Accepted Manuscript

Title: Clinical application of photodynamic diagnosis and

photodynamic therapy for gynecologic malignant diseases: a
review

Authors: Yusuke Matoba, Kouji Banno, Iori Kisu, Daisuke

Aoki

PII: S1572-1000(18)30241-2
DOI: https://doi.org/10.1016/j.pdpdt.2018.08.014
Reference: PDPDT 1234

To appear in: Photodiagnosis and Photodynamic Therapy

Received date: 23-7-2018

Revised date: 25-8-2018
Accepted date: 27-8-2018

Please cite this article as: Matoba Y, Banno K, Kisu I, Aoki D, Clinical
application of photodynamic diagnosis and photodynamic therapy for gynecologic
malignant diseases: a review, Photodiagnosis and Photodynamic Therapy (2018),
https://doi.org/10.1016/j.pdpdt.2018.08.014

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Title Page

Title: Clinical application of photodynamic diagnosis and photodynamic therapy for gynecologic

malignant diseases: a review

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Author names and affiliations:

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Yusuke Matoba M.D., Kouji Banno M.D., Ph.D., Iori Kisu M.D., Ph.D., Daisuke Aoki M.D., Ph.D.

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Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, 160-8582 Japan
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Corresponding author:
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Full name: Kouji Banno

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Address: 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 Japan ,Telephone with country code: +81-3-
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5363-3291 ,Email: kbanno@z7.keio.jp

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Highlights:

 Cure rate of PDT for cervical diseases ranged from 31.6% to 100% in 8 articles
 In the only article on PDT for endometrial cancer the cure rate was 75%
 The efficacy of PDD for ovarian cancer was high in 6 articles
Abstract

Introduction. Several types of photosensitizers such as 5-aminolevulinic acid are progenitors of

protoporphyrin IX (PpIX). PpIX accumulates in cancer cells and has photosensitivity. Based on these

characteristics, these are used in photodynamic diagnosis (PDD) and photodynamic therapy (PDT). These

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methods have recently been applied to gynecologic malignant diseases. Here, we review articles on clinical

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applications of PDD and PDT for these diseases. Materials and Methods. A systematic literature search in

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Pubmed was performed with a combination of keywords to collect the articles. Result. There were eight

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articles on PDT for uterine cervical diseases, including one study that included patients with cervical
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cancer. The disease remission rate ranged from 31.6% to 100%. PDD under hysteroscopy had positive
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effects on endometrial cancer, endometrial hyperplasia and secretory endometrial tissue, and 7 of 11
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patients were able to become pregnant after PDT for endometrial cancer. For ovarian cancer, the sensitivity
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and specificity of clinical PDD were high. Discussion. There is a need to improve the disease remission
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rate in uterine cervical diseases, and application of PDT for cervical cancer should be considered. For
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endometrial cancer, the risks and benefits of PDD that should be compared with those of hysteroscopy
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using narrow band imaging, which already has been shown to have high efficacy and no side effects. For

ovarian cancer, it will be necessary to collect more data to evaluate the effect of PDD on overall survival.

Conclusion. PDD and PDT can contribute to diagnosis and therapy in clinical practice for gynecologic
malignant diseases.

Keywords

5-aminolevulinic acid, photodynamic diagnosis, photodynamic therapy, cervical cancer, endometrial

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cancer, ovarian cancer

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Introduction

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Several types of photosensitizers such as 5-Aminolevulinic acid (5ALA) serve as a precursor of
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protoporphyrin IX (PpIX) in biosynthesis. Porphyrins including PpIX are common in nature and have
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various functions when complexed with metal ions, depending on the metal type. For example, when
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complexed with iron, the heme in a porphyrin can supply oxygen [1]. Recent studies have shown that
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uptake and efflux transporters are involved in accumulation of PpIX in tumor cells, although the
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mechanism remains unclear [2, 3]. PpIX emits red fluorescence at 650 nm when irradiated with blue
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excitation light at 400 nm [4], and this characteristic has led to use of photodynamic diagnosis (PDD) of
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cancer; i.e., tumor accumulation and fluorescence. PpIX may also result in the formation of reactive

oxygen species (e.g. singlet oxygen) when irradiated with strong excitation light, and based on this

principle, some photosensitizers are used in photodynamic therapy (PDT) for cancer. The first example of
PDT was reported by Kennedy et al. in 1990, with administration of 5ALA to patients with basal cell

carcinoma [5]. Subsequently, PDD and PDT have been used for other carcinomas, including PDT for

actinic keratosis, Bowen's disease and basal cell carcinoma [6], and PDD for bladder cancer [7-9] and

brain tumor[10]. PDD and PDT have also been used for gastrointestinal malignancy [11-13], malignant

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intrathoracic lesions [14], and various carcinomas [15-19].

