motexafin-lutetium and Prostatic-Neoplasms

Although in early stages of clinical development, photodynamic therapy (PDT) shows promise in delivering focal treatment of both primary and post-radiotherapy prostate cancer. This article will review the mechanism of action of PDT, previous research using PDT for treating prostate cancer including the development of newer vascular-acting photosensitizers, and the potential advantages and disadvantages of PDT in delivering focal therapy.

Topics: Dihematoporphyrin Ether; Humans; Male; Mesoporphyrins; Metalloporphyrins; Photochemotherapy; Photosensitizing Agents; Prostatic Neoplasms; Treatment Outcome

The time course of serum prostate-specific antigen (PSA) response to photodynamic therapy (PDT) of prostate cancer was measured.. Seventeen patients were treated in a phase I trial of motexafin lutetium-PDT. PDT dose was calculated in each patient as the product of the ex vivo measured pre-PDT photosensitizer level and the in situ measured light dose. Serum PSA level was measured within 2 months before PDT (baseline), and at day 1; weeks 1 to 3; months 1, 2, and 3; months 4 to 6; and months 7 to 11 after PDT.. At 24 hours after PDT, serum PSA increased by 98% +/- 36% (mean +/- SE) relative to baseline levels (P = 0.007). When patients were dichotomized based on median PDT dose, those who received high PDT dose showed a 119% +/- 52% increase in PSA compared with a 54% +/- 27% increase in patients treated at low PDT dose. Patients treated with high versus low PDT dose showed a median biochemical delay of 82 versus 43 days (P = 0.024), with biochemical delay defined as the length of time between PDT and a nonreversible increase in PSA to a value greater than or equal to baseline.. Results show PDT to induce large, transient increases in serum PSA levels. Patients who experienced high PDT dose showed greater short-term increase in PSA and a significantly more durable PSA response (biochemical delay). These data strongly promote the need for individualized delivery of PDT dose and assessment of treatment effect in PDT of prostate cancer. Information gained from such patient-specific measurements could facilitate the introduction of multiple PDT sessions in patients who would benefit.

Topics: Dose-Response Relationship, Drug; Humans; Light; Male; Metalloporphyrins; Models, Biological; Photochemotherapy; Photosensitizing Agents; Prostate-Specific Antigen; Prostatic Neoplasms; Radiometry; Recurrence; Time Factors; Treatment Outcome

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

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.. 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.. 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.. 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

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

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

Our purpose was to determine the feasibility of comprehensive treatment of the canine prostate with photodynamic therapy (PDT) using motexafin lutetium (Lu-Tex) and to evaluate the toxicity and tissue effects associated with this treatment. Twenty-five adult male beagles with normal prostate glands were given an i.v. injection of the second-generation photosensitizer Lu-Tex (2-6 mg/kg). An additional two dogs were used as controls and did not receive any photosensitizing drug. All 27 dogs underwent laparotomy to expose the prostate. Three hours postinjection, a total dose of 75-150 J/cm of 732 nm laser light was delivered interstitially and/or transurethrally to the prostate via cylindrical diffusing fibers. Dogs were euthanized between 2 days and 3 months after PDT. All subjects were monitored for clinical evidence of toxicity. Specimens were examined macroscopically and microscopically to characterize the tissue reaction and assess extent of tissue effect as a result of treatment. Interstitial and/or transurethral PDT were successfully delivered in all dogs with no perioperative complications. No clinical evidence of acute urinary obstruction or rectal bleeding was noted. At all dose levels, macroscopic and microscopic evaluation revealed a prostatic tissue reaction characterized initially (within 48 h) by inflammation and necrosis followed by fibrosis and glandular epithelial atrophy. Comprehensive treatment of the entire prostate could be achieved using the interstitial alone approach or combined transurethral and interstitial approach. The transurethral alone approach did not result in complete coverage of the prostate. Dogs receiving transurethral or combined interstitial and transurethral treatment developed erythema and urethral epithelial disruption at all dose levels. Those receiving combined treatment at the highest dose level (Lu-Tex 6 mg/kg, 150 J/cm light) developed urethral fistulae and peritonitis. Dogs treated with the interstitial alone approach were found to have the least amount of urethral damage. Comprehensive treatment of the canine prostate with Lu-Tex PDT is feasible using an interstitial alone or combined interstitial and transurethral approach. The interstitial alone technique results in the least amount of toxicity. The prostatic tissue reaction to treatment is characterized by initial inflammation and necrosis followed by fibrosis and glandular epithelial atrophy.

Topics: Animals; Dogs; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Endoscopy; Light; Male; Metalloporphyrins; Necrosis; Photosensitizing Agents; Phototherapy; Prostate; Prostatic Neoplasms; Time Factors; Urinary Bladder