Postgraduate Training Course in Reproductive Health/Chronic Disease

The role of photomedicine in gynecological oncology

Review prepared for the 12th Postgraduate Course in Reproductive Medicine and Biology, Geneva, Switzerland

Xiaojun Chen, MD
Obstetrics and Gynecology Hospital Fudan University, Shanghai, China
Tutor: Frank Ludicke, MD
Geneva Foundation for Medical Education and Research, Geneva, Switzerland

See also presentation

Abstract

Background

Photomedicine, which includes photodynamic diagnosis (PDD) and photodynamic therapy (PDT), is based on the application of a photosensitizer relatively selective for malignant tissue. Light activation of appropriate wavelength leads to either fluorescence for diagnostic purposes or to oxidation-mediated tissue destruction for treatment. In the field of gynecology, photomedicine is a fairly new method. This review aims to investigate the usage and effect of photomedicine in diagnosing and treating gynecological neoplasms.

Methods

Medline was searched. All in vitro or in vivo (in animal model) experimental studies were eligible. Since most of clinical studies in this field are preliminary or phase I/II studies, preference was given to controlled trials. Observational studies were also included if there were no controlled studies in this field identified.

Results

PDD is used in early detection and noninvasive staging of cervical intraepithelial neoplasia. PDD is especially useful in detecting macroscopically invisible intraperitoneal ovarian cancer nodules. For endometrial cancer, PDD is still at an experimental stage; nevertheless, some data seem to be promising.
There is no statistical difference between PDT and placebo in CIN I/II. But high quality data is limited. In the aspect of VIN, PDT is as effective as traditional therapy, but with shorter healing time, less pain and excellent cosmetic results. In animal models and in one clinical report, PDT was effective in treating intraperitoneal ovarian cancer nodules. One study using PDT in 9 endometrial cancer patients reported 1 complete response 12 months after treatment.

Discussion

Because of its high tumor selectivity, excellent cosmetic effect and low toxicity, photomedicine seems to be a promising tool for diagnosing (CIN and small intraperitoneal ovarian cancer nodules) and treating some gynecological neoplasm (VIN, intraperitoneal ovarian cancer and endometrial cancer).
Large part of the work in photomedicine is still experimental. High quality clinical data for PDT is limited. Further well designed, large sized clinical trials are needed.

The role of photomedicine in gynecological oncology

Background

Photomedicine, which includes photodynamic diagnosis (PDD) and photodynamic therapy (PDT), is based on the application of a photosensitizer relatively selective for malignant tissue. Light activation of appropriate wavelength leads to either fluorescence for diagnostic purposes or to oxidation-mediated tissue destruction for treatment (1).
The ancient Greek historian Herodotus recorded the therapeutic use of sunlight or heliotherapy for skin lesions. Photomedicine was developed into a science and popularized by Niels Finsen, a Faroe Island physician who won the Nobel Prize in 1903 (2). Nowadays, photomedicine has been successfully used in the diagnosis and treatment of superficial skin cancer, lung and tracheobronchial cancer, oesophageal cancer, Barrett’s esophagus, bladder cancer and pituitary tumors (3).
In the field of gynecology, photomedicine is a fairly new method. Preliminary studies have been done in certain areas like vulva and cervical neoplasm, intraperitoneal ovarian metastasis and some begin diseases like endometriosis and menorrhagia. In this article we are going to review the mechanisms of photomedicine, its use in diagnosing and treating gynecological neoplasm, and its effect compared with traditional methods.

Methods

Search strategy to identify studies

Medline was searched with Mesh words “phototherapy genital neoplasm, female” or “Photosensitizing Agents Genital Neoplasm, Female Diagnosis”.

Criteria for considering studies for this review

All in vitro or in vivo (in animal model) experimental studies were eligible for inclusion.
Since most of clinical studies in this field are preliminary or phase I/II studies, preference was given to controlled trials. Observational studies were included if there were no controlled studies in this field identified.

Results

 We identified 166 articles, including 33 clinical studies. Among these 33 clinical studies, 14 studies were included (see table 1, characteristics of clinical studies included), 9 studies were excluded (see table 2, characteristics of clinical studies excluded). Unfortunately, only abstracts were available for the remaining 10 studies (see table 3, characteristics of clinical studies with only abstract available), and as a result, they were not included in this review.

