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
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.
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.
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.
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
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.
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.
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.
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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.
- Major AL, Ludicke F, Campana A. Feasibility study to detect ovarian cancer micrometastases by fluorescence photodetection. Lasers Med Sci. 2002;17(1):2-5. [PubMed]
- Gannon MJ, Brown SB. Photodynamic therapy and its applications in gynaecology. Br J Obstet Gynaecol. 1999 Dec;106(12):1246-54. [PubMed]
- Barnett AA, Haller JC, Cairnduff F, Lane G, Brown SB, Roberts DJ. A randomised, double-blind, placebo-controlled trial of photodynamic therapy using 5-aminolaevulinic acid for the treatment of cervical intraepithelial neoplasia. Int J Cancer. 2003 Mar 1;103(6):829-32. [PubMed]
- Sporri S, Chopra V, Egger N, Hawkins HK, Motamedi M, Dreher E, Schneider H. Effects of 5-aminolaevulinic acid on human ovarian cancer cells and human vascular endothelial cells in vitro. J Photochem Photobiol B. 2001 Nov 1;64(1):8-20. [PubMed]
- Varriale L, Coppola E, Quarto M, Veneziani BM, Palumbo G. Molecular aspects of photodynamic therapy: low energy pre-sensitization of hypericin-loaded human endometrial carcinoma cells enhances photo-tolerance, alters gene expression and affects the cell cycle. FEBS Lett. 2002 Feb 13;512(1-3):287-90. [PubMed]
- Nakamura H, Suzuki Y, Takeichi M, Saito T, Takayama M, Aizawa K. Morphologic evaluation of the antitumor activity of photodynamic therapy (PDT) using mono-L-aspartyl chlorin e6 (NPe6) against uterine cervical carcinoma cell lines. Int J Gynecol Cancer. 2002 Mar-Apr;12(2):177-86. [PubMed]
- Fehr MK, Hornung R, Degen A, Schwarz VA, Fink D, Haller U, Wyss P. Photodynamic therapy of vulvar and vaginal condyloma and intraepithelial neoplasia using topically applied 5-aminolevulinic acid. Lasers Surg Med. 2002;30(4):273-9. [PubMed]
- Abdel-Hady ES, Martin-Hirsch P, Duggan-Keen M, Stern PL, Moore JV, Corbitt G, Kitchener HC, Hampson IN. Immunological and viral factors associated with the response of vulval intraepithelial neoplasia to photodynamic therapy. Cancer Res. 2001 Jan 1;61(1):192-6. [Free Full Text]
- Runnels JM, Chen N, Ortel B, Kato D, Hasan T. BPD-MA-mediated photosensitization in vitro and in vivo: cellular adhesion and beta1 integrin expression in ovarian cancer cells. Br J Cancer. 1999 Jun;80(7):946-53. [PubMed]
- Tochner ZA, Hahn S, Glatstein E. Photoimmunotherapy and ovarian cancer: an improbable fiction or a palpable hit? J Natl Cancer Inst. 1999 Sep 15;91(18):1526-7. [PubMed]
- 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]
- Hornung R, Fink D, Dobler-Girdziunaite D, Stallmach T, Haller U, Walt H. Photodynamic therapy for the hypercalcemic type of the small cell carcinoma of the ovary in a mouse xenograft model. Gynecol Oncol. 1999 Dec;75(3):447-52. [PubMed]
- Pahernik SA, Botzlar A, Hillemanns P, Dellian M, Kirschstein M, Abels C, Korell M, Mueller-Hoecker J, Untch M, Goetz AE. Pharmacokinetics and selectivity of aminolevulinic acid-induced porphyrin synthesis in patients with cervical intra-epithelial neoplasia. Int J Cancer. 1998 Oct 29;78(3):310-4. [PubMed]
- Bonnett R. Photosensitizers of the porphyrin and phthalocyanine series for photodynamic therapy. Chem Soc Rev 1995; 24:19-33.
- Wyss P, Svaasand LO, Tadir Y, Haller U, Berns MW, Wyss MT, Tromberg BJ. Photomedicine of the endometrium: experimental concepts. Hum Reprod. 1995 Jan;10(1):221-6. [PubMed]
- Wessels JM, Sroka R, Heil P, Seidlitz HK. Photodegradation of protoporphyrin-dimethylester in solution and in organized environments. Int J Radiat Biol. 1993 Nov;64(5):475-84. [PubMed]
- Chan JK, Monk BJ, Cuccia D, Pham H, Kimel S, Gu M, Hammer-Wilson MJ, Liaw LH, Osann K, DiSaia PJ, Berns M, Tromberg B, Tadir Y. Laparoscopic photodynamic diagnosis of ovarian cancer using 5-aminolevulinic acid in a rat model. Gynecol Oncol. 2002 Oct;87(1):64-70. [PubMed]
- Meyer-Beta F. Investigations on the biological (photodynamic) action of haematoporphyrin and other derivates of blood and bile pigments. Deutsch Arch Klin Med 1913; 112: 476-503 (18).
