Photoimmunotherapy and Ovarian Cancer: an Improbable Fiction or a Palpable Hit?
Authors: Z. A. Tochner, S. Hahn, E. Glatstein
Journal: JNCI Journal of the National Cancer Institute (1999)

For more than two decades, epithelial carcinoma of the ovary has been the number 1 killer of U.S. women with cancers of the female genital tract (1). Despite impressive response rates to combination chemotherapy, the large majority of tumors recur, and fewer than 20% of women who present with advanced disease will survive 10 years (2). Long-term survival figures with modern combinations of paclitaxel and platinum-based drugs are only slightly better than the survival figures with platinum-based combination chemotherapy studies of the late 1970s (2–4). Ongoing clinical research has focused primarily on the role of surgery and the development of new chemotherapy agents. The standard approach to treatment for patients with advanced intraperitoneal ovarian carcinoma is to resect as much disease as possible at initial laparotomy. Postoperatively, patients receive platinum-based systemic therapy combined with paclitaxel. To improve the still very disappointing results, several groups of investigators (5–7) have studied the use of intraperitoneal and high-dose chemotherapy, based on the assumption that changing the mode of administration of the same drugs will lead to substantive improvement of outcome. Ovarian carcinoma develops within the celomic epithelium that invaginates into the ovary. The neoplastic process typically penetrates the capsule, spreads along the ovarian surface, and frequently disseminates throughout the peritoneal cavity via peritoneal fluids. Spread by lymphatic and hematogenous dissemination may also occur, but generally later and at a more advanced stage of disease. The tumor cells that migrate within the peritoneal cavity eventually nest on the peritoneal surface and form colonies that initially receive their nutrients by diffusion; ultimately, these neoplastic colonies develop their own blood supply, although precisely how is unclear. The likelihood of intravenously administered chemotherapy reaching curative levels by diffusion into tissues and completely destroying micrometastases would appear to be limited; early events in this process of peritoneal spread are analogous to a dynamic in vitro system—that is, small colonies of cells on a smooth surface without a discrete blood supply. This would seem to be a logical reason for the frequent inability of systemic chemotherapy to eradicate micrometastatic ovarian carcinoma, despite excellent clinical response rates. High-dose chemotherapy and intraperitoneal chemotherapy are both intended to overcome this problem, but they are limited by these aspects of basic tumor physiology—that is, initial absence of blood supply and dependence on the diffusion process. Given the low long-term success rate of existing chemotherapy protocols, there is definitely a need for improved and different modalities. Photodynamic therapy consists of the administration of nontoxic photosensitizers that are retained in malignant tissues and activated by light delivered at a specific wavelength that is consistent with the absorption spectrum of the sensitizer. This activation results in a sequence of photochemical processes and the production of active molecular species. The cytotoxic properties of photodynamic therapy often result in rapid destruction of tumor cells even when the cells are either chemoresistant or radioresistant (8). That such treatment could work effectively for peritoneal (or pleural) disease might initially appear to be an example of Shakespeare’s “improbable fiction.” For photodynamic therapy to be effective in the treatment of ovarian cancer, several basic requirements must be fulfilled. First, there must be photosensitizer uptake by all malignant cells, including cells in macroscopic and microscopic disease. The reported relative selectivity of the photosensitizer for malignant cells compared with normal tissues is also important and gives photodynamic therapy its unique clinical appeal. The second requirement for this binary system is that a sufficient amount of light energy at the correct wavelength reach all tumor cells while the sensitizer is present. Third, there must be an adequate level of oxygen present to allow formation of the toxic molecular species. The concentration of oxygen required for optimal treatment of those small surface nodules is unclear. In general, sensitizers are administered intravenously; however, in the case of micrometastatic ovarian carcinoma within the peritoneal cavity, the concentration of sensitizers reaching the tumor cells might not suffice for an optimal photochemical reaction. Direct intracavitary administration of sensitizers into the peritoneum may overcome this potential problem. In studies of teratoma ascites tumor in mice (9,10), sensitizer was administered via the intraperitoneal route only, resulting in cure for most animals in a relatively virulent experimental system. In this issue of the Journal, Duska et al. (11) used antibodies against CA 125 to target the sensitizer to the tumor cells and further enhance tumor cytotoxicity in vitro. The authors established primary cultures from tumors taken from patients undergoing surgery. In these cultures and in established human tumor cell lines, they evaluated the combination of cisplatin and pho-