Photodiagnosis and Photodynamic Therapy (2006) 3, 71—84
REVIEW
Photodynamic therapy in China: Over 25 years of unique clinical experience Part two—–Clinical experience Zheng Huang MD, PhD ∗ Radiation Oncology Department, Colorado University Health Sciences Center, 1600 Pierce Street, Denver, CO 80214, USA Available online 18 April 2006 KEYWORDS Photodynamic therapy; PDT; China; Nasopharyngeal carcinoma; Liver cancer; Port-wine stains
Summary Photodynamic therapy (PDT) was started in the People’s Republic of China in the early 1980s after domestically produced hematoporphyrin derivative (HpD) became available. Since then, numerous photosensitizers have been synthesized and evaluated. Several promising ones have undergone clinical investigations and a few have entered into formal clinical trials. Various lasers and non-coherent light sources have been developed in China to facilitate domestic photosensitizers and clinical PDT applications. Chinese pioneered PDT protocols for treating nasopharyngeal carcinoma (NPC), liver carcinoma, port-wine stains (PWS) and urethral condylomata acuminata. Over the past 25 years Chinese physicians have treated several thousands patients, gained substantial experience in both basic sciences and clinical applications, and generated a great number of clinical reports. The Part One of this article provides an objective overview on China’s PDT history and an introduction of domestic photosensitizers. This article (Part Two) will summarize clinical PDT data of nasopharyngeal carcinoma, liver cancer and port-wine stains since these data are clinically valuable but less well known outside China. © 2006 Elsevier B.V. All rights reserved.
Contents Introduction.................................................................................................. Nasopharyngeal carcinoma PDT .............................................................................. Liver cancer PDT ............................................................................................. Port-wine stains PDT ......................................................................................... Future prospects ............................................................................................. Acknowledgments ............................................................................................ References ................................................................................................... ∗
Tel.: +1 303 2393567; fax: +1 303 2393562. E-mail address: zheng [email protected].
1572-1000/$ — see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.pdpdt.2006.03.001
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Introduction Photodynamic therapy (PDT) was first introduced into Chinese hospitals as a novel antitumor therapy in the early 1980s. PDT has been practiced in China for over 25 years. The Part One of this article has provided an objective and general overview on China’s PDT history and domestic photosensitizers. It might be overstated to say that PDT has experienced a roller coaster ride in China. But PDT practice has indeed experienced ups and downs in past years. Overall, PDT is still a viable experimental ground if not a mainstream practice yet (see Part One). During the early years the government sponsored multi-discipline and multi-centre initiative was the main driven force, which conceived the birth of several HpD photosensitizers. Domestically produced hematoporphyrin- or chlorophyll-derived photosensitizers and lasers have been used, almost exclusively, in clinical PDT in China until the early 2000s. Over the past 25 years Chinese clinicians have treated several thousands patients and published a great number of clinical reports—–some were very brief and some in detail. By reviewing those reports, one can find that the majority of clinical reports can be classified as case report or single hospital experience that generally focused on assessing feasibility and/or efficacy. In term of the study design those reports can be described as pilot study, comparison study or non-randomized Phase I/II/III trials. The 1984 national criterion for the evaluation of short-term antitumor PDT efficacy was used in majority reports (see details in Table 1 in Part One). This article (Part Two) attempts to provide an objective and balanced view of Chinese clinical PDT based on those publications. A comprehensive reference list has been compiled based on a literature survey of both Chinese and English scientific journals although it is nearly impossible to include every single PDT clinical report. A summary of clinical studies is organized according to their clinical specialties in Table 1. Selected references published in English or Chinese are organized by their clinical specialties in a chronological fashion [1—122]. There are a large number of clinical experimental data involving various photosensitizers (PS), light sources and diseases. The profound differences in PDT protocols and patient profiles prevent detailed discussion of all clinical information available. It is neither my intention to present entire clinical PDT activities in China in this article nor to report whole spectra of progress they have made nor to endorse any of those activities. But it is merely to present some examples of those works that are less well-
Z. Huang known to people outside China, and to demonstrate what have been done and what advances of these clinical researches might represent. In order to also provide an insight into some pioneering works, clinical PDT data of nasopharyngeal carcinoma (NPC), advanced primary liver cancer (PLC) and port-wine stains (PWS) will be discussed. The details of photosensitizers and light sources used in those clinical protocols can be found in the Part One of this article.