- Lipson FG, Baldes EJ, Olsen AM. The use of a derivative of hematopotphyrin in tumor detection. J Natl Ca Inst 1961; 26:350-2.
- Dougherty TJ, Mang TS. Characterization of intra-tumoral porphyrin following injection of hematoporphyrin derivative or its purified component. Photochem Photobiol. 1987 Jul;46(1):67-70. [PubMed]
- Shiah JJ, Sun Y, Peterson CM, Kopecek J. Biodistribution of free and N-(2-hydroxypropyl)methacrylamide copolymer-bound mesochlorin e(6) and adriamycin in nude mice bearing human ovarian carcinoma OVCAR-3 xenografts. J Control Release. 1999 Aug 27;61(1-2):145-57. [PubMed]
- Gharehbaghi K, Kubin A, Grusch M, Gharehbaghi-Schnell E, Wierrani F, Jayaram HN, Grunberger W, Szekeres T. Photodynamic action of meta-tetrahydroxyphenylchlorin (mTHPC) on an ovarian cancer cell line. Anticancer Res. 2000 Jul-Aug;20(4):2647-52. [PubMed]
- Griffiths SJ, Heelis PF, Haylett AK, Moore JV. Photodynamic therapy of ovarian tumours and normal cells using 5,10,15,20-tetra-(3-carboxymethoxyphenyl)-chlorin. Cancer Lett. 1998 Mar 13;125(1-2):177-84. [PubMed]
- Keefe KA, Chahine EB, DiSaia PJ, Krasieva TB, Lin F, Berns MW, Tadir Y. Fluorescence detection of cervical intraepithelial neoplasia for photodynamic therapy with the topical agents 5-aminolevulinic acid and benzoporphyrin-derivative monoacid ring. Am J Obstet Gynecol. 2001 May;184(6):1164-9. [PubMed]
- Ris HB, Altermatt HJ, Nachbur B, Stewart JC, Wang Q, Lim CK, Bonnett R, Althaus U. Effect of drug-light interval on photodynamic therapy with meta-tetrahydroxyphenylchlorin in malignant mesothelioma. Int J Cancer. 1993 Jan 2;53(1):141-6. [PubMed]
- Bedwell J, MacRobert AJ, Phillips D, Bown SG. Fluorescence distribution and photodynamic effect of ALA-induced PP IX in the DMH rat colonic tumour model. Br J Cancer. 1992 Jun;65(6):818-24. [PubMed]
- Lofgren LA, Ronn AM, Nouri M, Lee CJ, Yoo D, Steinberg BM. Efficacy of intravenous delta-aminolaevulinic acid photodynamic therapy on rabbit papillomas. Br J Cancer. 1995 Oct;72(4):857-64. [PubMed]
- Hillemanns P, Korell M, Schmitt-Sody M, Baumgartner R, Beyer W, Kimmig R, Untch M, Hepp H. Photodynamic therapy in women with cervical intraepithelial neoplasia using topically applied 5-aminolevulinic acid. Int J Cancer. 1999 Mar 31;81(1):34-8. [PubMed]
- Xiang W, Weingandt H, Liessmann F, Klein S, Stepp H, Baumgartner R, Hillemanns P. Photodynamic effects induced by aminolevulinic acid esters on human cervical carcinoma cells in culture. Photochem Photobiol. 2001 Oct;74(4):617-23. [PubMed]
- Gaullier JM, Berg K, Peng Q, Anholt H, Selbo PK, Ma LW, Moan J. Use of 5-aminolevulinic acid esters to improve photodynamic therapy on cells in culture. Cancer Res. 1997 Apr 15;57(8):1481-6. [PubMed]
- Lange N, Jichlinski P, Zellweger M, Forrer M, Marti A, Guillou L, Kucera P, Wagnieres G, van den Bergh H. Photodetection of early human bladder cancer based on the fluorescence of 5-aminolaevulinic acid hexylester-induced protoporphyrin IX: a pilot study. Br J Cancer. 1999 Apr;80(1-2):185-93. [PubMed]
- James DA, Swamy N, Paz N, Hanson RN, Ray R. Synthesis and estrogen receptor binding affinity of a porphyrin-estradiol conjugate for targeted photodynamic therapy of cancer. Bioorg Med Chem Lett. 1999 Aug 16;9(16):2379-84. [PubMed]
- Omelyanenko V, Gentry C, Kopeckova P, Kopecek J. HPMA copolymer-anticancer drug-OV-TL16 antibody conjugates. II. Processing in epithelial ovarian carcinoma cells in vitro. Int J Cancer. 1998 Feb 9;75(4):600-8. [PubMed]
- Kriegmair M, Zaak D, Knuechel R, Baumgartner R, Hofstetter A. 5-Aminolevulinic acid-induced fluorescence endoscopy for the detection of lower urinary tract tumors. Urol Int. 1999;63(1):27-31. [PubMed]