Mechanism

Photosensitizer delivery and effect

Photosensitizers, in general, tend to accumulate in neoplastic tissues. The ratio of photosensitizer concentration between tumor and surrounding normal tissue varies with the photosensitizer and the tissue and forms the basis for successful PDD and PDT. Selective photosensitizer uptake in vascular, proliferative tissues is used to target certain non-neoplastic tissues, as well as tumors, for destruction. As a rule, it can be stated that practically all photosensitizers that have been studied have a pronounced affinity for non-neoplastic tissues which are high in reticulo-endothelial components. What vary considerably between photosensitzers are the time intervals between administration and peak tissue levels, and photosensitizer retention in tisssues (2).
A photosensitizer remains stable in tissue until excited by light of an appropriate wavelength and sufficient energy. The light-activated photosensitizer reacts with ground-state molecular oxygen by a type I reaction, resulting in free radical formation, such as superoxide anions and hydrogen peroxides, or by a type II reaction involving the formation of highly reactive singlet oxygen. In the type II reaction, the absorption of light excites the photosensitizer to a short-lived singlet-state. The singlet-state photosensitizer can then either decay to its ground state, resulting in emission of light (fluorescence), or undergo intersystem crossing, resulting in a slightly more stable triplet-state of the photosensitizer. The excited triplet-state photosensitizer then transfers its energy to ground-state oxygen, resulting in highly reactive singlet oxygen (4).
The mechanisms of PDT that control cell death vary according to cell type and the type of photosensitizer (5). These mechanisms include: (a) cell necrosis: The single oxygen formed exerts cytocidal activity by inducing oxidative degeneration of organelles such as mitochondria, cell membranes, and lysosomes that finally result in cell death (4); (b) induce cell apoptosis (6); (c) destruction of the tumor vascular endothelial cells, causing obstruction of blood vessels surrounding the tumor, rendering the tumor hypoxic and thereby causing it to undergo necrosis (4,6); (d) immune effect: PDT induced local inflammation, recruitment of immune effectors, and the release of immunoregulators. Experiments showed that tumor-associated macrophages and CTLs have important roles in the long-term control of disease after PDT (7,8); (e) affect cellular- extracellular matrix interactions and result in loss of beta1 integrin-containing focal adhesion plaques formation. This may have an impact on long-term effects of PDT (9).
The cytotoxic properties of PDT often result in rapid destruction of tumor cells even when the cells are either chemoresistant or radioresistant (10). The lack of cumulative effects following PDT allows for repetitive treatments of new, partially responding or recurrent lesions (11). In addition, although controversially discussed, there is strong evidence that cells surviving sublethal PDT do not become resistant to chemotherapy, radiotherapy, or repeated cycles of PDT (12).
The tissue selectivity of the photosensitizer, the short half-life of such cytotoxic species and the laser irradiation restricted to the tumor area ensures that phototoxic damage localizes mainly to tumor tissue, sparing adjacent normal tissue (13).

Light application

Photosensitisers like porphyrins generally absorb well in the blue range of the visible spectrum. The porphyrin photosensitizers are thus most efficiently activated by blue light (14). As a result, blue light is commonly used for Photodynamic diagnosis (PDD).
In the aspect of PDT, light is needed to penetrate deep in tissue to activate photosensitizers and destruct tumor. Although some photosensitzers are most efficiently activated by blue light, endogenous tissue chromophobes including haemoglobin also absorb well in the blue. Fortunately, the haemoglobin absorption spectrum falls off rapidly above a wavelength of 600nm in the red. Longer wavelength is therefore chosen for PDT even though most photosensitizers absorb less well at these levels (14).
About 30% of incident light between wavelengths 600-800 nm reflects off the surface layer. This leaves about 70% of photons free to propagate into the tissue. Light propagation in tissue decreases exponentially with distance due to absorption and scattering. Both of these parameters differ between tissues. The average light penetration depth is about 1-3mm at 630 nm and 2-6 mm at 700-850 nm of light (15). The increased penetration depth of longer wavelength light is a major incentive for the development of new photosensitizers absorbing at such wavelengths.
Clinical activation of the photosensitizer is generally achieved by visible light derived from a laser and directed to the site by optical fiber. Large, complex laser systems were needed to deliver sufficient power (up to about 1W) for effective treatment. A primary pumping laser such as an argon-ion or a copper-vapor laser was coupled to a separate, tunable, dye laser. The high cost associated with this laser system was a limiting factor in the widespread application of PDT. More compact and less expensive sources such as diode laser and filtered arc lamps are now becoming available for use in PDT (2).