Nasopharyngeal carcinoma PDT In some areas of China the morbidity and the mortality of nasopharyngeal carcinoma are high. Radiotherapy is the most common treatment for cancer of the nasopharynx with approximately 50% 5-year survival. Radiotherapy is associated with a number of distressing or disabling side effects. Several Chinese groups started to explore the feasibility of PDT for the treatment of nasopharyngeal carcinoma in the early 1980s. In 1987, Zhao et al. [13] (The First Affiliated Hospital of Hunan Medical College, Changsha) reported treatment results of 12 patients (37—60 years old). Amongst them eight (seven of T1 N0 M0 and one of T1 N2 M0 ) were newly diagnosed and four had failed radiotherapy. Histopathologic examination confirmed that 11 were low-grade carcinoma and 1 high-grade carcinoma. Light outputs from three He—Ne laser units were integrated into a single optic fiber to generate combined fluence rates of 141—173 mW/cm2 . The first PDT session was performed at light dose levels of 251—314 J/cm2 48 and 72 h after the i.v. administration of HpD (5 mg/kg). The following sessions were performed 15 days later at half HpD dose (2.5 mg/kg). Patient received a total of two to seven repeated treatments. Complete remission (CR) was seen in four patients (33%) including two who had failed radiotherapy, and significant remission (SR) in eight patients (67%). No recurrence was reported during 4—16 months follow-up. Later, this group demonstrated that PDT could induce antitumor immune responses and NPC cell apoptosis in NPC patients [123,124]. Sun and Luo [16—18] (Tumor Hospital of Zhongshan Medical University, Guangzhou) reported treatment results of 191 cases in a series of publications in the 1990s. All patients had failed radiotherapy: 120 showed recurrent and 71 residual lesions after radiotherapy of maximal dose. Histopathologic examination confirmed that all were highgrade carcinoma at stage T1 N0 M0. Three sessions of PDT were delivered by Argon laser at 24, 48 and 72 h after the i.v. administration of YHpD
Summary of clinical studies in China
Disease Skin BCC, SCC, Bowen’s, Paget’s BCC, SCC BCC, chest wall recurrent BCC, SCC Bowen’s BCC, SCC BCC, SCC, Bowen’s, Paget’s BCC, SCC, Bowen’s, Paget’s Head and neck Oral and maxillofacial cancer and precancer Lip cancer Nasopharyngeal carcinoma Oral carcinoma Nasal cavity and paranasal sinus cancer Nasopharyngeal carcinoma Cancer and pre-cancer Tongue cancer
Number of patients
PS
Light source
Follow-up
References
50 (51 lesions)
BHpD
3 years
[1,2]
18 4 47 5 23 35 88
HpD YHpD, PSD-007 HpD ALA ALA YHpD ALA
He—Ne laser Argon pumped dye laser Non-coherent light Copper vapor laser Argon pumped dye laser He—Ne laser He—Ne laser He—Ne laser He—Ne laser
3 years 8 months 1—5 years 6 months 17 months 9 months 1—3 years
[3] [4] [5] [6] [7] [8] [9]
1—4 years
[10,11]
104
BHpD
12 10 14
HpD HpD HpD YHpD YHpD Photofrin
Argon laser, dye laser He—Ne laser Diode laser
5 years 3—8 years n/a
[16—18] [19] [20]
17
BHpD
Argon pumped dye laser
n/a
[21]
3—28 months
[22]
5—16 years 1—2 years 1—2 years
[23] [24,25] [26]
n/a 3—7 months n/a n/a n/a n/a 2—21 months
[27] [28] [29] [30] [31] [32] [33]
Brain Glioma, metastatic tumor, meningioma Glioma, metastatic tumor, meningioma Gliomas Gliomas Glioma
26
YHpD
10 34 28
HMME HMME Photofrin
Double frequency YAG laser dye pumped pulse laser (KTP laser) He—Ne laser He—Ne laser Diode laser
Lung Lung cancer Lung cancer Lung cancer Lung cancer Endobronchial lung carcinoma Endobronchial lung carcinoma Obstructive NSCLC
15 21 54 15 14 23 41
BHpD BHpD YHpD HpD Photosan Photosan Photofrin, HiPorfin
Argon pumped Argon pumped Argon pumped Argon pumped Diode laser Diode laser Diode laser
dye dye dye dye
laser laser laser laser
n/a
[12]
4—16 months 5—27 months 5 years
[13] [14] [15]
73
41 (44 lesions)
He—Ne laser, Argon pumped dye laser He—Ne laser, Argon pumped dye laser He—Ne laser Argon pumped dye laser He—Ne laser
191 44 14
BHpD
Photodynamic therapy in China
Table 1
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Table 1 (Continued ) Disease GI Early esophageal cancer
Number of patients 13
PS
Light source
Follow-up
References
HpD (USA)
Argon pumped dye laser
Up to 32 months n/a n/a n/a n/a n/a 4—9 months n/a n/a 1 year n/a n/a 6 months to 3 years n/a 6 months to 10 years n/a n/a 1—5 years 1—5 years n/a 6 months to 1 year 6 months to 1 year n/a 3 years n/a 1 year to 1 year six months 6 months to 16 months
[34]
10 months 9—12 months
[66] [67]
52 11 42 140 8 20 24 28 30 60 105 106
BHpD HpD BHpD, YHpD BHpD BHpD HMME HpD YHpD HpD BHpD PSD-007 HpD HpD
Argon pumped dye laser Argon pumped dye laser Argon pumped dye laser Argon pumped dye laser Gold vapor laser Copper vapor laser Copper vapor laser Copper vapor laser Argon pumped dye laser Copper vapor pumped dye laser Argon pumped dye laser He—Ne laser
Esophageal and cardiac cancers Recurrent GI cancers
30 103
HpD BHpD
Argon pumped dye laser Argon pumped dye laser
PSD-007 HpD PSD-007 BHpD BHpD PSD-007
Argon pumped dye laser Copper vapor laser Argon pumped dye laser Argon pumped dye laser Gold vapor laser Copper vapor pumped dye laser
HpD
Copper vapor pumped dye laser
Photofrin, Photosan ALA PSD-007 HpD
Diode laser Diode laser Copper pumped dye laser Copper vapor pumped dye laser
n/a
n/a
BHpD BHpD
Argon pumped dye laser Argon pumped dye laser
GI cancers Upper GI carcinoma Colon cancer Liver cancer Upper GI carcinoma Esophagocardiac cancer Obstructive Esophageal cancer Esophageal cancer Early esophageal cancer Upper GI carcinoma Upper GI carcinoma Esophageal cancer, colon cancer Bladder Bladder cancer Bladder cancer
35 1330 50 70 35 110 24 15 82 138 50 15
9 (19 lesions) 9 (20 lesions)
[35] [36] [37] [38—42] [43] [44] [45] [46] [47,48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65]
Z. Huang
Upper GI carcinoma Stomach cancer Carcinoma of gastric cardia Upper GI carcinoma, colon cancer GI cancers Obstructive upper GI carcinoma Colon cancer Esophageal cancer Liver cancer Upper GI carcinoma, colon cancer Upper GI carcinoma Upper GI carcinoma
21
Superficial bladder cancer Bladder cancer Bladder cancer
20 (50 lesions) Photofrin II 15 YHpD 65 BHpD, YHpD