- Kriegmair M, Baumgartner R, Knuchel R, Stepp H, Hofstadter F, Hofstetter A. Detection of early bladder cancer by 5-aminolevulinic acid induced porphyrin fluorescence. J Urol. 1996 Jan;155(1):105-9; discussion 109-10. [PubMed]
- Hillemanns P, Weingandt H, Baumgartner R, Diebold J, Xiang W, Stepp H. Photodetection of cervical intraepithelial neoplasia using 5-aminolevulinic acid-induced porphyrin fluorescence. Cancer. 2000 May 15;88(10):2275-82. [PubMed]
- Bogaards A, Aalders MC, Zeyl CC, de Blok S, Dannecker C, Hillemanns P, Stepp H, Sterenborg HJ. Localization and staging of cervical intraepithelial neoplasia using double ratio fluorescence imaging. J Biomed Opt. 2002 Apr;7(2):215-20. [PubMed]
- Major AL, Rose GS, Chapman CF, Hiserodt JC, Tromberg BJ, Krasieva TB, Tadir Y, Haller U, DiSaia PJ, Berns MW. In vivo fluorescence detection of ovarian cancer in the NuTu-19 epithelial ovarian cancer animal model using 5-aminolevulinic acid (ALA). Gynecol Oncol. 1997 Jul;66(1):122-32. [PubMed]
- Canis M, Botchorishvili R, Berreni N, Manhes H, Wattiez A, Mage G, Pouly JL, Bruhat MA. 5-aminolevulinic acid-induced (ALA) fluorescence for the laparoscopic diagnosis of peritoneal metastasis. AST An experimental study. Surg Endosc. 2001 Oct;15(10):1184-6. [PubMed]
- Hornung R, Major AL, McHale M, Liaw LH, Sabiniano LA, Tromberg BJ, Berns MW, Tadir Y. In vivo detection of metastatic ovarian cancer by means of 5-aminolevulinic acid-induced fluorescence in a rat model. J Am Assoc Gynecol Laparosc. 1998 May;5(2):141-8. [PubMed]
- Mang TS, McGinnis C, Liebow C, Nseyo UO, Crean DH, Dougherty TJ. Fluorescence detection of tumors. Early diagnosis of microscopic lesions in preclinical studies. Cancer. 1993 Jan 1;71(1):269-76. [PubMed]
- Wyss-Desserich MT, Sun CH, Wyss P, Kurlawalla CS, Haller U, Berns MW, Tadir Y. Accumulation of 5-aminolevulinic acid-induced protoporphyrin IX in normal and neoplastic human endometrial epithelial cells. Biochem Biophys Res Commun. 1996 Jul 25;224(3):819-24. [PubMed]
- Kurwa HA, Barlow RJ, Neill S. Single-episode photodynamic therapy and vulval intraepithelial neoplasia type III resistant to conventional therapy. Br J Dermatol. 2000 Nov;143(5):1040-2. [PubMed]
- Ward BG, Forbes IJ, Cowled PA, McEvoy MM, Cox LW. The treatment of vaginal recurrences of gynecologic malignancy with phototherapy following hematoporphyrin derivative pretreatment. Am J Obstet Gynecol. 1982 Feb 1;142(3):356-7. [PubMed]
- Menon C, Kutney SN, Lehr SC, Hendren SK, Busch TM, Hahn SM, Fraker DL. Vascularity and uptake of photosensitizer in small human tumor nodules: implications for intraperitoneal photodynamic therapy. Clin Cancer Res. 2001 Dec;7(12):3904-11. [PubMed]
- Molpus KL, Hamblin MR, Rizvi I, Hasan T. Intraperitoneal photoimmunotherapy of ovarian carcinoma xenografts in nude mice using charged photoimmunoconjugates. Gynecol Oncol. 2000 Mar;76(3):397-404. [PubMed]
- Molpus KL, Kato D, Hamblin MR, Lilge L, Bamberg M, Hasan T. Intraperitoneal photodynamic therapy of human epithelial ovarian carcinomatosis in a xenograft murine model. Cancer Res. 1996 Mar 1;56(5):1075-82. [PubMed]
- Hornung R, Fehr MK, Monti-Frayne J, Tromberg BJ, Berns MW, Tadir Y. Minimally-invasive debulking of ovarian cancer in the rat pelvis by means of photodynamic therapy using the pegylated photosensitizer PEG-m-THPC. Br J Cancer. 1999 Oct;81(4):631-7. [PubMed]
- Wierrani F, Fiedler D, Grin W, Henry M, Dienes E, Gharehbaghi K, Krammer B, Grunberger W. Clinical effect of meso-tetrahydroxyphenylchlorine based photodynamic therapy in recurrent carcinoma of the ovary: preliminary results. Br J Obstet Gynaecol. 1997 Mar;104(3):376-8. [PubMed]
