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Photofrin Uptake in the Tumor and Normal Tissues of Patients Receiving Intraperitoneal Photodynamic Therapy

Authors' Affiliations: Departments of ¹ Radiation Oncology, ² Biostatistics and Epidemiology, and ³ Surgery, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Requests for reprints: Theresa M. Busch, Department of Radiation Oncology, University of Pennsylvania, B13 Anatomy and Chemistry, 3620 Hamilton Walk, Philadelphia, PA 19104-6072. Phone: 215-573-3168; Fax: 215-898-0090; E-mail: buschtm{at}mail.med.upenn.edu.

	Abstract

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Purpose: A phase II trial of Photofrin-mediated i.p. photodynamic therapy shown in a previous report limited efficacy and significant acute, but not chronic, toxicity. A secondary aim of this trial and the subject of this report is to determine Photofrin uptake in tumor and normal tissues.

Experimental Design: Patients received Photofrin, 2.5 mg/kg, i.v., 48 hours before debulking surgery. Photofrin uptake was measured by spectroflurometric analysis of drug extracted from tumor and normal tissues removed at surgery. Differences in drug uptake among these tissues were statistically considered using mixed-effects models.

Results: Photofrin concentration was measured in 301 samples collected from 58 of 100 patients enrolled on the trial. In normal tissues, drug uptake significantly (P < 0.0001) differed as a function of seven different tissue types. In the toxicity-limiting tissue of intestine, the model-based mean (SE) Photofrin level was 2.70 ng/mg (0.32 ng/mg) and 3.42 ng/mg (0.24 ng/mg) in full-thickness large and small intestine, respectively. In tumors, drug uptake significantly (P = 0.0015) differed as a function of patient cohort: model-based mean Photofrin level was 3.32 to 5.31 ng/mg among patients with ovarian, gastric, or small bowel cancer; 2.09 to 2.45 ng/mg among patients with sarcoma and appendiceal or colon cancer; and 0.93 ng/mg in patients with pseudomyxoma. Ovarian, gastric, and small bowel cancers showed significantly higher Photofrin uptake than full-thickness large and/or small intestine. However, the ratio of mean drug level in tumor versus intestine was modest (2.31).

Conclusions: Some selectivity is found in Photofrin uptake between tumor and normal tissues of the peritoneal cavity, but absolute differences in drug uptake relative to toxicity-limiting normal tissues (intestine) are small. This narrow differential in drug selectivity likely contributes to a narrow window in therapeutic application, which has been previously reported.

Photofrin is the first-generation photosensitizer that has been approved by the Food and Drug Administration for superficial and obstructing non–small cell lung cancer, obstructing esophageal cancer, and Barrett's esophagus with high-grade dysplasia. We have been interested in evaluating the efficacy of Photofrin-mediated PDT for malignancies that spread or begin on serosal surfaces (3–5). A phase I trial of Photofrin-mediated i.p. PDT was done at the National Cancer Institute and determined a dose level that showed tolerable toxicity (6). Intestinal perforations were shown to be a significant toxicity of this treatment. We recently reported the clinical outcome of a phase II trial of i.p. PDT in 101 patients with recurrent cancers that had spread to the peritoneum (4). Limited clinical efficacy and substantial acute normal tissue toxicity were observed, suggesting that the therapeutic index of this treatment is quite narrow.

A component of this phase II study has been the collection of tumor and normal tissues to measure the absolute uptake, as well as tumor to normal tissue ratios (TTNR) of Photofrin. We have previously published the Photofrin uptake of individual tumor specimens from this trial (4, 7). The present report additionally documents the variation in drug concentration among the tumor of different cohorts of cancer patients and among different normal tissues. We present TTNR and consider, using statistical methods, the question of whether Photofrin is selectively retained by tumors compared with normal tissue.