Photobleaching

Photosensitizers are prone to photochemical decomposition known as photobleaching under light exposure. The rate of photobleaching depends on different photosensitizers and intensity of irradiating light. The concentration of photosensitizer which can participate in the photodynamic process decreases continuously during irradiation. Accordingly, the efficiency of PDD and PDT is maximal at the beginning of the light exposure and decrease gradually till the photosensitizer is exhausted (16).

Fluorescence

Photosensitizers produce fluorescence which can be used for photodiagnosis. With blue light excitation, the photosensitizer emits red fluorescent light in the cancerous lesions revealing a distinct contrast to the surrounding normal tissues (34). Some new photosensitizers based on a defined molecular structure have the potential to give quantitative fluorescence detection. The best florescence differential is usually produced by relatively low doses of photosensitizer. Low light levels are needed for image capture and this may be further refined by use of a charge-coupled device camera. Blue light which is absorbed weakly is used for fluorescence activation in photodiagnosis (2,17).

Photosensitizer

Haematoporphyrin and its derivatives

In 1913, a brave German scientist (Friedrich Meyer-Beta) injected himself with 20 mg of haematoporphyrin and became very sensitive to visible light. This led to further experiments on the use of haematoporphyrin as a photosensitizer (18).
The era of modern PDT and PDD began with the use of haematoporphyrin derivative (HpD or Photofrin I) in tumor detection by Lipson in 1961 (19). This haematoporphyrin derivative gave better fluorescence with lower dose and shorter administration time than crude haematoporphyrin. Later on it was shown that the most active components of the HpD mixture were dihematoporphyrin esters (DHE). This purified mixture was introduced by Dougherty as Photofrin II in 1980s, which is the most widely used first generation photosensitizer (20). 
However, haematoporphyrin derivative has significant disadvantages. It is a complex mixture whose variability may affect dose response relationships. Its tumor selectivity over surrounding normal tissues is not always optimal due to poor tumor uptake and retention versus normal tissues. Haematoporphyrin derivative absorbs only weakly above 600 nm where light exhibits the deepest penetration of tissue. Moreover, photosensitizer retention in skin necessitates protection of patients from light, especially bright sunlight, for as long as 6-7 weeks (13,21). These led to the development of the second generation photosensitizers.

Second generation photosensitizers

The second generation photosensitizers include Tin (II) etiopurpurindichloride (SnET2), benzoporphyrin derivate-monoacid ring A (BPD verteporfin; BPD-MA), meso-Tetra (m-hydroxyphenyl) porphyrin (m-THPP), meso-tetra-hydroxyphenyl- chlorin(m-THPC-MD), 5,10,15,20-tetra-(3-carboxymethoxyphenyl)-chlorin (m-TCMPC), mono-L-aspartyl chlorin e6 (NPe6), etc. Most of the second generation photosensitizers have good antitumor effect and a rapid clearance rate from the blood stream with a phototoxicity lasting for about 24 hours. They have a strong light absorption at longer wavelengths, where deeper penetration of light occurs in tissue and high oxygen radical species quantum yield. This characteristic is probably not optimal for PDD (2,6,21-25).

PpIX-precursors (ALA and h-ALA)

