-
Lasers in Surgery and Medicine Jun 2006Interstitial photodynamic therapy (PDT) is an emerging modality for the treatment of solid organ disease. Our group at the University of Pennsylvania has performed...
BACKGROUND AND OBJECTIVES
Interstitial photodynamic therapy (PDT) is an emerging modality for the treatment of solid organ disease. Our group at the University of Pennsylvania has performed extensive studies that demonstrate the feasibility of interstitial PDT for prostate cancer. Our preclinical and clinical experience is herein detailed.
STUDY DESIGN/MATERIALS AND METHODS
We have treated 16 canines in preclinical studies, and 16 human subjects in a Phase I study, using motexafin lutetium-mediated PDT for recurrent prostate adenocarcinoma. Dosimetry of light fluence, drug level and oxygen distribution for these patients were performed.
RESULTS
We demonstrate the safe and comprehensive treatment of the prostate using PDT. However, there is significant variability in the dose distribution and the subsequent tissue necrosis throughout the prostate.
CONCLUSIONS
PDT is an attractive option for the treatment of prostate adenocarcinoma. However, the observed variation in PDT dose distribution translates into uncertain therapeutic reproducibility. Our future focus will be on the development of an integrated system that is able to both detect and compensate for dose variations in real-time, in order to deliver a consistent overall PDT dose distribution.
Topics: Adenocarcinoma; Aged; Animals; Dogs; Dose-Response Relationship, Drug; Hemoglobins; Humans; Male; Metalloporphyrins; Middle Aged; Necrosis; Neoplasm Recurrence, Local; Oxygen; Photochemotherapy; Photosensitizing Agents; Prostate; Prostatic Neoplasms; Regional Blood Flow
PubMed: 16788929
DOI: 10.1002/lsm.20341 -
Photochemistry and Photobiology 2006Photodynamic therapy (PDT) requires oxygen to cause cellular and vascular tumor damage. Tissue oxygen concentration, in turn, is influenced by blood flow and blood...
Photodynamic therapy (PDT) requires oxygen to cause cellular and vascular tumor damage. Tissue oxygen concentration, in turn, is influenced by blood flow and blood oxygenation. Real-time clinical measurement of these hemodynamic quantities, however, is rare. This paper reports the development and application of a probe, combining diffuse reflectance spectroscopy (DRS) for measurement of tumor blood oxygenation and diffuse correlation spectroscopy (DCS) for measurement of tumor blood flow. The instrument was adapted for clinical use during interstitial prostate PDT. Three patients with locally recurrent prostate cancer received 2 mg/ kg motexafin lutetium (MLu) 3 h before illumination and a total light dose of 100 J/cm(2) at 150 mW/cm. Prostrate blood oxygen saturation (StO2) decreased only slightly (approximately 3%) after treatment. On the other hand, prostate blood flow and total hemoglobin concentration over the course of PDT decreased by 50% and 15%, respectively, suggesting MLu-mediated PDT has an anti-vascular effect. While it is certainly impossible to draw definite conclusions from measurements of only three patients, the observed differences in tumor blood flow and blood oxygenation responses during PDT can, in principle, be used to choose among tissue oxygen consumption models and therefore emphasize the potential clinical value for simultaneous monitoring of both parameters.
Topics: Dose-Response Relationship, Radiation; Drug Monitoring; Humans; Kinetics; Light; Lighting; Male; Metalloporphyrins; Neoplasm Recurrence, Local; Phantoms, Imaging; Photochemotherapy; Photosensitizing Agents; Prostatic Neoplasms
PubMed: 16696593
DOI: 10.1562/2005-10-19-RA-721 -
The Journal of Surgical Research Oct 2006Local recurrence of rectal cancer remains a significant clinical problem despite multi-modality therapy. Photodynamic Therapy (PDT) is a cancer treatment which generates... (Comparative Study)
Comparative Study
PURPOSE
Local recurrence of rectal cancer remains a significant clinical problem despite multi-modality therapy. Photodynamic Therapy (PDT) is a cancer treatment which generates tumor kill through the production of singlet oxygen in cells containing a photosensitizing drug when exposed to laser light of a specific wavelength. PDT is a promising modality for prevention of local recurrence of rectal cancer for several reasons: tumor cells may selectively retain photosensitizer at higher levels than normal tissues, the pelvis after mesorectal excision is a fixed space amenable to intra-operative illumination, and PDT can generate toxicity in tissues up to 1 cm thick. This study evaluated the safety, tissue penetration of 730 nm light, normal tissue toxicity and surgical outcome in a dog model of rectal resection after motexafin lutetium-mediated photodynamic therapy.