Argon pumped dye laser Argon pumped dye laser Argon pumped dye laser
Superficial bladder cancer
37 (79 lesions) YHpD
Argon ion laser, dye laser
Superficial bladder cancer
40 (104 lesions)YHpD
Argon ion laser, dye laser
Bladder cancer Bladder cancer
13 68
YHpD BHpD
Bladder cancer
117
BHpD
Bladder cancer
15
HpD
Argon Argon laser Argon laser Argon
Bladder cancer
20
BHpD
CuBr pumped dye laser
Bladder cancer
70
YHpD
Gold vapor laser
Bladder cancer
30
PSD-007
CuBr pumped dye laser
Infiltrative bladder cancer
32
CPD4
Argon pumped dye laser
Bladder cancer—post surgery Bladder cancer
60 54
CPD4 CP HS 801
Argon pumped dye laser Diode laser
Lower genital tract Genitourinary carcinomas Epidermoid carcinoma Urethral condylomata acuminata Tumours (mixed types)
BHpD
Argon pumped dye laser
pumped dye laser pumped dye laser, Gold vapor pumped dye laser, Gold vapor pumped dye laser
17 (26 lesions) YHpD 28 PSD-007 164 ALA
Argon pump dye laser Copper vapor laser He—Ne laser
13 47 114 54 110 165 18
Argon pump dye laser Argon pump dye laser Argon pump dye laser Argon laser Copper vapor laser Argon pumped dye laser Copper vapor laser, Gold vapor laser
BHpD BHpD BHpD CPD4 YHpD YHpD, BHpD YHpD, PSD-007
Up to 25 months 3 months n/a 6 months to 4 years 6 months to 3 years 6 months to 3 years 26—38 months 6 months to 5 years 6 months to 8 years 6 months to 7 years 6 months to 2 years 6 months to 4 years 2 years 6 months 6 months to 6 years n/a n/a
[68]
9—23 months 4 years 6 months to 2 years n/a n/a Varied n/a n/a n/a >5 years
[85] [86] [87,88]
[69] [70,71] [72] [73] [74] [75] [76]
Photodynamic therapy in China
Bladder cancer
[77] [78] [79] [80] [81] [82] [83] [84]
[89] [90,91] [92] [93] [94] [95] [96]
75
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Table 1 (Continued ) Disease
Ocular PDT CNV in AMD CNV in myopia CNV in AMD CNV in AMD CNV in AMD CNV in AMD CNV in myopia PWS PDT
Number of patients
PS
Light source
Follow-up
References
31 6 53
PSD-007 Photofrin Photofrin
Gold vapor laser Diode laser Diode laser
2—3 years n/a n/a
[97] [98] [99]
5 (7 eyes) 2 (3 eyes) 30 (35 eyes) 20 (31 eyes) 16 (16 eyes) 20 (20 eyes) 30 (31 eyes)
Visudyne Visudyne Visudyne Visudyne Visudyne Visudyne Visudyne
Diode Diode Diode Diode Diode Diode Diode
n/a n/a n/a n/a n/a n/a 1—2 years
[100] [101] [102] [103] [104] [105] [106]
40 50 50 (57 lesions) 56 21 130 24 (28 lesions) 18
BHpD PSD-007 PSD-007 n/a HMME PSD-007 HpD PSD-007
Argon ion laser, dye laser KTP laser Copper vapor laser n/a Copper vapor laser Copper vapor laser Copper vapor laser Non-coherent red light
[107,108] [109] [110] [111] [112] [113] [114] [115,116]
HMME HMME PSD-007 BHpD, HMME
Copper vapor laser Copper vapor laser Krypton laser Argon ion laser, dye laser, copper vapor laser Copper vapor laser
n/a >1 year 2—12 months 3—12 months 3—6 months > 6 months 6 months 6 months to 3 years 1—12 months 2—12 months 2 months Up to 10 years n/a
[122]
128 (147 lesions) 80 20 1216 (1632 lesions) 238 (296 lesions)
HMME
laser laser laser laser laser laser laser
[117] [118] [119,120] [121]
Note: (1) some publications did not specify which photosensitizer and laser were used. In these cases, they are listed as not available (n/a). (2) Some publications only used the term of HpD or hemotoporphyrin derivative but did not specify its origin and manufacturer. In these cases, they are collectively listed as HpD. (3) Detailed information of listed photosensitizer (PS) and light source were provided in Part One of this article.
Z. Huang
Photodynamic therapy in China (3—5 mg/kg; YHpD = HpD produced by Yangzhou Biochemical Pharmaceutical Factory). Spherical or microlens tip optic fiber was used to irradiate nasal cavity and the total power at the fiber tip was set at 800 mW. Each side of the nasal cavity received 30 min light irradiation. Authors claimed that all patients showed therapeutic response. CR was seen in 105 patients (55.0%), SR in 66 patients (34.6%), and MR (minor remission) in 20 patients (10.5%). Various degrees of nasal congestion, nasal discharge, and headache were reported. However, these symptoms were mild and without a need of treatment. Five-year follow-up was carried out for 130 patients. Three-year and five-year survivals were reported as 44.6% and 25.4%, respectively. The authors concluded that PDT could improve long-term survival and is feasible for the localized primary and recurrent NPC. Since Photofrin and Diomed 630 laser were introduced into China in the early 2000s, they have been used in several newly established PDT Centres for treating various tumors including advanced nasopharyngeal carcinoma. Li et al. [99] (South Hospital, Guangzhou) summarized their short-term observation of 12 patients in 2003. The first treatment was delivered 48 h after the administration of Photofrin (2 mg/kg) through a cylindrical diffuser fiber at a dose level of 300 J/cm. Light irradiation covered entire lesion and at least 0.5 cm margin. Two days later, the second treatment was carried out after clearing up necrotic tissues. Since the light irradiation involved the pharyngolaryngeal region, two patients complained about severe throat pain and required medication. Some patients also had swallowing difficulties. Evaluation of therapeutic effects was conducted at 1 month after PDT. No CR was seen in this group of patients. SR was seen in 8 patients (66.7%), MR in 3 patients (25%) and NR (no remission) in 1 patient (8.3%). Symptoms, such as obstruction, were significantly improved. Impact on the quality of life was also assessed although the detail methodology was not specified. Karnofsky performance score was increased from 30 (pre-PDT) to 75 (post-PDT). These data represent different subset patients, PDT protocols and clinical outcomes. Nevertheless, the authors conclude that for patients with advanced nasopharyngeal carcinoma, who have exhausted all standard treatment options, their preliminary results suggest that PDT might offer the possibility of an improvement in quality of life.