	Materials and Methods

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Trial design. The primary objective of this phase II study was to determine the efficacy and toxicities of Photofrin-mediated i.p. PDT in patients with peritoneal carcinomatosis and sarcomatosis. A secondary objective was to determine Photofrin content in normal and malignant tissues. Efficacy variables included complete response rate as well as failure-free and overall survival. A total of 100 patients were enrolled in this phase II study. Photofrin (Porfimer sodium), 2.5 mg/kg, was administered i.v. 48 hours before the planned laparotomy. Surgical resection and light delivery were done as described previously (4). The protocol permitted light administration to any patient whose peritoneal disease was resected to a thickness of 5 mm. Toxicity was scored using the National Cancer Institute Cooperative Group Common Toxicity Criteria, version 1.0.

Patient selection. Patients were selected based on the following eligibility criteria: biopsy-proven recurrent peritoneal carcinomatosis or sarcomatosis who had exhausted curative therapies, age >18 years, signed informed consent, and absence of distant metastatic disease. Patients were entered into one of three cohorts: ovarian cancer, sarcoma, and gastrointestinal cancers. The inclusion criteria were previously described (4). The protocol was conducted under an investigator-sponsored Investigational New Drug with the U.S. Food and Drug Administration. This study was done in accordance with the Declaration of Helsinki and had approval from the Institutional Review Board of the University of Pennsylvania and the University of Pennsylvania Clinical Trials Scientific Review and Monitoring Committee.

Specimen collection. Surgical debulking was done under the direction of the attending surgeon. The surgical goal was to resect all tumor to a thickness of 5 mm. Any normal tissue removed as part of the debulking surgery was collected for Photofrin measurement, with an emphasis placed on normal tissues that were at significant risk for toxicity (intestine). Tissue samples were collected from 58 of the 100 patients enrolled on the trial. In some instances, the attending surgeon stripped the mucosa from samples of small and large intestine ex vivo to allow separate determination of Photofrin levels in the intestinal wall versus mucosa. Before illumination began, tumor nodules or biopsies of larger disease and biopsies of normal tissue were resected, placed in specimen containers, protected from visible light, and frozen at –80°C. Tissue samples were collected whenever possible, regardless of whether or not patients received light delivery.

Determination of Photofrin concentration. The spectrofluorometric assay for Photofrin quantification was based on a previous report (8). Tissue samples were thawed to room temperature, weighed, and, depending on the amount available, 10 to 50 mg of tissue were placed in a vial with 0.150 to 0.500 mL of the tissue solubilizer, Solvable (Packard, Meriden, CT). The vial was capped and heated at 50°C overnight (20 ± 2 hours) in the dark. The following day, the solution was cooled to room temperature, mixed with an equal volume of distilled water, and transferred to a quartz cuvette of 200-µL (10 mg samples) or 600-µL (50 mg samples) capacity. The fluorescence of the solubilized sample was measured by a spectrofluorometer (FluoroMax-3; Jobin Yvon, Inc., Edison, NJ) with an excitation wavelength of 405 nm and an emission wavelength of 627 nm. Photofrin concentration in the tissue was calculated based on the increase in fluorescence resulting from the addition of a known amount of Photofrin to each sample after its initial reading. Data are presented as nanograms of Photofrin per milligram of tissue for each unique sample. If tissue mass was sufficient, samples were run in replicate and averaged. A total of 301 tissue samples from 58 patients were evaluated.

Statistical analysis. For initial descriptive purposes, samples from the same tissue type (e.g., small intestine, large intestine) and pathology (i.e., normal versus tumor) were averaged within a patient; medians and ranges were used to summarize these data. A mixed-effects model, a method similar to ANOVA, was subsequently used to examine differences in Photofrin uptake among normal tissue types and among tumor tissues for different cohorts of patients (9). The mixed-effects approach uses multiple measurements of Photofrin by taking into account the correlation between repeated measurements on multiple tissues within the same subject, and allows the estimation of a common intrasubject and intersubject variance. Initially, models were fit for all data from tumors alone and for all data from normal tissue alone. Results from these models are reported as means, SDs, and SEs. Likelihood ratio tests were used to determine an effect of cohort and tissue type on Photofrin concentration, and then Wald tests were used to determine whether mean Photofrin concentrations in individual cohorts or in individual normal tissues differed from zero. Additionally, Wald tests were used to compare uptake among selected tissues. Samples of liver and spleen were omitted from this analysis because these tissues, in addition to having high median (mean) values of Photofrin, tended to have higher variance, which could theoretically invalidate the assumptions needed to carry out the statistical tests.