METHODS
Ten mixed breed dogs were used. Eight dogs underwent proctectomy and low rectal end to end stapled anastomosis. Six dogs received the photosensitizing agent motexafin lutetium (MLu, Pharmacyclics, Inc., Sunnyvale, CA) of 2 mg/kg preoperatively and underwent subsequent pelvic illumination of the transected distal rectum of 730 nm light with light doses ranging from 0.5 J/cm(2) to 10 J/cm(2) three hours after drug delivery. Two dogs received light, but no drug, and underwent proctectomy and low-rectal stapled anastomosis. Two dogs underwent midline laparotomy and pelvic illumination. Light penetration in tissues was determined for small bowel, rectum, pelvic sidewall, and skin. Clinical outcomes were recorded. Animals were sacrificed at 14 days and histological evaluation was performed.
RESULTS
All dogs recovered uneventfully. No dog suffered an anastomotic leak. Severe tissue toxicity was not seen. Histological findings at necropsy revealed mild enteritis in all dogs. The excitation light penetration depths were 0.46 +/- 0.18, 0.46 +/- 0.15, and 0.69 +/- 0.39 cm, respectively, for rectum, small bowel, and peritoneum in dogs that had received MLu. For control dogs without photosensitizer MLu, the optical penetration depths were longer: 0.92 +/- 0.63, 0.67 +/- 0.10, and 1.1 +/- 0.80 cm for rectum, small bowel, and peritoneum, respectively.
CONCLUSION
Low rectal stapled anastomosis is safe when performed with MLu-mediated pelvic PDT in a dog model. Significant tissue penetration of 730 nm light into the rectum and pelvic sidewall was revealed without generation of significant toxicity or histological sequelae. Penetration depths of 730 nm light in pelvic tissue suggest that microscopic residual disease of less than 5 mm are likely to be treated adequately with MLu-mediated PDT. This approach merits further investigation as an adjuvant to total mesorectal excision and chemoradiation for rectal cancer.
Topics: Anastomosis, Surgical; Animals; Dogs; Evaluation Studies as Topic; Metalloporphyrins; Photochemotherapy; Photosensitizing Agents; Rectal Neoplasms
PubMed: 16650871
DOI: 10.1016/j.jss.2006.01.020 -
Journal of Environmental Pathology,... 2006Locally recurrent prostate cancer after treatment with radiation therapy is a clinical problem with few acceptable treatments. One potential treatment, photodynamic...
Locally recurrent prostate cancer after treatment with radiation therapy is a clinical problem with few acceptable treatments. One potential treatment, photodynamic therapy (PDT), is a modality that uses laser light, drug photosensitizer, and oxygen to kill tumor cells through direct cellular cytotoxicity and/or through destruction of tumor vasculature. A Phase I trial of interstitial PDT with the photosensitizer Motexafin lutetium was initiated in men with locally recurrent prostate cancer. In this ongoing trial, the primary objective is to determine the maximally tolerated dose of Motexafin lutetium-mediated PDT. Other objectives include evaluation of Motexafin lutetium uptake from prostate tissue using a spectrofluorometric assay and evaluation of optical properties in the human prostate. Fifteen men with biopsy-proven locally recurrent prostate cancer and no evidence of distant metastatic disease have been enrolled and 14 have been treated. Treatment plans were developed using transrectal ultrasound images. The PDT dose was escalated by increasing the Motexafin lutetium dose, increasing the 732 ran light dose, and decreasing the drug-light interval. Motexafin lutetium doses ranged from 0.5 to 2 mg/kg administered IV 24, 6, or 3 hr prior to 732 ran light delivery. The light dose, measured in real time with in situ spherical detectors was 25-100 J/cm2. Light was delivered via optical fibers inserted through a transperineal brachytherapy template in the operating room. Optical property measurements were made before and after light therapy. Prostate biopsies were obtained before and after light delivery for spectrofluorometric measurements of photosensitizer uptake. Fourteen patients have completed protocol treatment on eight dose levels without dose-limiting toxicity. Grade I genitourinary symptoms that are PDT related have been observed. One patient had Grade II urinary urgency that was urinary catheter related. No rectal or other gastrointestinal PDT-related tox-icities have been observed to date. Measurements of Motexafin lutetium demonstrated the presence of photosensitizer in prostate tissue from all patients. Optical property measurements demonstrated substantial heterogeneity in the optical properties of the human prostate gland which supports the use of individualized treatment planning for prostate PDT.
