We evaluate Photofrin-mediated photodynamic therapy (PDT) in a phase 2 clinical trial as an adjuvant to surgery to treat peritoneal carcinomatosis. We extract tissue optical [reduced scattering (mu(s)'), absorption (mu(a)), and attenuation coefficients (mu(eff))] and physiological [blood oxygen saturation (%S(t)O2), total hemoglobin concentration (THC), and photosensitizer concentration (c(Photofrin))] properties in 12 patients using a diffuse reflectance instrument and algorithms based on the diffusion equation. Before PDT, in normal intraperitoneal tissues %S(t)O2 and THC ranged between 32 to 100% and 19 to 263 microM, respectively; corresponding data from tumor tissues ranged between 11 to 44% and 61 to 224 microM. Tumor %S(t)O2 is significantly lower than oxygenation of normal intraperitoneal tissues in the same patients. The mean (+/-standard error of mean) penetration depth (delta) in millimeters at 630 nm is 4.8(+/-0.6) for small bowel, 5.2 (+/-0.67) for large bowel, 3.39(+/-0.29) for peritoneum, 5.19(+/-1.4) for skin, 1.0(+/-0.1) for liver, and 3.02(+/-0.66) for tumor. c(Photofrin) in micromolars is 4.9(+/-2.3) for small bowel, 4.8(+/-2.3) for large bowel, 3.0 (+/-1.0) for peritoneum, 2.5(+/-0.9) for skin, and 7.4(+/-2.8) for tumor. In all tissues examined, mean c(Photofrin) tends to decrease after PDT, perhaps due to photobleaching. These results provide benchmark in-vivo tissue optical property data, and demonstrate the feasibility of in-situ measurements during clinical PDT treatments.
Near-infrared diffuse reflectance spectroscopy (DRS) has been used to noninvasively monitor optical properties during photodynamic therapy (PDT). This technique has been extensively validated in tissue phantoms; however, validation in patients has been limited. This pilot study compares blood oxygenation and photosensitizer tissue uptake measured by multiwavelength DRS with ex vivo assays of the hypoxia marker, 2-(2-nitroimida-zol-1[H]-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide (EF5), and the photosensitizer (motexafin lutetium, MLu) from tissues at the same tumor site of three tumors in two patients with intra-abdominal cancers. Similar in vivo and ex vivo measurements of MLu concentration are carried out in murine radiation-induced fibrosarcoma (RIF) tumors (n=9). The selection of optimal DRS wavelength range and source-detector separations is discussed and implemented, and the association between in vivo and ex vivo measurements is examined. The results demonstrate a negative correlation between blood oxygen saturation (StO(2)) and EF5 binding, consistent with published relationships between EF5 binding and electrode measured pO(2), and between electrode measured pO(2) and StO(2). A tight correspondence is observed between in vivo DRS and ex vivo measured MLu concentration in the RIF tumors; similar data are positively correlated in the human intraperitoneal tumors. These results further demonstrate the potential of in vivo DRS measurements in clinical PDT.
Background The photosensitizer pro-drug 5-aminolevulinic acid (5-ALA) has been administered systemically for photodynamic therapy. Although several toxicities have been reported, nephrotoxicity has never been observed. Materials and Methods Patients with head and neck mucosal dysplasia have been treated on a phase 1 study of escalating light doses in combination with 60 mg/kg of oral 5-ALA. Serum creatinine was measured with the modified Jaffe method or an enzymatic method in the first 24 hours after 5-ALA. Interference by 5-ALA, as well as by its photosensitizing product protoporphyrin IX, was assessed. Results Among 11 subjects enrolled to date, 9 of 11 had blood chemistries collected within the first 5 hours with 7 demonstrating significant grade 3 creatinine elevations (p=0.030). There was no additional evidence of compromised renal function or increased PDT-induced mucositis. Creatinine levels measured by the Jaffe assay increased linearly as a function of the ex-vivo addition of ALA (p<.0001). The exogenous addition of PpIX did not alter creatinine levels. ALA did not interfere with creatinine levels as measured by an enzymatic assay. A total of 4 of the 11 subjects had creatinine levels prospectively measured by both the Jaffe and the enzymatic assays. Only the Jaffe method demonstrated significant elevations as a function of time after ALA administration. Conclusions The transient increase in creatinine after systematic ALA can be attributed, in part, if not entirely, to interference of ALA in the Jaffe reaction. Alternative assays should be employed in situations calling for monitoring of kidney function after systemic ALA.
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