5-aminolaevulinic acid (5-ALA) is an endogenous substance that is metabolized in a series of enzymatic reactions to protoporphyrin IX (PpIX), a precursor of haem in most body cells. Administration of excess ALA leads to accumulation of PpIX which acts as an endogenous photosensitizer. Like the other prophyrins, PpIX accumulates preferentially in tumor tissue. In normal tissue, ALA induced PpIX distributes primarily in surface and glandular epithelium of the skin and the lining of hollow organs. ALA-based PDT is particularly attractive because this drug is activated by conversion to protoporphyrin IX in rapidly growing cells thus reducing incidental damage to surrounding normal tissues (26).
The 5-ALA-induced PpIX has its peak absorbance at a wavelength of 635 nm, which theoretically renders it useful for the treatment of tumors in the deep dermis. A greater depth of necrosis might be achieved using higher doses of 5-ALA. Lofgren et al.  found necrosis up to 12 mm depth in a rabbit papilloma model after i.v. administration of 50-200 mg/kg 5-ALA (27).
ALA-induced protoporphyrin IX is cleared from the skin within 24 to 48 hr of topical or systemic administration, and shielding against exposure of light can be minimized. In addition, 5-ALA-PDT-treated tissues heal remarkably well, making it feasible to treat extensive superficial lesions (11).
PDT using topically applied ALA has been registered by the FDA for the treatment of actinic keratosis of the skin. Promising results have been reported for a variety of other skin diseases, including superficial basal cell carcinoma, superficial squamous cell carcinoma, psoriasis, Bowen’s disease, foot and hand warts, premalignant lesions of the oral cavity and high-grade dysplasia of Barrett's esophagus7. Vulvar dystrophy could be treated successfully with minimal side effects (11).
Furthermore, the selective uptake of ALA in vascular and proliferative tissues is used to target certain tissues, as well as tumors, for detection (2). The topical application of 5-ALA has been used clinically for the endoscopic detection of neoplastic lesions of the bladder and early stage lung cancer by means of induced fluorescence imaging (28).
In order to improve its uptake rate which is restricted by the hydrophilic nature of ALA, some esterified ALA derivatives were introduced. ALA esters, especially the ALA-hexylester hydrochloride (h-ALA), induced significantly faster PpIX formation than ALA at the same concentration (0.5 mM). The highest PpIX values could be achieved by an up to 1.3-13-fold lower concentration of ALA esters than with ALA. Apoptosis was found to be induced rapidly after irradiation in both ALA- and ALA esters-treated cells. The incubation with h-ALA induced a more pronounced photodamage (29,30). It was reported that the application of esterified ALA derivates could result in an up to 25-fold increase in PPIX fluorescence levels as compared to 5-ALA. H-ALA seems to be promising photosensitizer for both PDD and PDT (31).

Combined photosensitizer

In order to increase the tissue selectivity of photosensitizers, several “combined photosensitizers” have been produced. A certain degree of selectivity has been achieved by combining (covalent and non-covalent) porphyrins with antibodies, microspheres, liposomes, lipoproteins and estrodiol (32). For example, N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-anti-cancer drug-OV-TL16 antibody (Ab) conjugates were used in treating ovarian carcinoma OVCAR-3 cell line (33).
Photosensitizers can also be bound to chemotherapeutic agents. PDT using Photofrin combined with mitomycin C (ADR) demonstrated enhanced efficacy in preclinical studies. The area under the curve (AUC) of P-ADR is three times less than that of free ADR after i.v. administration. Higher amounts of P-ADR accumulated in the kidney, lung and spleen than in the intestine, muscle, skin and uterus when compared with free ADR (21).

Application in gynecological neoplasm

Photodynamic diagnosis (PDD)

PDD can also be interesting in surgical oncology for improving the early detection of breast, urogenital, pulmonary, and gastrointestinal cancers. Studies have been done to use porphyrin fluorescence detection after topical application of 5-ALA for the endoscopic detection of neoplastic lesions of the bladder (35). Furthermore, porphyrin fluorescence imaging is already used experimentally for the diagnosis of early stage lung carcinoma and the evaluation of resection borders during neurosurgery of malignant gliomas (36). Gynecological indications include lower genital tract intraepithelial neoplasm, endometrial cancer, intraperitoneal metastasis of ovarian cancer as well as some benign diseases like endometriosis (2).