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PDD and PDT are also used in clinical practice for malignant gynecologic disease. The incidence of

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cervical cancer is high in women of reproductive age [20].The National Comprehensive Cancer Network

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(NCCN) guidelines [21] indicate that patients with a lower stage than clinical stage IB1 cervical cancer can
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be treated with fertility preservation methods including a loop electrosurgical excision procedure (LEEP),
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conization and trachelectomy. However, the abortion rate and preterm prevalence are increased by these
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methods in patients who subsequently become pregnant [22, 23]. Therefore, therapies with fewer
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complications are needed. In addition, endometrial cancer has been increasing in young women and the
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morbidity of women of reproductive age ranges from 3% to 14% [24], with a number of affected young
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patients. For endometrial cancer with a tissue type of well-differentiated (grade 1) endometrioid
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adenocarcinoma, the NCCN guidelines [25] indicate that fertility preservation methods using hormone

therapy can be used for patients with endometrium-limited carcinoma. However, recurrence rates of

endometrial cancer are approximately 40%, even if patients are treated using fertility preservation
methods, and endometrial adhesions due to dilation and curettage during fertility preservation also have a

poor effect on pregnancy[26]. Therefore, alternative methods for dilation and curettage are under

development to remove as much residual cancer as possible and to avoid tissue damage to the extent

possible. Ovarian cancer is often in an advanced stage when detected, and treatment requires total

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extirpation, including bilateral salpingo-oophorectomy and hysterectomy. A smaller residual lesion gives

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better results [27], but outcomes after treatment are not satisfactory [28] and methods to identify and

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remove lesions are being studied. Identification of malignant gynecologic disease may be increased by

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PDD, and minimally invasive surgery combined with PDT may be clinically applicable. In this review, we
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summarize studies of clinical applications of PDD and PDT for malignant gynecological disease.
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Materials and Methods

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A systematic literature search in Pubmed was performed with the combination of keywords “cervical
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cancer”, “cervical intraepithelial neoplasia”, “endometrial cancer”, “ovarian cancer”, “aminolevulinic

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acid”, “photodynamic therapy” and “photodynamic diagnosis” to collect articles that referred to PDD or
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PDT. Articles on cervical intraepithelial neoplasia (CIN) were included in this review because CIN is a

premalignant lesion of cervical cancer. A manual search of the bibliographies of relevant papers was

carried out to identify additional studies for possible inclusion. Articles written in a language other than
English were excluded from the review.

Results

Cervical Cancer and Cervical Intraepithelial Neoplasia (CIN)

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Eight articles on cervical cancer, carcinoma in situ (CIS) and CIN treated with PDT are summarized in

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Table 1. Muroya et al. used PDT in 132 patients with cervical lesions, including 3 with cervical cancer

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[29], and found an extremely high complete response rate of 96.97%. Skin flare in 20 patients was the only

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complication of PDT. In a case series using PDT in 4 patients with CIN2 and one with CIN3, Wang et al.
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performed cervical histology 9 months after treatment and found no abnormality in the cervical cells of all
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patients, indicating the efficacy of PDT [30]. Yamaguchi et al. also performed cervical histology 3 months
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after PDT for patients with CIN and confirmed complete remission in 90% of cases [31]. Some of the
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patients without remission showed lesion elimination 3 months later, and the only adverse event was slight
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photosensitivity in about half of all the patients [31]. Soergel et al. performed PDT in 24 patients with CIN
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and obtained a complete remission rate of 63% [32]. In a further study, Soergel et al. found overall
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response rates, including complete and partial responses, after PDT of 33.33% in CIN1, 88.89% in CIN2,

and 53.85% in CIN3 [33]. At 12 months after treatment, Bodner et al. obtained complete remission rates of

91% in 11 patients with CIN2 and 100% in 11 patients with CIN who underwent conization, with no
significant difference between these groups [34]. In a study of PDT in 19 patients with CIN3 and 13 with

CIN2, Keefe et al. obtained a remission rate of 31% [35]. Finally, Barnett et al. [36] used PDT in patients

with CIN1 and CIN2, and obtained rates of lesion elimination, no significant remaining lesion, and lesion

progression of 33%, 42% and 25%, respectively, with no significant difference in the lesion elimination

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rate between the PDT group and a control group without intervention.