To consider TTNRs, the analysis was restricted to the 35 patients with samples from both normal and tumor tissues. Summary statistics for TTNR were based on the ratio of drug concentration in tumor and normal tissue within each patient. A mixed-effects model was constructed to estimate the ratio of mean drug level in tumor versus normal tissues across all 35 patients; similar analyses were carried out to those described above for the normal or tumor data alone.

All hypothesis tests were two-sided with a type I error rate of 0.05. Analyses were carried out in R, versions 1.9 and 2.2 (10).

	Results

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A total of 100 patients were enrolled in the clinical trial, whereas one additional patient received PDT on a compassionate use basis; 58 of these contributed samples to the results reported here. The division of these 58 patients among disease cohorts is presented in Table 1 . Each cohort had at least 10 subjects with Photofrin measurements in tumor and/or normal tissues and at least eight subjects with measurements in both tumor and normal tissue. Within the gastrointestinal cohort, over half of the patients with Photofrin measurements came from those with colon cancer, with no more than three patients from each of the remaining groups.

Photofrin uptake in tumor tissues. Among all tumor samples, median Photofrin uptake was 2.6 ng/mg with a range of 0.4 to 6.0 (see Table 2). Although the normal tissue site of some tumor samples was known, the majority (37 of 58) were identified only as "Other." This classification was a consequence of technical and temporal limitations at the time that tumor was collected. Those sites that were named generally had only one or two samples. As such, there was insufficient power to detect meaningful differences among locations, so location was not considered as a variable. However, differences in tumor Photofrin uptake among patient cohorts were statistically significant (P = 0.0015). Model-based mean levels of tumor Photofrin uptake, grouped by cohort, are listed in Table 4 .

Drug selectivity. The TTNR of photosensitizer concentration was calculated for each normal tissue site (Table 5 ). TTNRs ranged from 0.05 in liver to 2.59 in stomach, but statistical testing of the data was limited by the relatively small number of patients with TTNRs available for the same normal tissue. Furthermore, this presentation of the data does not incorporate cohort-dependent differences in tumor drug level, which were shown to be significant. A mixed-effects model was used to estimate differences in drug uptake as a function of tissue type for normal samples and patient cohort for tumor samples. However, the results of the model are presented as ratios of mean drug levels, not to be confused with the mean of the ratios, as shown in Table 5. Model results are listed in Table 6 : mean tumor drug uptake by cohort (first data column) and mean normal tissue drug uptake by tissue type (first data row) are listed, in addition to the TTNR for each cohort/normal tissue combination. Statistical testing was done based on the difference in mean drug uptake between tumor and normal tissue.

	Discussion

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PDT depends on the delivery or synthesis and retention of a photosensitizing agent in tissue to be treated, yet levels of photosensitizer accumulation in solid tumors have infrequently been investigated in a clinical setting. Furthermore, uptake of photosensitizer in normal tissue within the illumination field is a key determinant of therapeutic selectivity and of utmost concern when the treated area incorporates a large surface area and/or toxicity-limiting tissues. We measured the concentration of Photofrin in the tumor and normal tissues of patients participating in a phase II trial of Photofrin PDT for carcinomatosis and sarcomatosis of the peritoneal cavity. Mean tumor Photofrin level ranged from 0.93 ng/mg in three patients with pseudomyxoma to 5.31 ng/mg in one patient with small bowel cancer. Among more highly populated disease cohorts (n = 10-16), substantial Photofrin content was measured in ovarian (3.72 ng/mg) and colon (2.45 ng/mg) cancer, and sarcoma (2.13 ng/mg). Significant drug levels were also measured in treatment-relevant normal tissues, including full-thickness large and small intestine (2.70-3.42 ng/mg). In some instances, mean Photofrin level in these normal tissues was significantly lower than mean Photofrin uptake in tumor of ovarian, small bowel, or gastric cancer, providing some evidence of tumor-enhanced drug uptake. However, in absolute terms, the differential in drug concentration between tumor and normal tissue was small, leading to questionable selective benefit.