Cervical cancer

PDD has been used for early detection and noninvasive staging of CIN (cervical intraepithelial neoplasm).
Semi quantitative fluorescence microscopy indicated that topical application of 3% ALA in Intracite Gel for 3 hours resulted in PpIX accumulation in the cervical epithelium presenting with early dysplasia. PpIX florescence in the epithelium was greater than in the underlying lamina propria suggesting differential sensitization of the abnormal epithelium and its supporting connective tissue3. ALA showed greater selectivity for cervical dysplastic cells than BDP-MA (24).
By examining loop excision samples, Pahernik et al. observed a fluorescence ratio of 1.3 for CIN-I: normal ; 1.21 for CIN-II:normal and 2.35 for CIN-III: normal. The optimal administration time of topically applied 5-ALA was between 3 and 4 hr. Porphyrins induced by topically applied 5-ALA accumulated even in CIN II/III lesions grown into cervical glands (13).
Using a time interval of 60-90 minutes after topical application of 1% 5-ALA, Hillemanns et al. observed specific porphyrin fluorescence of CIN. HPV positive lesions showed significantly higher fluorescence. Fluorescence imaging after 60-90 minutes achieved similar sensitivity and specificity compared with colposcopy in detecting CIN with 94% and 51% versus 95% and 50%, respectively. However, the specificity was markedly improved by fluorescence spectroscopy, achieving 75%. The evaluation of spectral measurements revealed significantly higher values for CIN compared with normal tissue and for CIN II/III compared with CIN I (36).
Double ratio (DR) fluorescence imaging technique may be useful for noninvasive staging of CIN. Instead of single exciting wavelength, two different exciting wavelengths were used for fluorescence spectroscopy to distinguish normal and cancerous tissue. Strongly localized fluorescent hotspots were observed at the location where the disease was colposcopically visible. In the other cases the fluorescence showed a more diffuse multifocal image. The value of the DR determined at the site of biopsy correlated in a statistically significant way with the histopathologically determined stage of the disease (37).
However, the endocervical lesions cannot be used with the current equipment (36).

Ovarian cancer

PDD is an attractive concept for both primary and second-look laparotomies for ovarian cancer as it improves visualization and guides treatment of small cancerous nodules.
Fluorescent laparoscopic detection of micrometastatic ovarian cancer using ALA is significantly more sensitive than white-light laparoscopy in detecting smaller cancerous lesions in ovarian cancer rat models. Cancerous lesions that were difficult to differentiate from normal surrounding tissue under white light conditions were clearly detected by ALA-induced fluorescence. Micrometastatic lesions as small as 0.3 mm, which are extremely difficult to detect by visual means, can be accurately identified using fluorescent laparoscopy (1,34,38-40).  Similarly, Mang and colleagues have detected clinically occult micro metastases (50-100 cells) in lymph nodes confirmed by histopathology using fluorescence PDD (41).
Major et al applied 1% ALA topically to the rectum and peritoneum of the abdominal wall of an ovarian adenocarcinoma patient before explorative laparotomy. One hour later, blue excitation light was used to detect micrometastases. All visible metastases showed a red porphyrin-like fluorescence. Cancerous lesions as small as 5 mm in diameter could be detected in the fluorescence mode and which cannot be seen under standard white light inspection. Microscopic analysis of fluorescent-guided biopsies taken from eight different sites revealed signs of ovarian cancer. No skin phototoxicity or other adverse events were observed (1).

Endometrial cancer

In vitro experiments, malignant endometrial epithelial cells showed a statistically significant higher fluorescence of PpIX than normal epithelial cells after incubation with 1 mg ALA per ml medium during 24 hours. The well-differentiated cancer cells produced significantly more PpIX than the poorly differentiated cancer cells. This may be useful for targeted biopsies and selective photodynamic destruction of neoplastic micro-lesions (42). No clinical trial using PDD for endometrial cancer was identified.

Photodynamic treatment (PDT)

There has been an increased interest in conservative therapeutic techniques for gynecological cancers during the last years. Curative and palliative PDT for gynecological malignancies, such as vulva, vaginal, cervical, endometrial and ovarian neoplasm has been used. However, penetration of laser light at a wavelength of 630 nm is limited to 3 mm. Therefore, effective curative PDT can generally be performed only in superficial malignancies, such as intra-epithelial neoplasms (13).