Liver cancer PDT It was estimated that the primary liver cancer affected more than 500,000 people globally with
77 110,000 deaths annually in 2003. Unfortunately, more than one-half of them were Chinese [125]. In some areas of China the morbidity and the mortality are higher than that in other areas of China. PLC is still one of the most significant health problems in China even though more patients are diagnosed early and tend to undergo resection while receiving a better conservative treatment, which ensures a better prognosis. There is still a need to develop effective and less invasive procedures to treat localized PLC. The Cancer Research Centre of Xiamen University pioneered an interventional PDT procedure for treating advanced liver cancer in 1994. This Centre has a long-term interest and many years of experience in interstitial PDT [126,127]. They developed an ultrasound-guided percutaneous interstitial PDT technique and treated 70 patients. Short-term and long-term clinical observations were reported in 1996 and 2000, respectively [47,48,57]. Interstitial PDT was performed under local anesthesia 48 h after administering BHpD (i.v., 5 mg/kg; BHpD = HpD produced by Beijing Institute of Pharmaceutical Industry). First, positioning probes (18G) were inserted into the tumor through percutaneous punctures under ultrasound guidance. The authors indicated that the positioning probes and optic fibers were evenly placed inside the tumor but the actual number and their geometric distance were not specified in their papers. Light delivery fibers (400 m core diameter, 1-cm diffuser tip) were then placed into the tumor. An argon laser pumped dye laser (630 nm) was coupled into three diffuser fibers for simultaneously irradiation of three treatment spots. A light dose of 220 J/cm was delivered at fluence rates of 300—350 mW/cm for each spot. The 70 patients (12—67 years old, 64 males and 6 females) included 63 hepatocellular carcinomas, 2 cholangiocarcinoma, 1 hepatoblastoma, 1 tubular adenocarcinoma and 3 poorly differentiated adenocarcinoma. Fifty-six were newly diagnosed and other 14 patients had either failed chemotherapy or post-resection recurrence. Thirty-three patients had local or distant metastasis at the time of treatment. Tumor sizes ranged from 5 to >15 cm (5—10 cm, 26 cases; 11—15 cm, 35 cases; >15 cm, 9 cases). Thirty patients received onesession treatment and 40 multi-session treatments (two-session, 12 cases; three-session, 12 cases; ≥ four-session, 16 cases). The intervals between each session were 4—6 weeks. However, it is not clear whether the multi-session was designed for the previously untreated region of larger tumor or some regions received the repeated treatment.
78 Therapeutic effects were evaluated by ultrasound and CT scans, histopathologic examination of post-PDT biopsy, and laboratory analysis. Based on published data therapeutic responses were summarized as follows: at 7—15 days post-PDT Bmode sonography showed many hypoechoic spots or patches in treated areas. Honeycomb appearance was seen in treated areas in some patients. At one month the sonographic scan showed a slight signal enhancement in treated area and tumor boundary remained visible and size became smaller. CT scan confirmed tumor necrosis and the reduction of tumor mass. The histopathologic examination indicated a mix of necrosis, inflammation and fibrosis in the treated area. No damage was detected in the surrounding normal tissue. One patient underwent resection 1 month post-PDT. Histopathologic examination showed larger areas of tumor necrosis. Infiltration of numerous lymphocytes and macrophages was seen in the adjacent non-irradiated liver tissue [128]. Post-PDT AFP examination showed various degrees of decrease in AFP levels. In their 1996 paper, they reported short-term therapeutic effects of the first 30 patients (28 hepatocellular carcinomas, 2 adenocarcinomas) [47,48]. Amongst them 25 patients were evaluated and all of them showed partial response (48%) or stable (52%). Long-term follow up of 70 patients (up to 5 years) showed that multiple treatments might prolong survival [57]. Amongst them 1-year survival rate was 10% in one-session group (n = 30), 50% in two-session group (n = 12), 75% in three-session group (n = 12), and 92% in ≥four-session group (n = 16). It is arguable that whether (advanced) liver cancer is a suitable PDT indication. Nevertheless, the preliminary results of this single hospital study demonstrated that PDT was effective and safe for the treatment of inoperable large primary and recurrent liver cancers. Multiple treatments could improve survival. They concluded that interstitial PDT might become an effective modality for the palliative treatment of liver cancer and to improve the quality of life for an extended period. However, further investigation is needed in order to determine if PDT is a useful modality.
Port-wine stains PDT Port-wine stains PDT study outside China is still limited and the clinical outcomes are controversial [129]. A combination modality of photothermal and photodynamic therapy has recently been proposed [130]. However, Chinese have been pursuing PWS PDT for over a decade. In the early 1990s, inspired by the emerging facts of anti-vascular nature of antitumor PDT [131], the Chinese started
Z. Huang to explore the feasibility of utilizing vascular targeting PDT to eliminate abnormal blood vessels of port-wine stains (PWS, capillary vascular malformations). Firstly, they used an ex vivo human vein model of the umbilical cord to demonstrate the strong absorption of HpD by vascular endothelium cells. Then, they established an in vivo animal model using chicken comb to demonstrate that HpD-PDT could selectively destroy micro-vessels in the dermis and spare surrounding normal epidermal tissues [132]. These clinicians may not have been aware, but PWS PDT had been proposed as early as 1985 and similar studies had already been done outside China [133,134]. Anyway, encouraged by these promising pre-clinical discoveries, the first Chinese clinical study was quickly launched in Chinese People’s Liberation Army (PLA) General Hospital (known as Beijing 301 Hospital) in early 1991. A total of 20 lesions in 19 subjects (3—45 years old) were treated. They described PWS as a pink, purple, thicker or nodular lesion. In their pilot study, there were 11 thicker or nodular lesions, although the location and size were not specified, and 4 were already subjected to other therapies. In this experimental study, BHpD was given at dosages of 0.8—5 mg/kg and the area of light irradiation was 1—50 cm2 . Light fluences of 50—550 J/cm2 were delivered by argon ion laser (514.5 nm) or dye laser (630 nm). Although not being specified, the choice of light source was possibly based on the depth of lesion. Drug—light intervals and length of followup were not reported. Therapeutic responses were examined visually and recorded in five grades: (I) excellent (complete blanching, become normal skin), (II) good (marked blanching, thicker lesion become flat), (III) fair (significant blanching, thicker lesion become flat moderately), (IV) poor (slight blanching, thicker lesion become flat slightly) and (V) no change (no change). Nevertheless, except for one failed case and three needing second treatment, good-to-excellent responses were observed [107]. This study was then expanded to another 20 or so subjects and promising clinical outcomes convinced Chinese physicians that PDT was a safe and highly selective modality for effectively bleaching PWS [108]. A year later, the same hospital tested another domestic photosensitizer, namely PSD-007 (a code name for Photocarcinorin—–a mixture of 7 different porphyrins), and a KTP laser (532 nm) in 50 lesions (6 pink, 35 purple and 9 thicker) of 50 subjects (1—50 years old). The majority of lesions (44/50) were located on the face. In this study the photosensitizer was given at a fixed dose level of 5 mg/kg and light administered in a dose escalating fashion ranging from 90 to 540 J/cm2 at the light fluence