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Endometrial cancer

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One study on clinical application of PDD [37] and one on clinical application of PDT [38] were found
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in patients with endometrial cancer. Wyss et al. performed PDD in 44 patients with endometrial cancer
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who were scheduled to undergo hysteroscopy [37] and collected 60 specimens by total endometrial
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curettage and targeted biopsy. In a comparison of the PDD with that obtained histopathologically, PDD-
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positive patients comprised 6.2%, 16.6%, 84.6%, and 81.3% of patients diagnosed with endometrial
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atrophy, proliferative phase endometrium, secretory phase endometrium, and endometrial hyperplasia,
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respectively. Furthermore, specimens diagnosed as endometrial cancer or atypical endometrial hyperplasia

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were also obtained from PDD-positive cases. Based on these results, Wyss et al. concluded that PDD can

be used to diagnose endometrial lesions more accurately considering the menstrual cycle [37]. In 16

patients with endometrial cancer (pathological diagnosis: 14 grade 1, 2 grade 2) without muscle invasion
preoperatively and with no extrauterine cancer progression, PDT was performed by injecting

hematoporphyrin into the uterine cavity and irradiating with a laser at 630 nm to the uterine cavity 48 h

later [38]. PDT had to be performed twice in some patients due to relapse and remaining lesions, but 11

patients finally reached a complete response and 7 became pregnant. Adverse events of mild facial

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angioedema occurred in 4 patients, but remitted with conservative therapy [38]. For comparison,

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recurrence rates of endometrial cancer treated with hormone therapy for fertility preservation are about

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40% [26, 39]; therefore, the report showed that the recurrence rate after PDT for endometrial cancer of

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about 33% appears to be lower than that of conventional therapies [38].
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Ovarian Cancer, Fallopian Tube Cancer and Primary Peritoneal Cancer

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Since outcomes in patients with ovarian cancer, fallopian tube cancer and primary peritoneal carcinoma
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are improved by eliminating as many cancer cells as possible, many studies of PDD have been conducted
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to improve lesion identification rates (Table 2). In 2004, Löning et al. performed PDD laparoscopically by
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intraperitoneal injection of 5ALA [40]. The sensitivity and specificity of PDD for identification of ovarian
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cancer were 92% and 95%, and lesions <0.5 mm were identified. Furthermore, lesions were identified only

by PDD in 4 of 13 patients with ovarian cancer, suggesting the utility of PDD for ovarian cancer treatment.

Also, in 2006, Löning et al. performed PDD in 36 patients with ovarian and fallopian tube cancer by
intraperitoneal injection of 5ALA, followed by laparoscopy 5 h later [41]. The sensitivity and specificity of

PDD for identification of ovarian cancer were 100% and 88%. Specimens were observed by fluorescence

microscopy, with the fluorescence of PpIX being stronger at sites with many tumor cells. Löning et al.

suggested that these results showed PpIX accumulation in tumor cells, with consistency of PDD-positive

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findings and histological malignant findings. Hillemanns et al. published a case report of a 61-year-old

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patient with recurrent ovarian cancer who underwent laparotomy 6 h after 5ALA oral administration, and

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in whom lymph node metastasis was identified by PDD [42]. Fluorescence was detected in a region

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suspected preoperatively to be a metastasis of ovarian cancer, and the metastasis was confirmed
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pathologically. PDD showed no fluorescence in other areas, and the absence of metastasis in these areas
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was also confirmed pathologically. Hillemanns et al. examined the optimal conditions of PDD with 5ALA
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to identify peritoneal metastasis of ovarian cancer by grading dose levels of 5ALA and the time from
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administration of 5ALA to PDD [43]. PDD was performed 4 to 9 h after oral administration of 5ALA at a
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dose of 10 mg per body weight and the sensitivity and specificity for identification of peritoneal metastasis
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were 75% and 100%, which were the best outcomes. Liu et al. performed PDD 2 h after oral
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administration of 5ALA, and obtained sensitivity and specificity for detection of a malignant tumor of 95%

and 100% [44]. Minor adverse events occurred peri- and postoperatively, but there were no deaths during

the follow-up period. Yonemura et al. performed PDD 4 h after oral administration of 5ALA in 9 patients
with ovarian cancer and peritoneal carcinoma [45], and found a sensitivity and specificity for detection of

a malignant tumor of 89% and 100%.