Tumor concentrations of Photofrin significantly differed as a function of patient cohort. We speculate that these differences may be a consequence of cohort-dependent differences in disease histology or tumor microenvironment. Previously we reported that even very small (1-2 mm) tumor nodules of peritoneal disease can be vascularized and show substantial Photofrin content (11), yet despite the presence of a vascular system small tumor nodules of peritoneal disease can be hypoxic (7). These observations indicate that the presence of tumor hypoxia within a given individual cannot be interpreted to indicate poor drug delivery/content in that patient. Continuing studies are required to determine the association between hypoxia, photosensitizer uptake, vascularization, and other microenvironmental factors within individual nodules, as well as the effect of disease type (cohort) on these relationships.

As could be expected, significant differences in Photofrin levels were also detected between different types of normal tissue. High drug levels in organs of the reticuloendothelial system, e.g., liver and spleen, were likely associated with macrophage accumulation of Photofrin, as has been reported by others (12, 13). Moderately high Photofrin content in the isolated mucosal layer of both the large and small intestine could perhaps be a consequence of residual fecal matter on this surface after the gross removal of material by handheld instruments and rinsing (14); additionally, the intestinal lining contains high numbers of low-density lipoprotein receptors (15, 16), which have been shown to mediate photosensitizer uptake (17, 18). Substantial Photofrin content in the appendix might also be explained by presence of digestive matter.

The presence of low Photofrin content in the skin and muscle of these patients is consistent with that found in other animal and clinical investigations (2, 19, 20). Muscle and skin Photofrin content in the present study, i.e., 0.71 ± 0.63 and 1.20 ± 0.62 ng/mg, respectively, are in general agreement with mean values of 2.24 ng/mg (range 0.69-3.86 ng/mg) in muscle and 2.19 ng/mg (range 0.67-3.16 ng/mg) in skin, reported in patients exposed to the same photosensitizing conditions as used in our trial (20). Photofrin uptake in fat was also similar between our study (1.38 ± 0.33 ng/mg) and the aforementioned study (2.54 ng/mg; range 0.59-5.48 ng/mg).

Some heterogeneity in photosensitizer uptake was apparent. Intrasubject and intersubject SDs in drug uptake were similar: 0.85 and 0.96 ng/mg, respectively, in normal tissues, and 1.0 and 1.1 ng/mg, respectively, in tumor tissue. In the majority of normal and tumor tissues, the SE in Photofrin concentration was 50% of the model-based mean (Tables 3 and 4). Exceptions include the normal tissues of mesentery, muscle, and pancreas, as well as tumor tissue of pseudomyxoma; these tissues all showed low photosensitizer uptake (<1.61 ng/mg); thus, small intrasubject differences in drug level represented a large percentage (up to 90%) of the mean value. Differences in Photofrin uptake among tumors can be a consequence of microenvironmental factors, as already discussed. Differences in Photofrin uptake among normal tissues of the same histology can be a function of sampling, i.e., biopsies of normal tissues were done by eye and a possible contribution from microscopic disease cannot be ruled out completely. In some instances, different tissues of the same organ were associated with different concentrations of Photofrin, e.g., mucosa versus wall of the intestines; this could contribute to intrasubject and intersubject heterogeneity because at the time of assay individual samples of intestinal tissue were not precisely standardized to include equal proportions of mucosa and intestinal wall. Finally, it should be noted that only a small number of samples were available for some tissue types, which complicates analysis of heterogeneity.