- Duska LR, Hamblin MR, Miller JL, Hasan T. Combination photoimmunotherapy and cisplatin: effects on human ovarian cancer ex vivo. J Natl Cancer Inst. 1999 Sep 15;91(18):1557-63. [PubMed]
- Goff BA, Blake J, Bamberg MP, Hasan T. Treatment of ovarian cancer with photodynamic therapy and immunoconjugates in a murine ovarian cancer model. Br J Cancer. 1996 Oct;74(8):1194-8. [PubMed]
- Hamblin MR, Miller JL, Rizvi I, Ortel B, Maytin EV, Hasan T. Pegylation of a chlorin(e6) polymer conjugate increases tumor targeting of photosensitizer. Cancer Res. 2001 Oct 1;61(19):7155-62. [PubMed]
- Hornung R, Fehr MK, Monti-Frayne J, Krasieva TB, Tromberg BJ, Berns MW, Tadir Y. Highly selective targeting of ovarian cancer with the photosensitizer PEG-m-THPC in a rat model. Photochem Photobiol. 1999 Oct;70(4):624-9. [PubMed]
- Shiah JG, Sun Y, Peterson CM, Straight RC, Kopecek J. Antitumor activity of N-(2-hydroxypropyl) methacrylamide copolymer-Mesochlorine e6 and adriamycin conjugates in combination treatments. Clin Cancer Res. 2000 Mar;6(3):1008-15. [Free Full Text]
- Lu JM, Peterson CM, Guo-Shiah J, Gu ZW, Peterson CA, Straight RC, Kopecek J. Cooperativity between free and N-(2-hydroxypropyl) methacrylamide copolymer bound adriamycin and meso-chlorin e6 monoethylene diamine induced photodynamic therapy in human epithelial ovarian carcinoma in vitro. Int J Oncol. 1999 Jul;15(1):5-16. [PubMed]
- Peterson CM, Lu JM, Gu ZW, Shiah JG, Lythgoe K, Peterson CA, Straight RC, Kopecek J. Isobolographic assessment of the interaction between adriamycin and photodynamic therapy with meso-chlorin e6 monoethylene diamine in human epithelial ovarian carcinoma (OVCAR-3) in vitro. J Soc Gynecol Investig. 1995 Nov-Dec;2(6):772-7. [PubMed]
- Peterson CM, Lu JM, Sun Y, Peterson CA, Shiah JG, Straight RC, Kopecek J. Combination chemotherapy and photodynamic therapy with N-(2-hydroxypropyl) methacrylamide copolymer-bound anticancer drugs inhibit human ovarian carcinoma heterotransplanted in nude mice. Cancer Res. 1996 Sep 1;56(17):3980-5. [PubMed]
- Raab GH, Schneider AF, Eiermann W, Gottschalk-Deponte H, Baumgartner R, Beyer W. Response of human endometrium and ovarian carcinoma cell-lines to photodynamic therapy. Arch Gynecol Obstet. 1990;248(1):13-20. [PubMed]
- Koren H, Alth G. Photodynamic therapy in gynaecologic cancer. J Photochem Photobiol B. 1996 Nov;36(2):189-91. [PubMed]
- Keefe KA, Tadir Y, Tromberg B, Berns M, Osann K, Hashad R, Monk BJ. Photodynamic therapy of high-grade cervical intraepithelial neoplasia with 5-aminolevulinic acid. Lasers Surg Med. 2002;31(4):289-93. [PubMed]
Reference for excluded clinical studies
- 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]
- 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]
- 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]
- 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]
- Wierrani F. [Experimental investigations and clinical use of photodynamic therapy (PDT) in the Rudolf Foundation Hospital] Gynakol Geburtshilfliche Rundsch. 1999;39(4):217-25. [PubMed]
- 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]
- Monk BJ, Brewer C, VanNostrand K, Berns MW, McCullough JL, Tadir Y, Manetta A. Photodynamic therapy using topically applied dihematoporphyrin ether in the treatment of cervical intraepithelial neoplasia. Gynecol Oncol. 1997 Jan;64(1):70-5. [PubMed]
- Korell M, Untch M, Abels C, Dellian M, Kirschstein M, Baumgartner R, Beyer W, Goetz AE. [Use of photodynamic laser therapy in gynecology] Gynakol Geburtshilfliche Rundsch. 1995;35(2):90-7. [PubMed]