Photodynamic therapy in China rate of 50—100 mW/cm2 . The area of light irradiation ranged from 3 to 85 cm2 . Although the effectiveness did not correspond well with the delivered light dose, fair-to-excellent responses were seen in 94% (47/50) of the lesions after a single treatment and these improvements remained unchanged at 1-year follow up. No scarring or skin damage was observed and temporary skin pigmentation induced by the treatment caused little cosmetic concern [109]. Interestingly, in the following year, they treated another 57 lesions in 50 subjects (2—47 years old) using the same photosensitizer (4—5 mg/kg) and a copper vapor laser (510.6 and 578.2 nm), hoping that the copper vapor laser would improve the efficacy of PWS PDT [110]. Light was delivered at dose levels of 160—360 J/cm2 at the light fluence rate of 70—100 mW/cm2 . The lesions (4 pink, 48 purple and 5 thickening or nodules) were mainly located on the face (52/57). The area of light irradiation ranged from 3 to 64 cm2 . All lesions showed responses to a single treatment. Fair-to-excellent responses were seen in 98% (56/57) of the lesions. Again, it is not clear whether light doses were assigned to lesions in a random fashion or based on the nature of the lesion. Therefore, it is impossible to correlate the results with the light dose retrospectively. Drug—light intervals were not specifically reported in the articles but one could speculate that light might be applied immediately after the completion of drug infusion. Nevertheless, in both studies more than half of the lesions had already undergone radioisotope, laser or cryosurgery therapies prior to PDT. In addition to original PWS lesion scarring, abnormal pigmentation induced by previous treatment often co-existed. But the authors claimed that their effect on PDT efficacy was minimal. Based on these studies, pink and purple lesions showed 100% and 57—75% good-to-excellent responses, respectively. Thicker and nodular lesions also showed significant and non-reversible response, which indicates the destruction of the abnormal micro-vessels. In an effort to further prove PDT-mediated vascular acting effect, another study was launched in the same hospital to measure skin blood perfusion in normal and PWS areas in 56 subjects before and after PDT [111]. There was no mention in this article on what photosensitizer and laser were used for this study. Using a laser Doppler flowmeter, blood perfusion rate was measured at the same area (2 cm2 ) before and after PDT. A reduction of blood flow in PWS area was noticeable at 30 min after PDT and blood flow continued to decrease at 6 and 24 h after PDT. Long-term follow-up (3—12 months) showed marked reduction in the blood perfusion in the treated area although values were
79 still higher than the contralateral normal control. In this article authors only presented perfusion data (e.g., mean, maximal and minimal values) in four separate groups based on the clinical outcome—– excellent (11), good (25), fair (13) and poor (7). Difference in blood perfusion rate was statistically significant in PWS areas before and after PDT in all groups. But there was no statistically significant difference between treated and untreated normal areas in excellent and good response groups. There were statistically significant differences between treated and untreated normal areas in fair and poor response groups. These results further demonstrate that the mechanism of PWS PDT is mediated through the impact on the microcirculation. Later they conducted a similar study on 28 lesions of 24 subjects [114] using HpD instead. Their results showed that a marked decrease in blood perfusion was seen after PDT in all lesions and the difference between before and after PDT was statistically significant even at six months after PDT. Lin et al. [113] (the Ninth People’s Hospital of Shanghai) reported their similar study in the Journal of Plastic and Reconstructive Surgery in 1997. Using PSD-007 (4—7 mg/kg) and a copper vapor laser (578 nm, 40—90 mW/cm2 ), they treated a total of 130 subjects (3—65 years old). Five children less than 6 years old required general anesthesia. They classified PWS lesions into three groups: ordinary (flat, pink to purple), dilated (thicker, nodular) and post-treatment (scar, abnormal pigmentation). They retrospectively followed 118 subjects (82 ordinary, 18 dilated and 18 post-treatment) for a minimum of 6 months. Overall 98% lesions (116/118) showed fair-to-excellent responses. Poor response was seen in post-treatment group involving hypertropic scars. However, other hospitals reported that in their trial of 80 subjects (2½—65 years old) all subjects experienced a varying degree of PDTrelated pain and younger subjects (
REVIEW
Photodynamic therapy in China: Over 25 years of unique clinical experience Part two—–Clinical experience Zheng Huang MD, PhD ∗ Radiation Oncology Department, Colorado University Health Sciences Center, 1600 Pierce Street, Denver, CO 80214, USA Available online 18 April 2006 KEYWORDS Photodynamic therapy; PDT; China; Nasopharyngeal carcinoma; Liver cancer; Port-wine stains
Summary Photodynamic therapy (PDT) was started in the People’s Republic of China in the early 1980s after domestically produced hematoporphyrin derivative (HpD) became available. Since then, numerous photosensitizers have been synthesized and evaluated. Several promising ones have undergone clinical investigations and a few have entered into formal clinical trials. Various lasers and non-coherent light sources have been developed in China to facilitate domestic photosensitizers and clinical PDT applications. Chinese pioneered PDT protocols for treating nasopharyngeal carcinoma (NPC), liver carcinoma, port-wine stains (PWS) and urethral condylomata acuminata. Over the past 25 years Chinese physicians have treated several thousands patients, gained substantial experience in both basic sciences and clinical applications, and generated a great number of clinical reports. The Part One of this article provides an objective overview on China’s PDT history and an introduction of domestic photosensitizers. This article (Part Two) will summarize clinical PDT data of nasopharyngeal carcinoma, liver cancer and port-wine stains since these data are clinically valuable but less well known outside China. © 2006 Elsevier B.V. All rights reserved.
Contents Introduction.................................................................................................. Nasopharyngeal carcinoma PDT .............................................................................. Liver cancer PDT ............................................................................................. Port-wine stains PDT ......................................................................................... Future prospects ............................................................................................. Acknowledgments ............................................................................................ References ................................................................................................... ∗
Tel.: +1 303 2393567; fax: +1 303 2393562. E-mail address: zheng [email protected].