Within all but pseudomyxoma patients, some selectivity in Photofrin uptake for tumor versus a normal tissue of the peritoneal cavity was apparent (Table 6), although significance was not achieved for comparisons to appendiceal tumor. When considering the primary toxicity-limiting normal tissue of this study, i.e., the normal intestine, only cancer of the small bowel was found to show statistically significant selective uptake relative to all types of normal intestinal tissue sampled (large intestine with mucosa, large intestine without mucosa, small intestine with mucosa, and small intestine without mucosa). Colon, ovarian, and gastric disease showed selectivity relative to certain of the normal intestinal tissues. The selectivity in Photofrin uptake between small bowel, colon, ovarian, or gastric cancer and normal tissue of the intestine was in the range of 1.5 to 5, which is in agreement with tumor to normal tissue selectivity reported in other trials (3, 20–22).

Although in some cases the difference in Photofrin content between tumor and normal tissue was statistically significant, these differences were actually very modest. The largest differential in tumor drug content relative to full-thickness intestinal tissue was 3 ng/mg, but differentials of 1.5 to 2.0 ng/mg were more common. Thus, tumor did not have a large therapeutic advantage with regard to photosensitizer accumulation. This is not to say that tumor did not accumulate sufficient photosensitizer to undergo effective photodynamic therapy. Median tumor content of Photofrin in this study (2.6 ng/mg; range 0.4-6 ng/mg) is higher than that reported in basal cell carcinomas (0.53 ng/mg; range 0.29-1.59 ng/mg) treated with a clinically successful protocol (23). However, treatment of the basal cell carcinomas was carried out to a total dose of 215 J/cm², >20-fold higher than the maximum (10 J/cm²) dose delivered in the i.p. trial. High light doses are possible in the treatment of basal cell carcinomas because light delivery can be selectively focused on the disease. In the i.p. trial, the maximum tolerated light dose is limited by normal tissue toxicity within the light field, which includes the entire peritoneal cavity; in other words, the presence of significant drug content in normal tissues necessitates use of a low treatment light dose. Together, a low light dose and the difficulties of precisely delivering this dose to the complicated peritoneal geometry exacerbate the limitations of a small differential in Photofrin content between malignant and normal tissue: All factors likely contribute to the limited efficacy of our i.p. PDT trial (4).

This investigation highlights the importance of measuring photosensitizer uptake in clinical trials of PDT, especially those of large areas or sensitive regions that require drug-based selectivity to control toxicity. Based on data collected from the human peritoneal cavity, we suggest that it is important to consider disease histology as a variable when analyzing tumor content of photosensitizers. However, a caveat of such an analysis is that histology-based differences in drug content may not directly translate into differences in outcome because photosensitizer content is not the sole factor determining therapy response. Regardless of this limitation, knowledge of drug content in the tumor and normal tissues of the peritoneal cavity has significantly aided in the interpretation of outcome in our phase II study of i.p. PDT. Ultimately, we seek to measure tumor drug content through use of minimally invasive, in situ technologies (24, 25).

Our i.p. PDT trial has afforded a valuable opportunity to build a comprehensive data set on Photofrin uptake in tumor and normal tissues of the human peritoneal cavity. However, consistent with the nature of clinical study, it was not possible to collect the same types and numbers of normal tissue specimens from all patients. We present the results in a manner that is intended to allow the reader to view the raw data. Statistical modeling was used to help identify the more subtle aspects of differential Photofrin uptake that might otherwise have been lost due to the complex sampling scheme and the potential confounding of differences between normal tissues as a function of tissue type and between tumor tissues as a function of cohort. To the best of our knowledge, this study represents the largest systematic investigation of tumor and normal tissue levels of Photofrin completed to date in a clinical environment.

	Acknowledgments

 
We thank Rosemarie Mick for her contribution to the statistical analysis of these data.

	Footnotes

 
Grant support: NIH grants PO1 CA-87971 and RO1 CA-85831 and RSNA Scholar Grant.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 4/18/06; revised 6/13/06; accepted 6/30/06.

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