Cervical neoplasm

Potential advantages of photodynamic therapy for cervical disease relative to conventional treatments (cryotherapy, carbon dioxide laser ablation and electrosurgical excision) include the possibility that it could eliminate intraepithelial lesions without causing profuse bleeding, vaginal discharge, or a change in the location of the squamo-colummnar junction. Besides, it could spare those young women with cervical neoplasm from conization which may cause adhesion and other side effects. It is also possible that large or multifocal lesions or those lesions that extend into the endocervical canal could be targeted through selective drug uptake while sparing adjacent normal cervical tissue (24).
Barnett et al conducted a randomized, double-blind, placebo-controlled trial of PDT for cervical intraepithelial neoplasm (CIN). 3% ALA was applied to the cervix in a cervical cap for 3 hours. All patients tolerated the treatment well. Histological examination of the treated tissue following loop excision 3 months post PDT indicated that 33% (4/13) of patients had no evidence of CIN, 42% (5/13) had no change in the grade of their disease, whilst 25% (3/13) exhibited an apparent progression of disease. In the placebo group, the respective figures were 31%(4/12), 38%(5/12), and 31%(4/12). There was no significant difference in response between the groups receiving ALA-PDT and those receiving placebo treatment (3).
The effect of PDT seems to be discouraging for high grade CIN (28, 60). In one observational study, 16 CIN II patients and 24 CIN III patients were treated by topically applied 200 mg/ml ALA 630 nm laser light. Success rate was 31% (10/32) 12 months after treatment, and 3 patients progressed from CIN II to CIN III (60).

Vulvar and vaginal neoplasm

Clinical trials have been done on the treatment of vulvar neoplasm and some pre-malignant conditions such as condylomata.
PDT for condylomata and intraepithelial neoplasm appears to be as effective as conventional treatments (laser evaporation and excision), but with shorter healing time (2 weeks), less pain and excellent cosmetic results (especially no destruction of normal clitoris and periurethral vestibule) due to selective photosensitization of the lesions by photosensitizer. In one trial (7), 57% (12/21) VIN or VAIN were free of disease 8 weeks after PDT. Recurrence free rates were 45%, 56%, 51% in the PDT, local excision and laser group respectively 12 months after treatment (p=0.34). Lower grades (VIN I) and monofocal and bifocal high grades (VIN II-III) are much more responsive to topical ALA-PDT treatment  than multifocal VIN II-III. Pigmented and hyperkeratotic lesions respond poorly to PDT (7,8).  Fehr et al. reported that 12 of the 15 patients with VIN without pigmentation or hyperkeratosis of the lesion had a histologically confirmed complete response, whereas only one of four pigmented lesions responded and none of five lesions with marked hyperkeratosis (7).  There was a greater likelihood that being HPV positive is associated with a lack of response of VIN to PDT, VIN non-responders were more likely to show HLA class I loss compared with responders (7). Abdel-Hady et al found that 4 out of 10 women who showed normal histology at the treatment site after PDT (responders) were HPV negative before treatment, 5 became HPV negative after treatment. By contrast, of 22 non-responders, 17 had persistent high-risk HPV infection of the type detected before or after PDT treatments (8).
Single episode of topical PDT is not effective for persistent VIN III. Kurwa HA et al performed one episode of topical PDT in 6 patients with VIN III, 5 of whom had persistent disease following other treatments including 5-fluorouracil cream, cryotherapy, carbon dioxide laser ablation and excision. All patients had clinically evident persistent VIN III at 1-month review (43).
PDT was also used to treat vaginal cancer. Ward et al reported 5 patients with recurrent vaginal cancer treated with PDT following the intravenous injection of hematoporphyrin derivative. Complete response was seen in 2 out of 5 patients 10-12 months after treatment (44).