Topics: Adenocarcinoma; Aged; Humans; Male; Maximum Tolerated Dose; Metalloporphyrins; Middle Aged; Photochemotherapy; Photosensitizing Agents; Prostatic Neoplasms
PubMed: 16566729
DOI: 10.1615/jenvironpatholtoxicoloncol.v25.i1-2.230 -
Medical Physics Dec 2005The primary aim of this study was to determine whether optimized photodynamic therapy (PDT) treatment planning (seeking optimized positions, lengths, and strengths of...
The primary aim of this study was to determine whether optimized photodynamic therapy (PDT) treatment planning (seeking optimized positions, lengths, and strengths of the light sources to satisfy a given dose prescription) can improve dose coverage to the prostate and the sparing of critical organs relative to what can be achieved by the standard PDT plan. The Cimmino algorithm and search procedures based on that algorithm were tested for this purpose. A phase I motexafin lutetium (MLu)-mediated photodynamic therapy protocol is ongoing at the University of Pennsylvania. PDT for the prostate is performed with cylindrical diffusing fibers of various lengths inserted perpendicular to a base plate to obtain longitudinal coverage by a matrix of parallel catheters. The standard plan for the protocol uses sources of equal strength with equal spaced (1-cm) loading. Uniform optical properties were assumed. Our algorithms produce plans that cover the prostate and spare the urethra and rectum with less discrepancy from the dose prescription than the standard plan. The Cimmino feasibility algorithm is fast enough that changes to the treatment plan may be made in the operating room before and during PDT to optimize light delivery.
Topics: Algorithms; Biophysical Phenomena; Biophysics; Clinical Protocols; Humans; Male; Metalloporphyrins; Optics and Photonics; Photochemotherapy; Photosensitizing Agents; Prostatic Neoplasms
PubMed: 16475751
DOI: 10.1118/1.2107047 -
IDrugs : the Investigational Drugs... Mar 2001Pharmacyclics is developing the photosensitizer, motexafin lutetium as Antrin for the potential treatment of restenosis and atherosclerotic plaques, Lutrin for the...
Pharmacyclics is developing the photosensitizer, motexafin lutetium as Antrin for the potential treatment of restenosis and atherosclerotic plaques, Lutrin for the possible treatment of cancer, and Optrin for the possible treatment of age-related macular degeneration (AMD). ANTRIN: A phase II multicenter, randomized, controlled study involving 375 peripheral artery disease (PAD) patients is being conducted in the US. It is designed to evaluate Antrin photoangioplasty as a primary treatment for PAD and for the prevention of restenosis following balloon angioplasty [341341,347151]. LUTRIN: Lutrin is being developed for the possible treatment of a number of cancers [348919]. In July 1997, the compound entered phase II trials for breast cancer [323952,323929]. In August 2000, the compound was undergoing a phase IIb trial for advanced refractory breast cancer [380234]. OPTRIN: In May 2000, Pharmacyclics reported preliminary results from an ongoing phase II dose-ranging study with Optrin for the photodynamic therapy of patients with AMD [365074].