- Xu YL, Gan DQ, Li DJ, Tao BP, Su WF, Wanfan S. The selective killing effect of special wavelength light in the treatment of human superficial cancer. Cancer. 1990 Jun 1;65(11):2482-7. [PubMed]
Reference for clinical studies only abstract available
- 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]
- 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]
- 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]
- Lobraico RV, Grossweiner LI. Clinical experiences with photodynamic therapy for recurrent malignancies of the lower female genital tract. J Gynecol Surg. 1993 Spring;9(1):29-34. [PubMed]
- Hetzel H, Muller-Holzner E, Marth C, Kostron H. [Photodynamic therapy in patients with recurrent gynecologic cancers] Geburtshilfe Frauenheilkd. 1993 May;53(5):333-6. [PubMed]
- DeLaney TF, Sindelar WF, Tochner Z, Smith PD, Friauf WS, Thomas G, Dachowski L, Cole JW, Steinberg SM, Glatstein E. Phase I study of debulking surgery and photodynamic therapy for disseminated intraperitoneal tumors. Int J Radiat Oncol Biol Phys. 1993 Feb 15;25(3):445-57. [PubMed]
- Sindelar WF, DeLaney TF, Tochner Z, Thomas GF, Dachoswki LJ, Smith PD, Friauf WS, Cole JW, Glatstein E. Technique of photodynamic therapy for disseminated intraperitoneal malignant neoplasms. Phase I study. Arch Surg. 1991 Mar;126(3):318-24. [PubMed]
- Lele SB, Piver MS, Mang TS, Dougherty TJ, Tomczak MJ. Photodynamic therapy in gynecologic malignancies. Gynecol Oncol. 1989 Sep;34(3):350-2. [PubMed]
- Gadducci A, De Punzio C, Facchini V, Rispoli G, Fioretti P. The therapy of verrucous carcinoma of the vulva. Observations on three cases. Eur J Gynaecol Oncol. 1989;10(4):284-7. [PubMed]
- Rettenmaier MA, Berman ML, DiSaia PJ, Burns RG, Berns MW. Photoradiation therapy of gynecologic malignancies. Gynecol Oncol. 1984 Feb;17(2):200-6. [PubMed]
Table 1. Characteristics of included clinical studies
1.1 Cervical neoplasm, diagnosis
|Study||Bogards 2002 (37)|
|Methods||controlled clinical trial (patients served as own controls)|
|Participants||38 patients were in the protocol, with 16 colposcopically selected for biopsy (19 sites were biopsied)|
|Intervention||ALA topically applied. The fluorescence imaging was quantified by double ratio (DR) fluorescence imaging technique.|
|Outcomes||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 [Spearman rank correlation, r=0.881, p<0.001 (confidence interval 0.7044-0.9552)].|
|Notes||Only abstract available, however, this is the only trial that used DR for quantitative detection of cervical neoplasm, so it was included.|
|Study||Kristin 2001 (24)|
|Participants||18 women with biopsy proven CIN II or III|
|Intervention||18 patients were randomly assigned to receive 1.5, 3, or 6 hours of exposure to either 5-ALA (200mg/ml) or BPD-MA(2mg/ml). (3 patients for each time interval with each drug). Colposcopically directed cervical biopsy specimens were evaluated for selective drug absorption with hematoxylin and eosin staining and fluorescence microscopy.|
|Outcomes||After exposure to 5-ALA, cervical tissue showed maximal fluorescence in dysplastic cells relative to normal cells, with negligible stromal fluorescence. BPD-MA demonstrated nonselective, diffusion-driven uptake.|
|Notes||Random method not mentioned. Results derived from observation only, no detail data showed.|
|Study||Hillemanns 2000 (36)|
|Methods||Self-controlled clinical trial|
|Participants||Randomly selected 68 women attending colposcopy clinic.|
|Intervention||0.5% or 1.0% 5-aminolevulinic acid (5-ALA) were topically applied. After 30-360 minutes, real-time image analysis was performed, and spectra were obtained from 685 sites.|
|Outcomes||0.5% 5-ALA proved ineffective for fluorescence assessment.
