Hypoxia and Photofrin uptake in the intraperitoneal carcinomatosis and sarcomatosis of photodynamic therapy patients.
OBJECTIVE
Response to photodynamic therapy depends on adequate tumor oxygenation as well as sufficient accumulation of photosensitizer in the tumor. The goal of this study was to investigate the presence of hypoxia and retention of the photosensitizer Photofrin in the tumors of patients with intra-abdominal carcinomatosis or sarcomatosis.


METHODS
Tumor nodules from 10 patients were studied. In nine of these patients, hypoxia was identified in histological sections of biopsied tumor after administration of the hypoxia marker 2-(2-nitroimidazol-1[H]-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide (EF5). In separate tumor nodules from 10 patients, Photofrin uptake was measured by fluorescence after tissue solubilization.


RESULTS
Hypoxia existed in the tumors of five patients, with three of these patients demonstrating at least one severely hypoxic nodule. Physiological levels of oxygen were present in the tumors of four patients. An association between tumor size and hypoxia was not evident because some tumor nodules as small as approximately 2 mm in diameter were severely hypoxic. However, even these tumor nodules contained vascular networks. Three patients with severely hypoxic tumor nodules exhibited moderate levels of Photofrin uptake of 3.9 +/- 0.4 to 3.9 +/- 0.5 ng/mg (mean +/- SE). The four patients with tumors of physiological oxygenation did not consistently exhibit high tumor concentrations of Photofrin: mean +/- SE drug uptake among these patients ranged from 0.6 +/- 0.8 to 5.8 +/- 0.5 ng/mg.


CONCLUSIONS
Carcinomatosis or sarcomatosis of the i.p. cavity may exhibit severe tumor hypoxia. Photofrin accumulation in tumors varied by a factor of approximately 10x among all patients, and, on average, those with severe hypoxia in at least one nodule did not demonstrate poor Photofrin uptake in separate tumor samples. These data emphasize the need for reconsideration of the generally accepted paradigm of small tumor size, good oxygenation, and good drug delivery because this may vary on an individual tumor basis.
Department of Radiation Oncology, Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA. buschtm@mail.med.upenn.edu
Theresa M
TM
Busch
Stephen M
SM
Hahn
E Paul
EP
Wileyto
Cameron J
CJ
Koch
Douglas L
DL
Fraker
Paul
P
Zhang
Mary
M
Putt
Kristen
K
Gleason
Daniel B
DB
Shin
Michael J
MJ
Emanuele
Kevin
K
Jenkins
Eli
E
Glatstein
Sydney M
SM
Evans
D001063:Appendiceal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D001562:Benzimidazoles / Q000737:chemistry; D001667:Binding, Competitive / Q000187:drug effects; D002232:Carbocyanines / Q000737:chemistry; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D017323:Dihematoporphyrin Ether / Q000493:pharmacokinetics*; D017341:Etanidazole / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D046152:Gastrointestinal Stromal Tumors / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry / Q000378:metabolism; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology; D008297:Male; D008856:Microscopy, Fluorescence; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D010100:Oxygen / Q000494:pharmacology; D010778:Photochemotherapy; D012509:Sarcoma / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D005466:Fluorocarbons
D001562:Benzimidazoles; D002232:Carbocyanines; D017323:Dihematoporphyrin Ether; D017341:Etanidazole; D006845:Hydrocarbons, Fluorinated; D010100:Oxygen; C089187:cyanine dye 3; C096011:2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide; D005466:Fluorocarbons; C017807:bisbenzimide ethoxide trihydrochloride