Ovarian cancer

PDT as a surface treatment may be advantageous in the treatment of intraperitoneal ovarian malignancies, because the major clinical issue after surgery is not the bulk of tumor but rather the large surface area of the peritoneum. This surface potentially contains either small tumor nodules too numerous to be resected or microscopic disease that is always present in this clinical setting. Although light dispersion in the peritoneal cavity sometimes could be hampered by contamination of blood, it is theoretically possible that the large surface areas of the peritoneum could be exposed to light. Moreover, the effective treatment depth of PDT caused by light penetration is only a few millimeters in tissue, thus avoiding life-threatening toxicity (45). Photosensitizer can be administered both intraperitoneally or intravenously (46).
Promising attempts to use PDT for advanced stages of ovarian cancer have been proposed. Diffuse intra-abdominal metastases have been successfully treated with PDT in a mouse model, resulting in prolongation of survival (47). Minimally invasive debulking of non-resectable pelvic tumors was effective in a rat ovarian cancer model (48). Hornung et al. used m-THPC mediated PDT to treat the hypercalcemic type of the small cell carcinoma of the ovary (HTSCCO) in nude mice mode and found that superficial and interstitially irradiation of m-THPC sensitized tumors showed over three times and seven times more necrosis than control tumors respectively (12). Wierrani et al. performed m-THPC mediated PDT without additional surgery in a laparoscopic procedure on recurrent ovarian caner in two patients. In another patient they used m-THPC PDT on the peritoneum following surgical tumor debulking. After a postoperative period of more than 2 years all three patients remained free of relapses (49).
In order to improve tumor selectivity, several conjugated photosensitizers have been used to treat ovarian cancer, eg. photoimmunoconjugate (46,50,51), pegylation of chlorine6 (attachment of polyethylene glycol to a polyacetylated conjugate between poly-l-lysine and chlorine6 (52,53). Michael R. et al. found that pegylation increased the relative phototoxicity in vitro towards ovarian cancer cells.
Molpus et al. tested the effect of a photoimmunoconjugate (chlorin(e6) conjugated to the F(ab')(2) fragment of the murine anti-ovarian cancer monoclonal antibody OC125) in a murine model. The conjugate was injected intraperitoneally followed after 3 h by red light delivered through a fiber into the peritoneal cavity. Results showed that mice had no systemic toxicity or morbidity from the treatment. In this initial study the mean residual tumor weights in all treatment groups ranged from 33 to 73 mg, as compared with 330 mg in untreated controls46. Pretreatment with OC-125-targeted photoimmunotherapy may also reverse platinum resistance in human ovarian cancer cells (50).
A novel concept of combination chemotherapeutic drug and PDT was developed: e.g. HPMA copolymer-bound drugs (ADR and Mce6); Photofrin combined with mitomycin C (21,54-56). In one human ovarian carcinoma nude mice model it was revealed that combination therapy with P-ADR (HPMA copolymer-ADR conjugate) and P-Mce6 (HPMA copolymer-Mce6 conjugate) showed tumor cures that could not be obtained with either chemotherapy or PDT alone (57). The study of Shiah et al. demonstrated that HPMA copolymer-bound adriamycin exhibited selective tumor accumulation contrary to free drugs and combination chemotherapy and photodynamic therapy with HPMA copolymer-ADR and HPMA copolymer-Mce6 conjugates was the most effective regimen (54). In addition, the use of a macromolecular photosensitizer (such as P-Mce6) has the potential to decrease skin accumulation and resulting light sensitivity after treatment (21).

Endometrial cancer

In vitro experiment showed promising effect of PDT treating human endometrial carcinoma cells (HEC-1-A cell). The porphyrin compound Photosan III (Ph III) was used for photosensitization of the cells after incubation times of 24 h. HEC-1-A cells did not survive photodynamic therapy with 10 J/cm² after incubation with 5 micrograms/ml for 48 h. After a shorter incubation time of 24 h, 10 micrograms/ml Ph III was necessary for the same effect (58).
Koren reported 9 patients (7 with endometrial carcinomas stage FIGO Ia, 2 with recurrent endometrial carcinoma vaginally) treated primarily by PDT. Tumor illumination was performed by an Argon dye laser 24-72 h following the intravenous administration of haematoporphyrin derivatives (HPD) (Photosan III, 2 mg kg-1 body weight). The intracavitary tumor irradiation by means of fibre glass was controlled by ultrasound. Tumor response was assessed 1 month after therapy: 6 complete responses (CR) were observed: 5 in the 7 Ia patients, 1 in the 2 recurrent patients; 3 patients were non-responders; 12 months later, all but 1 patient were recurrent;1 patient with Ia remained CR (59).

