EDITORIALS

Photoimmunotherapy and Ovarian Cancer: an Improbable Fiction or a Palpable Hit?

 "If this were played upon a stage now

 I could condemn it as an improbable fiction."

  —William Shakespeare, Twelfth Night, Act 3, Scene 4

Zelig A. Tochner, Stephen Hahn, Eli Glatstein

Affiliation of authors: Radiation Oncology Department, The Hospital of the University of Pennsylvania School of Medicine, Philadelphia.

Correspondence to: Zelig A. Tochner, M.D., Radiation Oncology Department, The Hospital of the University of Pennsylvania School of Medicine, 3400 Spruce St., 2 Donner, Philadelphia, PA 19104.

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 photoimmunotherapy. Their findings suggest that photoimmunotherapy may prove to be a valuable therapeutic approach to enhance the cytotoxicity to platinum, even when patients appear to be clinically resistant to platinum. The use of antibody-conjugated photosensitizers is attractive as a means of further improving specificity, but its clinical value has yet to be established.

Despite these promising studies, relying on intraperitoneal photodynamic therapy or photoimmunotherapy alone in the clinical setting will not suffice for bulk disease because of the limited depth of light penetration. Adequate surgical debulking is the key to success for intraperitoneal photodynamic therapy or photoimmunotherapy; such laser-based treatments may eventually become an important adjunct to the surgical debulking procedure, especially in those diseases for which curative strategies need to include serosal surface spread as a specific target for treatment.

A complex light delivery and monitoring system is also crucial. Because of limited light penetration into tissue, the treated tumor should be as thin as possible, ideally less than 3-4 mm. A clinical phase I study at the National Cancer Institute showed that effective photodynamic therapy can be delivered to the entire peritoneal cavity with acceptable morbidity (12-14). More importantly, a few long-term survivors were seen in this phase I study, an uncommon observation among patients with recurrent peritoneal neoplasms (15). Phase II studies on intraperitoneal photodynamic therapy are now ongoing at the University of Pennsylvania.

Future studies on the potential role of photodynamic therapy in ovarian cancer will combine this modality with currently used standard chemotherapy protocols. The optimal time to use photodynamic therapy or photoimmunotherapy of the entire peritoneal surface would most logically be after achieving a complete clinical response from initial surgery and chemotherapy. At that time, only subclinical foci of disease should remain, thereby technically simplifying both the surgical debulking and the photodynamic therapy. With better sensitizers now becoming available and the additional enhanced effects of photoimmunotherapy as reported by Duska et al. (11), perhaps in the future we will quote from Shakespeare's Hamlet (Act 5, Scene 2): "A hit, a very palpable hit."

REFERENCES

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12 Sindelar WF, DeLaney TF, Tochner Z, Thomas GF, Dachoswki LJ, Smith PD, et al. Techniques of photodynamic therapy for disseminated intraperitoneal malignant neoplasms. A phase I study. Arch Surg 1991;126:318-24.[Abstract]

13 DeLaney TF, Sindelar WF, Tochner Z, Smith PD, Friauf WS, Thomas G, et al. Phase I study of debulking surgery and photodynamic therapy for disseminated intraperitoneal tumors. Int J Radiat Oncol Biol Phys 1993;25:445-57.[Medline]

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15 Sindelar WF, Sullivan FJ, Abraham E, DeLaney PD, Smith WS, Friauf GF, et al. Intraperitoneal photodynamic therapy shows efficacy in phase I trial [abstract]. Proc ASCO 14:1995;abstract 1550.



             
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