parts: a probe plate with an ultrasonic transducer in the center and a control unit that displays the SSD in millimeters. The probe plate can be slid into the block tray accessory slot of any treatment machine at the time of the SSD measurement. The probe plate contains an ultrasonic transducer as both the source and the detector for measuring the distance between the transducer and the target surfaces on the basis of an echo-detecting technique. The device was calibrated by a mechanical ruler with an accuracy of 0.01 mm and corrected by an offset of 601.7 mm, which is the distance from the radiation source to the ultrasonic transducer surface for the Siemens Primus linear accelerator (Linac). The ultrasound device provided digital readout with an accuracy of +/-0.1 mm for a flat surface after calibration. The SSD measurement experiments were done with the USD, an optical distance indicator (ODI), and an AKTINA 53-104 Mechanical Front Pointer (FP) on a Siemens Primus Linac with a full-sized female phantom. Ten measurements were carried out at each gantry angle of 0 degrees , 52 degrees , 85 degrees , 90 degrees , and 227 degrees for anatomic locations of head, thorax, breast, and pelvis, to obtain the average values and standard deviations. RESULTS: The comparison study with the ODI and FP showed that the USD had an accuracy of less than +/-1.0 mm and that USD measurements had the minimum standard deviations among the three methods; therefore, USD gave more consistent and accurate readouts for SSD measurement. When considering the FP as a reference, the USD yields smaller deviations than the ODI for all measured locations (less than +/-2 mm). The variation of USD digital readout with a room temperature change of +/-2 degrees C is +/-0.1 mm, which is sufficiently accurate for SSD measurement. CONCLUSIONS: The USD method has the following advantages. First, it decreases patient setup time by avoiding problems related to the blocking of the device by the patient or by the immobilization device. Second, it is more accurate than the other two methods currently used, as the test data show. Last, the digital readout eliminates the possibility of human reading error associated with the visual scales.

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.

Plug pattern optimization for gamma knife radiosurgery treatment planning.

PURPOSE: To develop a novel dose optimization algorithm for improving the sparing of critical structures during gamma knife radiosurgery by shaping the plug pattern of each individual shot. METHOD AND MATERIALS: We first use a geometric information (medial axis) aided guided evolutionary simulated annealing (GESA) optimization algorithm to determine the number of shots and isocenter location, size, and weight of each shot. Then we create a plug quality score system that checks the dose contribution to the volume of interest by each plug in the treatment plan. A positive score implies that the corresponding source could be open to improve tumor coverage, whereas a negative score means the source could be blocked for the purpose of sparing normal and critical structures. The plug pattern is then optimized via the GESA algorithm that is integrated with this score system. Weight and position of each shot are also tuned in this procedure. RESULTS: An acoustic tumor case is used to evaluate our algorithm. Compared to the treatment plan generated without plug patterns, adding an optimized plug pattern into the treatment planning process boosts tumor coverage index from 95.1% to 97.2%, reduces RTOG conformity index from 1.279 to 1.167, lowers Paddick's index from 1.34 to 1.20, and trims the critical structure receiving more than 30% maximum dose from 16 mm(3) to 6 mm(3). CONCLUSIONS: Automated GESA-based plug pattern optimization of gamma knife radiosurgery frees the treatment planning team from the manual forward planning procedure and provides an optimal treatment plan.

An anthropomorphic phantom for quality assurance and training in gynaecological brachytherapy.

BACKGROUND AND PURPOSE: An anthropomorphic water filled polymethylmethacrylate (PMMA) phantom designed to serve as a Quality Assurance (QA) tool and a training aid in brachytherapy of gynaecological tumours is investigated and presented. Several dosimetric parameters associated with the dose rate calculation can be verified with the aid of this phantom such as the source positioning, its imaging reconstruction from radiographs and the accuracy of the algorithm used for manual or computer dose rate calculation. MATERIAL AND METHODS: The phantom walls and the internal structure are 5mm thick and consist of PMMA, in the form of the abdomen taken from a female Alderson Phantom Marker points representing the organs of interest were determined from computed tomography scans of a patient of similar size. Three PMMA inserts designed to hold a Farmer type ionization chamber of 0.6 cm(3) were positioned at the points to represent the bladder, rectum and point A. The formalism proposed by the IAEA TRS-277 dosimetry protocol was used for the conversion of readings of the ionization chamber to dose rate values with a modification to take into account the dose rate gradient in the detector. Five 137Cs sources were used and the dose rate was evaluated by measurements and Monte Carlo simulations using the PENELOPE code. Four different treatment planning systems with different algorithms and source reconstruction techniques were also used in this investigation and compared with the manual dose rate calculations made using Karen and Breitman's tables. RESULTS: The dose rate calculations performed with Monte Carlo and the four treatment planning systems are in good agreement with the experimental results as well as with the manual calculations when the colpostat shielding and the tandem attenuation are taken into account. The comparison between experiment and calculations by the four treatment planning systems shows a maximum variation of 5.1% between the calculated and measured dose rate at the point A. CONCLUSIONS: This phantom is suitable for use during the acceptance tests of treatment planning systems and applicators, as educational tool, for dosimetric research problems and for the QA of brachytherapy sources.

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.

Implementation of the isocenter-shift technique for smoothing MLC field edge on a 3D treatment planning system.

Stepped leaf edges are the major limitation of conforming to the prescribed treatment contour defined by the conventional multileaf collimator (MLC), which produces a scalloped dose pattern. The commercial HD-270 MLC (HDI) technique provides a software solution of the conventional MLC to achieve smoothed edge and optimal penumbra of the MLC shaped field. We implemented the HDI functionality on a 3D treatment planning system and compared the dosimetric effects of the HDI delivery in simulation with those in experiment for a number of the MLC fields. The fields from the contour of varied shapes with different sizes of the leaf stepping were tested for the HDI delivery. There is a good agreement of the dose distribution between the calculation as implemented in the planning system and the measurement performed on the treatment machine. It has been shown that the HDI delivery significantly smooths the stepped field edge with the reduced isodose undulation and effective penumbra. A problem may be present when the HDI is applied for the treatment of the circular contour of smaller diameter, and the conformity of the MLC shaping may not be achievable satisfactorily with the existing system. The optimization of leaf configuration is suggested to improve the conformity of the HDI technique. The HDI planning then can be used to assist in the decision making of applying the HDI treatment delivery.

Dosimetric considerations for patients with HIP prostheses undergoing pelvic irradiation. Report of the AAPM Radiation Therapy Committee Task Group 63.

This document is the report of a task group of the Radiation Therapy Committee of the AAPM and has been prepared primarily to advise hospital physicists involved in external beam treatment of patients with pelvic malignancies who have high atomic number (Z) hip prostheses. The purpose of the report is to make the radiation oncology community aware of the problems arising from the presence of these devices in the radiation beam, to quantify the dose perturbations they cause, and, finally, to provide recommendations for treatment planning and delivery. Some of the data and recommendations are also applicable to patients having implanted high-Z prosthetic devices such as pins, humeral head replacements. The scientific understanding and methodology of clinical dosimetry for these situations is still incomplete. This report is intended to reflect the current state of scientific understanding and technical methodology in clinical dosimetry for radiation oncology patients with high-Z hip prostheses.

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.

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.

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.

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.

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.