Using 1% 5-ALA, fluorescence contrast showed a maximum at 60-90 minutes (ratio 11:1). HPV DNA positive lesions showed significantly higher fluorescence (p<0.01). 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. 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 2/3 compared with CIN 1 (P < 0.001).
|Notes||Confidence interval not available for sensitivity and specificity.|
|Study||Pahernik 1998 (13)|
|Methods||Self-controlled clinical trial|
|Participants||28 non pregnant women with a cytological diagnosis of low-grade or high-grade squamous intra-epithelial lesions. (3 patients with CIN I, 3 with CIN II, 8 with CIN III, 14 with normal epithelium).|
|Intervention||3% 5-ALA was topically applied 1 to 6 hrs prior to conization using a cervical cap. Quantitative fluorescence microscopy was used to quantify porphyrin-induced fluorescence after excision.|
|Outcomes||Fluorescence ratios were 1.3 for CIN-1: normal ; 1.21 for CIN-2:normal and 2.35 for CIN-3: normal. The optimal administration time of topically applied 5-ALA was between 3 and 4 hr.|
1.2 Ovarian cancer, diagnosis
|Study||Major 2002 (1)|
|Methods||Self-controlled clinical trial|
|Participants||An ovarian adenocarcinoma patient|
|Intervention||1% ALA applied topically to the rectum and peritoneum of the abdominal wall for 1 hour. Blue excitation light was used to detect the micrometastases.|
|Outcomes||All visible metastases and small unvisible lesions (5 mm in diameter) could be detected in the fluorescence mode.
Microscopic analysis of fluorescent-guided biopsies taken from eight different sites all revealed signs of ovarian cancer.
No skin phototoxicity or other adverse events were observed.
1.3 Cervical neoplasm, treatment
|Study||Barnett 2003 (3)|
|Methods||Randomized, double-blind, placebo-controlled trial (using randomization table)|
|Participants||41 patients with histologically confirmed CIN I or II.|
|Intervention||3% ALA topically applied to the cervix for 4 hr followed by superficial illumination with 100Jcm-2 635 nm light with diode laser. Histologic examination was done 3 month after PDT. Placebo was used as control.|
|Outcomes||Treatment of CIN with ALA-PDT was well tolerated, there was no significant difference in response between the groups receiving ALA-PDT and those receiving placebo treatment (p>0.9).|
|Notes||Of the 41 recruited patients, 10 underwent fluorescence microscopy, 6 dropped out. It was not known to which group these 6 patients belonged to.|
|Study||Keefe 2002 (60)|
|Methods||Uncontrolled observational study|
|Participants||16 CIN II patients and 24 CIN III patients|
|Intervention||200 mg/ml ALA applied topically to cervix followed by five escalating radiant energies (increments of 25 J/cm2, beginning at 50-150 J/cm2) with 630 nm laser light.|
|Outcomes||Success rate was 31% (10/32) 12 month after treatment, and was not light-dose dependent 3 patients progressed from CIN II to CIN III. Toxicity was tolerable.|
|Notes||8 patients (20%) were lost during follow up. Since spontaneous regression is less likely to occur in high grade CIN, this uncontrolled study is also included.|
|Study||Hillemanns 1999 (28)|
|Methods||4 patients with CIN II and 3 patients with CIN III|
|Participants||Uncontrolled observational study|
|Intervention||10 ml of 20% 5-ALA was topically applied. Combined ectocervical and endocervical irradiation was performed to a total irradiation of 100 J/cm2 with irradiance limited to 150 mW/cm2 (635 nm laser light).|
|Outcomes||None of the 7 patients showed a regression of the high-grade CIN lesion 12 weeks after treatment: 4 patients presented with no change of the CIN lesions after PDT, 3 progressed from CIN II to CIN III. Side effects were minimal.|
|Notes||Since spontaneous regression is less likely to occur in high grade CIN, this uncontrolled study is also included.|
1.4 Vulvar or vaginal neoplasm, treatment
|Study||Fehr 2002 (7)|
|Methods||Controlled clinical trial|
|Participants||Experimental group:22 patients with VIN II/III or VAIN III/IIII, 16 with condylomata.
Control group: 44 patients with VIN III treated with CO2 laser evaporation or excision, 26 patients with condylomata treated with CO2 laser evaporation.
|Intervention||10% ALA applied topically for 2-4h, followed by 80-125 J/cm(2) laser light at a wavelength of 635 nm.|
|Outcomes||For condyloma, the complete clearance rate for being treated by PDT was 66%, no statistical significant difference was seen in disease free survival rate between the two groups.