Discussion

Because of its high tumor selectivity, excellent cosmetic effect and low toxicity, photomedicine seems to be a promising tool for diagnosing and treating some gynecological neoplasm, especially superficial, precancerous lesions.
PDD can be used for early detection and noninvasive staging of CIN. PDD is especially useful in detecting superficial, small, macroscopically invisible neoplasm nodules. This cannot only help clinicians to stage ovarian cancer correctly before explorative laparotomy, but also direct the surgery instead of performing blind biopsy. PDD may also be helpful for second-look laparotomy to detect early recurrent lesions. Although PDD has not been used clinically to detect endometrial neoplasm, laboratory studies promised the use of PDD in detecting early endometrial neoplasm by hysteroscopy.
Limited by its penetrating depth, PDT may be more suitable for treating superficial, noninvasive neoplasm (eg VIN, CIN) rather than deep invasive lesions. Because of its excellent cosmetic effect and low toxicity, PDT seems to be a better choice for VIN than conventional treatment, but it may not be suitable for those with high risk HPV infection or with multifocal, pigmented or hyperkeratotic lesions. The data for the effect of PDT on CIN is limited. Although one trial implied that PDT has no effect on CIN I/II, this may be due to the small sample size, inadequate drug dose, light delivery or treatment cycles etc. Taking account that PDT was effective might spare young CIN patients from conization, a large, well designed clinical trial should be done to evaluate the effect of PDT on CIN. The treatment of intraperitoneal ovarian cancer nodules by PDT in animal models showed promising results. PDT may be an attractive choice for recurrent, multidrug resistant ovarian cancer. Still, clinical trials are needed before conclusions on the effect of this method in humans can be drawn. This is also true for stage Ia endometrial cancer which may be another indication of PDT.
Conjugated photosensitzers which have higher tumor cell selectivity or toxicity provide a promising alternative for treating gynecological malignant neoplasm.
High quality clinical data for PDT is limited. Further well designed, large sized clinical trials are needed.

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Reference for excluded clinical studies

1. Fehr MK, Hornung R, Schwarz VA, Simeon R, Haller U, Wyss P. Photodynamic therapy of vulvar intraepithelial neoplasia III using topically applied 5-aminolevulinic acid. Gynecol Oncol. 2001 Jan;80(1):62-6. [PubMed]
2. Hillemanns P, Untch M, Dannecker C, Baumgartner R, Stepp H, Diebold J, Weingandt H, Prove F, Korell M. Photodynamic therapy of vulvar intraepithelial neoplasia using 5-aminolevulinic acid. Int J Cancer. 2000 Mar 1;85(5):649-53. [PubMed]
3. Henta T, Itoh Y, Kobayashi M, Ninomiya Y, Ishibashi A. Photodynamic therapy for inoperable vulval Paget's disease using delta-aminolaevulinic acid: successful management of a large skin lesion. Br J Dermatol. 1999 Aug;141(2):347-9. [PubMed]
4. Martin-Hirsch PL, Whitehurst C, Buckley CH, Moore JV, Kitchener HC. Photodynamic treatment for lower genital tract intraepithelial neoplasia. Lancet. 1998 May 9;351(9113):1403. [PubMed]
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6. Wierrani F, Kubin A, Jindra R, Henry M, Gharehbaghi K, Grin W, Soltz-Szotz J, Alth G, Grunberger W. 5-aminolevulinic acid-mediated photodynamic therapy of intraepithelial neoplasia and human papillomavirus of the uterine cervix--a new experimental approach. Cancer Detect Prev. 1999;23(4):351-5. [PubMed]
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1. Krimbacher E, Zeimet AG, Marth C, Kostron H. Photodynamic therapy for recurrent gynecologic malignancy: a report on 4 cases. Arch Gynecol Obstet. 1999;262(3-4):193-7. [PubMed]
2. Corti L, Mazzarotto R, Belfontali S, De Luca C, Baiocchi C, Boso C, Calzavara F. Photodynamic therapy in gynaecological neoplastic diseases. J Photochem Photobiol B. 1996 Nov;36(2):193-7. [PubMed]
3. Muroya T, Suehiro Y, Umayahara K, Akiya T, Iwabuchi H, Sakunaga H, Sakamoto M, Sugishita T, Tenjin Y. [Photodynamic therapy (PDT) for early cervical cancer] Gan To Kagaku Ryoho. 1996 Jan;23(1):47-56. [PubMed]
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Table 1.  Characteristics of included clinical studies

1.1 Cervical neoplasm, diagnosis

1.2 Ovarian cancer, diagnosis

1.3 Cervical neoplasm, treatment

1.4 Vulvar or vaginal neoplasm, treatment

1.5 Ovarian cancer, treatment

1.6 Endometrial cancer, treatment

Table 2. Character of clinical studies excluded

2.1 Vulvar neoplasm

2.2 Cervical neoplasm

Table 3. Character of clinical studies only abstract available

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Edited by Aldo Campana,