Discussion

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PDT was performed for cervical lesions of CIN [29-36], CIS [29] and cervical cancer [29]. The

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therapeutic effect of PDT for these lesions ranges from 31.6% to 100% in published studies. In reports

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with a low rate of lesion elimination of about 30%, 5ALA was used as a photosensitizer [35, 36]. This

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outcome may be due to the hydrophilicity of 5ALA, as one of many factors that decrease the therapeutic
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effect. The hydrophilicity of 5ALA may result in poor penetration into deeper layers, which might lead to
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reduced effects of PDT in these layers and may contribute to the differences in lesion elimination rates
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among studies. In a comparison of photosensitizers [46], Xiang et al. administered several 5ALA analogs
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with different characteristics, and concluded that ALA-hexylester was the most favorable because at lower
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doses this compound produced PpIX activity equivalent to that with 5ALA. New photosensitizers for PDT
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may improve therapeutic outcomes for cervical lesions using less-invasive therapy than conization and
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other current treatments.

Choi et al. used a combination of PDT with surgical treatment using conization or LEEP for fertility

preservation in patients with cervical cancer [47]. The clinical stages of cervical cancer were stages IA1,
IA2, IB1 and IIA1 in 10, 1, 9 and 1 cases, respectively. Cases of stage IB1 or higher underwent conization

using a cold knife and pelvic lymphadenectomy, with subsequent PDT after confirmation of a negative

surgical margin and no lymph node metastasis in frozen section pathological analysis. Over a mean

observation period of 52.6 months (6-114 months), only one patient had recurrent lymph node metastasis,

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the recurrence rate was 4.7%, and there were no deaths. Therefore, Choi et al. concluded that PDT may be

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a less-invasive fertility preservation treatment for cervical cancer based on the good therapeutic outcomes,

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no PDT-related complication, and lower rates of complications related to conization, LEEP and pelvic

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lymphadenectomy compared to those with trachelectomy, a current fertility preservation treatment.
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However, the patients included those who underwent total hysterectomy as standard care. There are no
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accumulated data on long-term outcomes of PDT for cervical cancer and there is a need to discuss its
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clinical application and for strict follow up of patients for conditions including recurrence.
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We found one study each on PDT and PDD for endometrial cancer [37, 38]. Though there was a case
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report of endometrial stromal sarcoma treated with PDT[48], there were few reports about PDT and PDD
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for endometrial malignant diseases. Several studies of the properties of 5ALA in the endometrium,
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myometrium and endometrial cancer cells have been performed. Gannon et al. [49], Fehr et al. [50] and

Degen et al. [51] examined the distribution of 5ALA in the uterine body. After injection of 5ALA into the

human endometrium, 5ALA-derived PpIX accumulated in the endometrium more than in the myometrium
[49, 50], the amount of PpIX in endometrial glands was highest 4 to 8 h after intrauterine injection of

5ALA [50], endometrial glands were more fluorescence-positive in premenopausal than in postmenopausal

patients [50], and fluorescent-positive rates of PpIX were higher in patients histopathologically diagnosed

with endometrial hyperplasia and secretory phase endometrium [51]. In a cellular study, Wyss-Desserich

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administered 5ALA to well-differentiated HEC-1A endometrial cancer cells, poorly differentiated KLE

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cells, and normal endometrial cells, and found that the cancer cells had more PpIX than normal cells [52].

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Data from these basic experiments make it possible to conduct a uterine cavity-targeted biopsy using PDD

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and develop a less-invasive fertility preservation treatment. However, hysteroscopic diagnosis using
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narrow band imaging (NBI) is already performed for endometrial cancer diagnosis, and its sensitivity and
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specificity of 97.2% and 90.6% are higher than the values of 82.6% and 85.1% for diagnosis using PDD
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[53]. NBI also causes no adverse events. Therefore, clinical application of PDD for endometrial cancer
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must provide benefits that exceed the adverse reactions of the photosensitizer, such as identification of
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microlesions more effectively than hysteroscopy using NBI.