PubMed: 16025394
DOI: No ID Found -
Investigative Ophthalmology & Visual... Jun 2005Anastomotic vessels in exudative age-related macular degeneration (AMD) represent a serious clinical feature that reportedly does not respond well to either...
PURPOSE
Anastomotic vessels in exudative age-related macular degeneration (AMD) represent a serious clinical feature that reportedly does not respond well to either photocoagulation or photodynamic therapy (PDT). Anastomoses also occur in various animal models of choroidal neovascularization (CNV). In the present study, anastomotic vessels and their patency were evaluated in two primate CNV laser-trauma models after PDT, by using two novel photosensitizers.
METHODS
In cynomolgus (Macaca fascicularis) and squirrel (Saimiri sciureus) monkey eyes (n = 20), matrix placement of laser photocoagulation sites elicited CNV as a component of the development of fibrovascular tissue (FVT). FVT sites received PDT according to specific drug infusion and laser light treatment parameters. FVTs and anastomoses were evaluated by fundus photography, fluorescein angiography, and histologic examination.
RESULTS
Anastomoses averaged approximately 48% of FVT sites, with greatest occurrence in the macaque. Although PDT with each photosensitizer effectively produced FVT closure, both retinal vessels and anastomoses remained patent.
CONCLUSIONS
Although PDT is effective in closing the choroidal neovascularization in FVT, this technique was ineffective in occluding anastomotic vessels and their associated tributaries within the mid- to proximal retina. Various factors (vascular diameter, composition, blood flow, orientation) may contribute to continued anastomotic patency. By convention, such vessels would typically be defined as chorioretinal anastomoses (CRAs); however, continuing studies suggest the possibility that these neovessels constitute dual-origin hybrids. Regardless of origin, viable anastomoses provide one potential mechanism for revascularization to occur after PDT and may help to explain why CRAs are considered a poor prognostic sign in patients with AMD.
Topics: Animals; Arteriovenous Anastomosis; Choroid; Choroidal Neovascularization; Disease Models, Animal; Fibrosis; Fluorescein Angiography; Laser Coagulation; Macaca fascicularis; Metalloporphyrins; Photochemotherapy; Photosensitizing Agents; Regional Blood Flow; Retinal Vessels; Saimiri
PubMed: 15914638
DOI: 10.1167/iovs.04-1442 -
Journal of Photochemistry and... Jun 2005It is desirable to quantify the distribution of the light fluence rate, the optical properties, the drug concentration, and the tissue oxygenation for photodynamic... (Clinical Trial)
Clinical Trial
Determination of the distribution of light, optical properties, drug concentration, and tissue oxygenation in-vivo in human prostate during motexafin lutetium-mediated photodynamic therapy.
It is desirable to quantify the distribution of the light fluence rate, the optical properties, the drug concentration, and the tissue oxygenation for photodynamic therapy (PDT) of prostate cancer. We have developed an integrated system to determine these quantities before and after PDT treatment using motorized probes. The optical properties (absorption (micro(a)), transport scattering (micro(s'), and effective attenuation (micro(eff)) coefficients) of cancerous human prostate were measured in-vivo using interstitial isotropic detectors. Measurements were made at 732 nm before and after motexafin lutetium (MLu) mediated PDT at different locations along each catheter. The light fluence rate distribution was also measured along the catheters during PDT. Diffuse absorption spectroscopy measurement using a white light source allows extrapolation of the distribution of oxygen saturation StO2, total blood volume ([Hb]t), and MLu concentration. The distribution of drug concentration was also studied using fluorescence from a single optical fiber, and was found to be in good agreement with the values determined by absorption spectroscopy. This study shows significant inter- and intra-prostatic variations in the tissue optical properties and MLu drug distribution, suggesting that a real-time dosimetry measurement and feedback system for monitoring these values during treatment should be considered in future PDT studies.