For IN, 57%(12/21) 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). No scarring occurred, and postoperative discomfort lasted 4.9 +/- 3.4 days. Reduced disease-free survival (DFS) was associated with multifocal VIN III (p=0.02, OR 2.17, 95% CI 1.15-4.08).
|Notes||Control group was retrospectively selected. 22 patients were recruited in the IN PDT groups, but only 21 patients’ outcomes were reported, the information about the remaining patient was not reported. No confidence interval about the outcome between the three IN group.|
|Study||Abdel Hady 2001 (8)|
|Methods||Self controlled study|
|Participants||32 patients with pathologically diagnosed VIN II or III|
|Intervention||20% ALA cream applied topically to the affected area for 5 h, followed by red light at 630 nm with the dose of light escalated from 50 J/cm2 for the first 10 patients to 100 J/cm2 for all of the other patients. At 12 weeks after PDT, all of the patients were evaluated both clinically and histopathologically.|
|Outcomes||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. VIN lesions that failed to respond to PDT were more likely to have detectable HPV compared with the responders (P = 0.002)|
|Notes||Only part of the data was used in this study. The result of PDT on VIN was not included because no control group was available.|
|Study||Kurwa 2000 (43)|
|Methods||Observational clinical study|
|Participants||6 patients with biopsy proven VIN III, all but one patient were resistant to conventional treatment.|
|Intervention||20% ALA applied topically for 4 hour followed by 150 J cm2 light at wavelength of 580-740 nm.|
|Outcomes||All patients had clinically evident persistent VIN III at 1-month review.|
|Notes||Although this is a controlled trial, but the outcome is obvious, so it is also included.|
|Study||Ward 1988 (44)|
|Methods||Observational clinical study|
|Participants||5 patients with recurrent vaginal cancer|
|Intervention||5 mg/kg hematoporphyrin derivate infused intravenously over 3 hour period. 620-640nm laser (500mW at the tip of probe) was used either superficially or intertissually 3 days later for 7-25 20-min exposure.|
|Outcomes||CR was seen in 2 out of 5 patients 10-12 months after treatment.|
|Notes||It is not mentioned whether these 5 patients received other therapy or not at the same time.|
1.5 Ovarian cancer, treatment
|Study||Wierrani 1997 (49)|
|Participants||3 patients with recurrent ovarian cancer|
|Intervention||0.15 mg/ kg body weight m-THPC administered intravenously 96 hours before irradiation. 5J/cm2 laser light at 625nm wavelength was delivered by laparoscopy. 2 patients received PDT solely, 1 patient received palliative debulking surgery.|
|Outcome||All 3 patients remained free of relapse 2 years after treatment.|
|note||The condition of relapse was not reported (diameter of cancer nodule, site, number of recurrent nodule)|
1.6 Endometrial cancer, treatment
|Study||Koren 1996 (59)|
|Participants||7 endometrial adenocacinoma Ia, 2 adenocarcinoma or adenokantoma T1N0 relapsed after surgery radiation|
|Intervention||2mg/kg body weight Photosan III injected intravenously 24-72 hours before irradiation. A continuous wave Argon Dye laser at wavelength of 632nm was used for 200 J cm2 total light dose.|
|Outcome||1 month after PDT, 6 CR was observed , 5 in the 7 Ia patients, 1 in the 2 recurrent patients. 3 patients were NR. 12 months later, all but 1 patient were recurrent.1 patient with Ia remained CR.|
|Note||Tumor size and depth were not mentioned.|
Table 2. Character of clinical studies excluded
2.1 Vulvar neoplasm
|Study||Reason for exclusion|
|Fehr 2000||This study seems to be one part of the study published in Fehr 2002 (6).|
|Hillemanns 2000||Uncontrolled trial on the effect of PDT on VIN.|
|Henta 1999||Case report about vulval extramammary Paget's disease treated by VP16 and PDT together.|
|Martin-Hirsch 1998||Uncontrolled report about PDT treating VIN and CIN. Research letter only. No detail information about the grade, size of the lesion.|
2.2 Cervical neoplasm
|Study||Reason for exclusion|
|Wierrani 1999||Uncontrolled study for the treatment of CIN I/II and HPV infection with PDT, since spontaneous regression of low grade CIN lesions may occur even when no treatment was administered|
|Wierrani 1999||Uncontrolled study for the treatment of CIN I/II and HPV infection with PDT.|
|Pahernik 1997||Uncontrolled study for the treatment of CIN I-III with PDT.|
|Korell 1995||Uncontrolled study for the treatment of 2 CIN and 3 VIN patients with PDT.|