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PDD has been used for many patients with ovarian cancer [40-45]. In particular, high sensitivity and
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specificity for identification of peritoneal metastasis lesions has been found in all of these studies. A

combination of PDD with an operation enables identification of metastatic lesions of <1 mm. Peritoneal

metastatic lesions have been identified by PDD using 5ALA in colorectal cancer [13] and advanced gastric
cancer [54]. Ushimaru et al. conducted staging laparoscopy combined with PDD and subsequent resection

[54]. Metastatic lesions were identified only by PDD in 13 patients (11%), and these patients underwent

postoperative chemotherapy and had a three-year survival curve that was very similar to that for patients

without metastasis [54]. Ushimaru et al. suggested that accurate staging based on early detection of

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peritoneal metastasis and use of postoperative adjuvant therapy contributed to these outcomes [54]. There

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are no data showing improved long-term prognosis of PDD combined with cytoreductive surgery for

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ovarian cancer; however, similarly to studies on gastric cancer, the combination of surgery and PDD for

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ovarian cancer is likely to improve staging and permit more appropriate additional treatment, which should
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lead to improved long-term outcomes.
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No clinical study of PDT for ovarian cancer was found, but several basic studies have been reported
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and these reports showed tumor regression [55-59]. In a rat model of peritoneal metastasis following
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transplant of ovarian cancer cells, Song et al. assessed the therapeutic effects of cytoreductive surgery
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alone and in combination with PDT or with excitation light irradiation, and found significantly longer
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survival after cytoreductive surgery+PDT in Kaplan-Meier survival analysis [60]. A study of combination
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therapy with PDT and carboplatin has also been reported [61], and further application of PDT to ovarian

cancer is under consideration. However, in a study of PDT using hexaminolevulinate as a photosensitizer

in a rat model of peritoneal metastasis [62], Guyon et al. found adverse reactions of PDT-related death due
to rhabdomyolysis, intestinal necrosis, and liver function test anomalies in 2 of 34 rats. Therefore, human

application of PDT for ovarian cancer should be performed after its safety is verified in further studies.

Conclusion

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We reviewed studies on clinical application of PDD and PDT for malignant gynecologic disease. Many

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of these studies examined cervical cancer and ovarian cancer, but only one study was found on clinical

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application of PDD and PDT in endometrial cancer. The success rate of PDT for cervical cancer varied,

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which indicates a need to determine the causes through accumulation of further cases. Basic studies on
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endometrial cancer are ongoing and should improve application in practice. It remains unclear whether
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PDD for ovarian cancer will contribute to long-term prognosis, and further long-term observation is
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necessary. However, all case reports of clinical applications showed that PDD or PDT had no serious
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adverse events and contributed to treatment and diagnosis. Basic studies of PDD and PDT for malignant
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gynecologic diseases should lead to further clinical applications.

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Conflicts of interest:
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This study did not receive a specific grant from a funding agency in the public, commercial, or not-for-

profit sector.
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 R I
SC
Table 1. Therapeutic efficacy of photodynamic therapy for uterine cervical diseases.

U
Year Author Disease Number of Type and Laser Radiant Irradiance Fiber laser Time to CR Remarks

N
A
Patients application of exposure geometry wavelength procedure

M
photosensitizer

1999 Muroya Dysplasia

ED
31 Dehemato excimer dye 100 J/cm2 N/A N/A 630-635 nm 48 hr 96.80%
PT

et al. porphyrin YAG-OPO 620-670 nm

E

ester/ether
CC

1.5-2.0 mg/kg
A

body intravenous

CIS 96 96.88%

SCC Stage 3 100%

 R I
SC
IA

U
AdenoCa 1 100%

N
A
Stage IA

M
2002 Keefe et CIN2 13 200 mg/ml 5- argon pumped 50-150 150 mW/cm2 400 mm silica 630 nm 1.5 hr 31.70%

al.
ED ALA topically dye J/cm2 fiber
PT

CIN3 19 31.60%
E

2003 Bodner CIN2 11 5 ml of 12% 5- halogen lamp 100 J/cm2 90 mW/cm2 N/A (portio 580-800 nm 8 hr 91.00%
CC

et al. ALA topically (portio (portio (portio vaginalis (porio)