Topics: Dose-Response Relationship, Drug; Drug Monitoring; Humans; Light; Male; Metalloporphyrins; Optics and Photonics; Oxygen; Photochemotherapy; Prostatic Neoplasms; Spectrophotometry
PubMed: 15896650
DOI: 10.1016/j.jphotobiol.2004.09.013 -
Proceedings of SPIE--the International... Apr 2005Among the challenges to the clinical implementation of photodynamic therapy (PDT) is the delivery of a uniform photodynamic dose to induce uniform damage to the target...
Among the challenges to the clinical implementation of photodynamic therapy (PDT) is the delivery of a uniform photodynamic dose to induce uniform damage to the target tissue. As the photodynamic dose depends on both the local sensitizer concentration and the local fluence rate of treatment light, knowledge of both of these factors is essential to the delivery of uniform dose. In this paper, we investigate the distribution and kinetics of the photosensitizer motexafin lutetium (MLu, Lutrin®) as revealed by its fluorescence emission. Our current prostate treatment protocol involves interstitial illumination of the organ cylindrical diffusing fibers (CDF's) inserted into the prostate though clear catheters. For planning and treatment purposes, the prostate is divided into 4 quadrants. We use one catheter in each quadrant to place an optical fiber-based fluorescence probe into the prostate. This fiber is terminated in a beveled tip, allowing it to deliver and collect light perpendicular to the fiber axis. Excitation light is provided by a 465 nm light emitting diode (LED) source coupled to a dichroic beamsplitter, which passes the collected fluorescence emission to a CCD spectrograph. Spectra are obtained before and after PDT treatment in each quadrant of the prostate and are analyzed a linear fitting algorithm to separate the MLu fluorescence from the background fluorescence originating in the plastic catheter. A computer-controlled step motor allows the excitation/detection fiber to be moved along the catheter, building up a linear profile of the fluorescence emission spectrum of the tissue as a function of position. We have analyzed spectral fluorescence profiles obtained in 4 patients before and after MLu-mediated PDT. We find significant variation both within individual prostates and among patients. Within a single quadrant, we have observed the fluorescence signal to change by as much as a factor of 3 over a distance of 2 cm. Comparisons of pre- and post-PDT spectra allow a quantification treatment-induced photobleaching. Like the drug distribution, the extent of photobleaching varies widely among patients. In two cases, we observed bleaching of approximately 50% of the drug, while others exhibited negligible photobleaching.
PubMed: 26136613
DOI: 10.1117/12.590709 -
Proceedings of SPIE--the International... Apr 2005To deliver uniform photodynamic dose to the prostate gland, it is necessary to develop algorithms that optimize the location and strength (emitted power × illumination...
To deliver uniform photodynamic dose to the prostate gland, it is necessary to develop algorithms that optimize the location and strength (emitted power × illumination time) of each light source. Since tissue optical properties may change with time, rapid (almost real-time) optimization is desirable. We use the Cimmino algorithm because it is fast, linear, and always converges reliably. A phase I motexafin lutetium (MLu)-mediated photodynamic therapy (PDT) protocol is on-going at the University of Pennsylvania. The standard plan for the protocol uses equal source strength and equal spaced loading (1-cm). PDT for the prostate is performed with cylindrical diffusing fibers (CDF) of various lengths inserted to longitudinal coverage within the matrix of parallel catheters perpendicular to a base plate. We developed several search procedures to aid the user in choosing the positions, lengths, and intensities of the CDFs. The Cimmino algorithm is used in these procedures to optimize the strengths of the light catheters at each step of the iterative selection process. Maximum and minimum bounds on allowed doses to points in four volumes (prostate, urethra, rectum, and background) constrain the solutions for the strengths of the linear light sources. Uniform optical properties are assumed. To study how different opacities of the prostate would affect optimization, optical kernels of different light penetration were used. Another goal is to see whether the urethra and rectum can be spared, with minimal effect on PTV treatment delivery, by manipulating light illumination times of the sources. Importance weights are chosen beforehand for organ volumes, and normalized. Compared with the standard plan, our algorithm is shown to produce a plan that better spares the urethra and rectum and is very fast. Thus the combined selection of positions, lengths, and strengths of interstitial light sources improves outcome.
PubMed: 26136612
DOI: 10.1117/12.590343