1572-1000/$ — see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.pdpdt.2006.03.001
72 72 77 78 80 81 81
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Introduction Photodynamic therapy (PDT) was first introduced into Chinese hospitals as a novel antitumor therapy in the early 1980s. PDT has been practiced in China for over 25 years. The Part One of this article has provided an objective and general overview on China’s PDT history and domestic photosensitizers. It might be overstated to say that PDT has experienced a roller coaster ride in China. But PDT practice has indeed experienced ups and downs in past years. Overall, PDT is still a viable experimental ground if not a mainstream practice yet (see Part One). During the early years the government sponsored multi-discipline and multi-centre initiative was the main driven force, which conceived the birth of several HpD photosensitizers. Domestically produced hematoporphyrin- or chlorophyll-derived photosensitizers and lasers have been used, almost exclusively, in clinical PDT in China until the early 2000s. Over the past 25 years Chinese clinicians have treated several thousands patients and published a great number of clinical reports—–some were very brief and some in detail. By reviewing those reports, one can find that the majority of clinical reports can be classified as case report or single hospital experience that generally focused on assessing feasibility and/or efficacy. In term of the study design those reports can be described as pilot study, comparison study or non-randomized Phase I/II/III trials. The 1984 national criterion for the evaluation of short-term antitumor PDT efficacy was used in majority reports (see details in Table 1 in Part One). This article (Part Two) attempts to provide an objective and balanced view of Chinese clinical PDT based on those publications. A comprehensive reference list has been compiled based on a literature survey of both Chinese and English scientific journals although it is nearly impossible to include every single PDT clinical report. A summary of clinical studies is organized according to their clinical specialties in Table 1. Selected references published in English or Chinese are organized by their clinical specialties in a chronological fashion [1—122]. There are a large number of clinical experimental data involving various photosensitizers (PS), light sources and diseases. The profound differences in PDT protocols and patient profiles prevent detailed discussion of all clinical information available. It is neither my intention to present entire clinical PDT activities in China in this article nor to report whole spectra of progress they have made nor to endorse any of those activities. But it is merely to present some examples of those works that are less well-
Z. Huang known to people outside China, and to demonstrate what have been done and what advances of these clinical researches might represent. In order to also provide an insight into some pioneering works, clinical PDT data of nasopharyngeal carcinoma (NPC), advanced primary liver cancer (PLC) and port-wine stains (PWS) will be discussed. The details of photosensitizers and light sources used in those clinical protocols can be found in the Part One of this article.
Nasopharyngeal carcinoma PDT In some areas of China the morbidity and the mortality of nasopharyngeal carcinoma are high. Radiotherapy is the most common treatment for cancer of the nasopharynx with approximately 50% 5-year survival. Radiotherapy is associated with a number of distressing or disabling side effects. Several Chinese groups started to explore the feasibility of PDT for the treatment of nasopharyngeal carcinoma in the early 1980s. In 1987, Zhao et al. [13] (The First Affiliated Hospital of Hunan Medical College, Changsha) reported treatment results of 12 patients (37—60 years old). Amongst them eight (seven of T1 N0 M0 and one of T1 N2 M0 ) were newly diagnosed and four had failed radiotherapy. Histopathologic examination confirmed that 11 were low-grade carcinoma and 1 high-grade carcinoma. Light outputs from three He—Ne laser units were integrated into a single optic fiber to generate combined fluence rates of 141—173 mW/cm2 . The first PDT session was performed at light dose levels of 251—314 J/cm2 48 and 72 h after the i.v. administration of HpD (5 mg/kg). The following sessions were performed 15 days later at half HpD dose (2.5 mg/kg). Patient received a total of two to seven repeated treatments. Complete remission (CR) was seen in four patients (33%) including two who had failed radiotherapy, and significant remission (SR) in eight patients (67%). No recurrence was reported during 4—16 months follow-up. Later, this group demonstrated that PDT could induce antitumor immune responses and NPC cell apoptosis in NPC patients [123,124]. Sun and Luo [16—18] (Tumor Hospital of Zhongshan Medical University, Guangzhou) reported treatment results of 191 cases in a series of publications in the 1990s. All patients had failed radiotherapy: 120 showed recurrent and 71 residual lesions after radiotherapy of maximal dose. Histopathologic examination confirmed that all were highgrade carcinoma at stage T1 N0 M0. Three sessions of PDT were delivered by Argon laser at 24, 48 and 72 h after the i.v. administration of YHpD
Summary of clinical studies in China
Disease Skin BCC, SCC, Bowen’s, Paget’s BCC, SCC BCC, chest wall recurrent BCC, SCC Bowen’s BCC, SCC BCC, SCC, Bowen’s, Paget’s BCC, SCC, Bowen’s, Paget’s Head and neck Oral and maxillofacial cancer and precancer Lip cancer Nasopharyngeal carcinoma Oral carcinoma Nasal cavity and paranasal sinus cancer Nasopharyngeal carcinoma Cancer and pre-cancer Tongue cancer
Number of patients
PS
Light source
Follow-up
References
50 (51 lesions)
BHpD
3 years
[1,2]
18 4 47 5 23 35 88
HpD YHpD, PSD-007 HpD ALA ALA YHpD ALA
He—Ne laser Argon pumped dye laser Non-coherent light Copper vapor laser Argon pumped dye laser He—Ne laser He—Ne laser He—Ne laser He—Ne laser
3 years 8 months 1—5 years 6 months 17 months 9 months 1—3 years
[3] [4] [5] [6] [7] [8] [9]
1—4 years
[10,11]
104
BHpD
12 10 14
HpD HpD HpD YHpD YHpD Photofrin
Argon laser, dye laser He—Ne laser Diode laser
5 years 3—8 years n/a
[16—18] [19] [20]
17
BHpD
Argon pumped dye laser
n/a
[21]
3—28 months
[22]
5—16 years 1—2 years 1—2 years
[23] [24,25] [26]
n/a 3—7 months n/a n/a n/a n/a 2—21 months