A

vaginalis vaginalis vaginalis uteri) 652 nm

uteri) uteri) uteri) 1.5 cm long (cervical

KTP:YAG 50 J/cm2 300 mW/cm2 cylinder canal)

 R I
SC
pumped dye (cervical (cervical diffusing fiber

U
(cervical canal) canal) (600micro

N
A
canal) meter core

M
diameter)
ED (cervical
PT

canal)
E

2003 Barnett CIN1-2 12 10 g of 3% or diode 100 J/cm2 100 mW/cm2 N/A 635 nm 4 hr 33.30%
CC

et al. 5%5-ALA
A

topically

2005 Yamagu CIN1 4 Porfimer sodium excimer dye 100 J/cm2 N/A N/A 630 nm 48-60 hr 100%

chi et al. 2 mg/kg body YAG-OPO

 R I
SC
intravenous

U
CIN2 6 100%

N
A
CIN3 95 88.40%

M
2008 Soergel CIN1 7 10 ml of 10mM red coherent 100 J/cm2 100 mW/cm2 cylindrical 633 nm 3-5 hr 71.40% Includin

et al.
ED HAL topically light catheter g partial
PT

remissio
E

n
CC

CIN2 10 50.00%
A

CIN3 7 85.70%

2010 Soergel CIN1 3 10 ml of 10mM red coherent 100 J/cm2 100 mW/cm2 cylindrical 633 nm 12 hr 33.30% Includin

et al. or 40mM HAL light catheter g partial

 R I
SC
or 10ml of 1.2 remissio

U
mM MAL n

N
A
topically

M
CIN2 9 88.90%

CIN3
ED 13 53.80%
PT

2010 Wang et CIN2 4 2–3 g of 118 semiconducto 100 J/cm2 100–150 N/A 635 nm 3-4 hr 100%
E

al. mg/g 5-ALA r mW/cm2

CC

topically
A

CIN3 1 100%

CR: complete remission, CIS: carcinoma in situ, SCC: squamous cell carcinoma, AdenoCa: adenocarcinoma, CIN: cervical intraepithelial neoplasia, 5-ALA: 5-
 R I
SC
Aminolevulinic acid, HAL: hexylaminolevulinate, MAL: methylaminolevulinate, N/A: not applicable.

U
There were eight reports on photodynamic therapy for uterine cervical diseases. One report included patients with cervical cancer. The disease remission rate ranged

N
A
from 31.6% to 100%.

M
ED
E PT
CC
A
 R I
SC
Table 2. Accuracy of photodynamic diagnosis for ovarian cancer, fallopian tube cancer and primary peritoneal cancer.

U
Year Author Number of Number of Sensitivity Specificity Application of 5-ALA Time to surgery Wavelength of Instrument for PDD Remarks

N
A
patients specimens excitation light

M
2004 Löning et al. 30 123 92% 95% 30 mg/kg body 5 hr 350–440 nm Combilight PDD 5133
ED intraperitoneally (Richard Wolf)
PT

2006 Löning et al. 36 36 100% 88% 30 mg/kg body 5 hr 350–440 nm Combilight PDD 5133
E

intraperitoneally (Richard Wolf)

CC

2007 Hillemanns et al. 1 1 100% N/A 10 mg/kg body orally 6 hr 380–440 nm D-light system Case report
A

(Karl Storz)

2014 Liu et al. 20 158 95% 100% 20 mg/kg body orally 2 hr 440 nm N/A

2016 Yonemura et al. 9 N/A 89% 100% 20 mg/kg body orally 4 hr 375-445 nm xenon lamp (300W)
 R I
SC
2017 †Hillemanns et 15 15 75% 100% 1 mg/kg body or 10 mg/kg 3-14 hr 380–440nm D-light system

U
al. body orally 4-9 hr (Karl Storz)

N
A
9-16 hr

M
5-ALA: 5-Aminolevulinic acid, PDD: photodynamic diagnosis, N/A: not applicable
ED
†Patients were divided into three different groups. 5-ALA administered 3–14 hours before surgery using a dosage of 1 mg/kg, 4–9 hours using 10 mg/kg, and 9–16
PT

hours using 10 mg/kg, respectively.

E

There were six reports on photodynamic diagnosis for ovarian cancer, fallopian tube cancer and primary peritoneal cancer. 5-ALA was used in every report. The
CC

sensitivity and specificity ranged from 75% to 100% and 88% to 100%, respectively.
A