|Xu 1990||Of the 25 cancer patients, only 2 were cervical cancer, and the detail information were not known (stage, size, response etc.)|
Table 3. Character of clinical studies only abstract available
|Participants||4 patients with recurrent gynecological malignancy|
|Intervention||4 days after intravenous 0.15 mg/kg m-THPC, light at 652 nm delivered superficially at a total light dose of 20 J/cm2.|
|Results||Within 24 h necrosis occurred which was restricted to the tumor area. All tumors responded to PDT, however wound healing was significantly delayed and survival times were disappointingly short.|
|Participants||26 patients with vaginal recurrences of gynaecological cancers.|
|Intervention||5 mg kg-1 body weight hematoporphyrin with light dose ranged between 60 and 500 J cm-2.|
|Results||For patients treated with a palliative aim, complete absence of symptoms for at least 60 days was observed in 66% patients; for curative group, 12 patients (70.58%) achieved cytological and/or histological absence of lesions.|
|Participants||39 CIS and 17 CIN|
|Intervention||PDT is performed 48 hours after intravenous injection of 1.5 to 2 mg/kg PHE|
|Results||54 CR (96.4%), 1 NC, and 1 PR|
|Participants||17 patients with recurrent carcinoma in situ of the vulva, vagina, and perianum.|
|Intervention||PDT with Photofrin II|
|Results||A histologically complete response 3 months after PDT was achieved for 27 of 38 (71%) anatomic sites. 10 patients remain free of recurrences for periods of 2-7 years. Condylomata acuminata associated with CIS in 16 of 17 patients recurred rapidly in 7 patients after PDT. Only short-term palliative results were achieved for 4 patients treated with PDT for invasive carcinoma.|
|Participants||3 patients with a recurrent vulva carcinoma, 1 with a recurrent cervical carcinoma, 1 with a recurrent endometrial carcinoma, and 1 with a recurrent breast carcinoma|
|Intervention||PDT after parenteral or topical sensitization with Photosan 3. The energy of laser light ranged between 225 and 750J/cm2.|
|Results||2 patients showed a complete response with no evidence of disease for 32 and 29 months. 1 responded partially with two recurrences. 3 patients showed partial response and died 3 to 8 months after PDT.|
|Method||Observational study (Phase I)|
|Participants||39 patients with recurrent, disseminated intraperitoneal tumors.|
|Intervention||DHE 1.5-2.5 mg/kg by i.v. injection 48-72 hours prior to surgery. Patients resected to < or = 5 mm of residual disease underwent whole peritoneal PDT supplemented with boost doses of 10-15 J/cm2 red light or 5-7.5 J/cm2 green light to high risk areas.|
|Results||PDT of 630 nm 2.8-3.0 J/cm2 induced small bowel edema and resulted in 3 small bowel perforations after bowel resection or enterotomy. Dose limiting toxicities occurred in 2 of 3 patients at the highest light dose of 5.0 J/cm2 green light with boost. At potential follow-up times of 3.8-43.1 months (median 22.1 months), 30/39 patients are alive and 9/39 are free of disease.|
|Method||Observational study (phase I)|
|Participants||23 patients with disseminated intraperitoneal malignant neoplasm (13 with ovarian cancer, eight with sarcoma, and two with pseudomyxoma peritonei)|
|Intervention||1.5 to 3.0 mg/kg dihematoporphyrin ethers intravenously administered 48 to 72 hours before laparotomy, 630 nm light was delivered to all peritoneal surfaces at doses ranging from 0.2 to 3.0 J/cm2 after tumor debulking surgery.|
|Results||5 of 8 patients cleared positive peritoneal cytology after treatment. 6 remained clinically free of disease for up to 18 months, and 5 had treatment-related complications.|
|Participants||21 patients with recurrent gynecologic malignancies|
|Intervention||PDT using Photofrin II and argon dye laser|
|Results||7of 21 patients with cutaneous lesions treated palliatively had a complete response and 4 of 11 patients with cervical and vaginal recurrences had an objective response, 2 with complete response continued to be free of disease after 28 and 36 months|
|Participants||3 patients with vulvar verrucous carcinoma|
|Participants||Four patients with gynecologic tumors recurrent either to the vagina or skin|
|Intervention||630 nm laser light delivered 72 hours after intravenously administered hematoporphyrin derivative|
|Results||Of 7 tumor sites which were treated, 1 was completely destroyed, 2 were diminished in volume by more than 30%, and no response was seen in 4.|