[27] [28] [29] [30] [31] [32] [33]
Brain Glioma, metastatic tumor, meningioma Glioma, metastatic tumor, meningioma Gliomas Gliomas Glioma
26
YHpD
10 34 28
HMME HMME Photofrin
Double frequency YAG laser dye pumped pulse laser (KTP laser) He—Ne laser He—Ne laser Diode laser
Lung Lung cancer Lung cancer Lung cancer Lung cancer Endobronchial lung carcinoma Endobronchial lung carcinoma Obstructive NSCLC
15 21 54 15 14 23 41
BHpD BHpD YHpD HpD Photosan Photosan Photofrin, HiPorfin
Argon pumped Argon pumped Argon pumped Argon pumped Diode laser Diode laser Diode laser
dye dye dye dye
laser laser laser laser
n/a
[12]
4—16 months 5—27 months 5 years
[13] [14] [15]
73
41 (44 lesions)
He—Ne laser, Argon pumped dye laser He—Ne laser, Argon pumped dye laser He—Ne laser Argon pumped dye laser He—Ne laser
191 44 14
BHpD
Photodynamic therapy in China
Table 1
74
Table 1 (Continued ) Disease GI Early esophageal cancer
Number of patients 13
PS
Light source
Follow-up
References
HpD (USA)
Argon pumped dye laser
Up to 32 months n/a n/a n/a n/a n/a 4—9 months n/a n/a 1 year n/a n/a 6 months to 3 years n/a 6 months to 10 years n/a n/a 1—5 years 1—5 years n/a 6 months to 1 year 6 months to 1 year n/a 3 years n/a 1 year to 1 year six months 6 months to 16 months
[34]
10 months 9—12 months
[66] [67]
52 11 42 140 8 20 24 28 30 60 105 106
BHpD HpD BHpD, YHpD BHpD BHpD HMME HpD YHpD HpD BHpD PSD-007 HpD HpD
Argon pumped dye laser Argon pumped dye laser Argon pumped dye laser Argon pumped dye laser Gold vapor laser Copper vapor laser Copper vapor laser Copper vapor laser Argon pumped dye laser Copper vapor pumped dye laser Argon pumped dye laser He—Ne laser
Esophageal and cardiac cancers Recurrent GI cancers
30 103
HpD BHpD
Argon pumped dye laser Argon pumped dye laser
PSD-007 HpD PSD-007 BHpD BHpD PSD-007
Argon pumped dye laser Copper vapor laser Argon pumped dye laser Argon pumped dye laser Gold vapor laser Copper vapor pumped dye laser
HpD
Copper vapor pumped dye laser
Photofrin, Photosan ALA PSD-007 HpD
Diode laser Diode laser Copper pumped dye laser Copper vapor pumped dye laser
n/a
n/a
BHpD BHpD
Argon pumped dye laser Argon pumped dye laser
GI cancers Upper GI carcinoma Colon cancer Liver cancer Upper GI carcinoma Esophagocardiac cancer Obstructive Esophageal cancer Esophageal cancer Early esophageal cancer Upper GI carcinoma Upper GI carcinoma Esophageal cancer, colon cancer Bladder Bladder cancer Bladder cancer
35 1330 50 70 35 110 24 15 82 138 50 15
9 (19 lesions) 9 (20 lesions)
[35] [36] [37] [38—42] [43] [44] [45] [46] [47,48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65]
Z. Huang
Upper GI carcinoma Stomach cancer Carcinoma of gastric cardia Upper GI carcinoma, colon cancer GI cancers Obstructive upper GI carcinoma Colon cancer Esophageal cancer Liver cancer Upper GI carcinoma, colon cancer Upper GI carcinoma Upper GI carcinoma
21
Superficial bladder cancer Bladder cancer Bladder cancer
20 (50 lesions) Photofrin II 15 YHpD 65 BHpD, YHpD
Argon pumped dye laser Argon pumped dye laser Argon pumped dye laser
Superficial bladder cancer
37 (79 lesions) YHpD
Argon ion laser, dye laser
Superficial bladder cancer
40 (104 lesions)YHpD
Argon ion laser, dye laser
Bladder cancer Bladder cancer
13 68
YHpD BHpD
Bladder cancer
117
BHpD
Bladder cancer
15
HpD
Argon Argon laser Argon laser Argon
Bladder cancer
20
BHpD
CuBr pumped dye laser
Bladder cancer
70
YHpD
Gold vapor laser
Bladder cancer
30
PSD-007
CuBr pumped dye laser
Infiltrative bladder cancer
32
CPD4
Argon pumped dye laser
Bladder cancer—post surgery Bladder cancer
60 54
CPD4 CP HS 801
Argon pumped dye laser Diode laser
Lower genital tract Genitourinary carcinomas Epidermoid carcinoma Urethral condylomata acuminata Tumours (mixed types)
BHpD
Argon pumped dye laser
pumped dye laser pumped dye laser, Gold vapor pumped dye laser, Gold vapor pumped dye laser
17 (26 lesions) YHpD 28 PSD-007 164 ALA
Argon pump dye laser Copper vapor laser He—Ne laser
13 47 114 54 110 165 18
Argon pump dye laser Argon pump dye laser Argon pump dye laser Argon laser Copper vapor laser Argon pumped dye laser Copper vapor laser, Gold vapor laser
BHpD BHpD BHpD CPD4 YHpD YHpD, BHpD YHpD, PSD-007
Up to 25 months 3 months n/a 6 months to 4 years 6 months to 3 years 6 months to 3 years 26—38 months 6 months to 5 years 6 months to 8 years 6 months to 7 years 6 months to 2 years 6 months to 4 years 2 years 6 months 6 months to 6 years n/a n/a
[68]
9—23 months 4 years 6 months to 2 years n/a n/a Varied n/a n/a n/a >5 years
[85] [86] [87,88]
[69] [70,71] [72] [73] [74] [75] [76]
Photodynamic therapy in China
Bladder cancer
[77] [78] [79] [80] [81] [82] [83] [84]
[89] [90,91] [92] [93] [94] [95] [96]
75
76
Table 1 (Continued ) Disease
Ocular PDT CNV in AMD CNV in myopia CNV in AMD CNV in AMD CNV in AMD CNV in AMD CNV in myopia PWS PDT
Number of patients
PS
Light source
Follow-up
References
31 6 53
PSD-007 Photofrin Photofrin
Gold vapor laser Diode laser Diode laser
2—3 years n/a n/a
[97] [98] [99]
5 (7 eyes) 2 (3 eyes) 30 (35 eyes) 20 (31 eyes) 16 (16 eyes) 20 (20 eyes) 30 (31 eyes)
Visudyne Visudyne Visudyne Visudyne Visudyne Visudyne Visudyne
Diode Diode Diode Diode Diode Diode Diode
n/a n/a n/a n/a n/a n/a 1—2 years
[100] [101] [102] [103] [104] [105] [106]
40 50 50 (57 lesions) 56 21 130 24 (28 lesions) 18
BHpD PSD-007 PSD-007 n/a HMME PSD-007 HpD PSD-007
Argon ion laser, dye laser KTP laser Copper vapor laser n/a Copper vapor laser Copper vapor laser Copper vapor laser Non-coherent red light
[107,108] [109] [110] [111] [112] [113] [114] [115,116]
HMME HMME PSD-007 BHpD, HMME
Copper vapor laser Copper vapor laser Krypton laser Argon ion laser, dye laser, copper vapor laser Copper vapor laser
n/a >1 year 2—12 months 3—12 months 3—6 months > 6 months 6 months 6 months to 3 years 1—12 months 2—12 months 2 months Up to 10 years n/a
[122]
128 (147 lesions) 80 20 1216 (1632 lesions) 238 (296 lesions)
HMME
laser laser laser laser laser laser laser
[117] [118] [119,120] [121]
Note: (1) some publications did not specify which photosensitizer and laser were used. In these cases, they are listed as not available (n/a). (2) Some publications only used the term of HpD or hemotoporphyrin derivative but did not specify its origin and manufacturer. In these cases, they are collectively listed as HpD. (3) Detailed information of listed photosensitizer (PS) and light source were provided in Part One of this article.
Z. Huang
Photodynamic therapy in China (3—5 mg/kg; YHpD = HpD produced by Yangzhou Biochemical Pharmaceutical Factory). Spherical or microlens tip optic fiber was used to irradiate nasal cavity and the total power at the fiber tip was set at 800 mW. Each side of the nasal cavity received 30 min light irradiation. Authors claimed that all patients showed therapeutic response. CR was seen in 105 patients (55.0%), SR in 66 patients (34.6%), and MR (minor remission) in 20 patients (10.5%). Various degrees of nasal congestion, nasal discharge, and headache were reported. However, these symptoms were mild and without a need of treatment. Five-year follow-up was carried out for 130 patients. Three-year and five-year survivals were reported as 44.6% and 25.4%, respectively. The authors concluded that PDT could improve long-term survival and is feasible for the localized primary and recurrent NPC. Since Photofrin and Diomed 630 laser were introduced into China in the early 2000s, they have been used in several newly established PDT Centres for treating various tumors including advanced nasopharyngeal carcinoma. Li et al. [99] (South Hospital, Guangzhou) summarized their short-term observation of 12 patients in 2003. The first treatment was delivered 48 h after the administration of Photofrin (2 mg/kg) through a cylindrical diffuser fiber at a dose level of 300 J/cm. Light irradiation covered entire lesion and at least 0.5 cm margin. Two days later, the second treatment was carried out after clearing up necrotic tissues. Since the light irradiation involved the pharyngolaryngeal region, two patients complained about severe throat pain and required medication. Some patients also had swallowing difficulties. Evaluation of therapeutic effects was conducted at 1 month after PDT. No CR was seen in this group of patients. SR was seen in 8 patients (66.7%), MR in 3 patients (25%) and NR (no remission) in 1 patient (8.3%). Symptoms, such as obstruction, were significantly improved. Impact on the quality of life was also assessed although the detail methodology was not specified. Karnofsky performance score was increased from 30 (pre-PDT) to 75 (post-PDT). These data represent different subset patients, PDT protocols and clinical outcomes. Nevertheless, the authors conclude that for patients with advanced nasopharyngeal carcinoma, who have exhausted all standard treatment options, their preliminary results suggest that PDT might offer the possibility of an improvement in quality of life.
Liver cancer PDT It was estimated that the primary liver cancer affected more than 500,000 people globally with
77 110,000 deaths annually in 2003. Unfortunately, more than one-half of them were Chinese [125]. In some areas of China the morbidity and the mortality are higher than that in other areas of China. PLC is still one of the most significant health problems in China even though more patients are diagnosed early and tend to undergo resection while receiving a better conservative treatment, which ensures a better prognosis. There is still a need to develop effective and less invasive procedures to treat localized PLC. The Cancer Research Centre of Xiamen University pioneered an interventional PDT procedure for treating advanced liver cancer in 1994. This Centre has a long-term interest and many years of experience in interstitial PDT [126,127]. They developed an ultrasound-guided percutaneous interstitial PDT technique and treated 70 patients. Short-term and long-term clinical observations were reported in 1996 and 2000, respectively [47,48,57]. Interstitial PDT was performed under local anesthesia 48 h after administering BHpD (i.v., 5 mg/kg; BHpD = HpD produced by Beijing Institute of Pharmaceutical Industry). First, positioning probes (18G) were inserted into the tumor through percutaneous punctures under ultrasound guidance. The authors indicated that the positioning probes and optic fibers were evenly placed inside the tumor but the actual number and their geometric distance were not specified in their papers. Light delivery fibers (400 m core diameter, 1-cm diffuser tip) were then placed into the tumor. An argon laser pumped dye laser (630 nm) was coupled into three diffuser fibers for simultaneously irradiation of three treatment spots. A light dose of 220 J/cm was delivered at fluence rates of 300—350 mW/cm for each spot. The 70 patients (12—67 years old, 64 males and 6 females) included 63 hepatocellular carcinomas, 2 cholangiocarcinoma, 1 hepatoblastoma, 1 tubular adenocarcinoma and 3 poorly differentiated adenocarcinoma. Fifty-six were newly diagnosed and other 14 patients had either failed chemotherapy or post-resection recurrence. Thirty-three patients had local or distant metastasis at the time of treatment. Tumor sizes ranged from 5 to >15 cm (5—10 cm, 26 cases; 11—15 cm, 35 cases; >15 cm, 9 cases). Thirty patients received onesession treatment and 40 multi-session treatments (two-session, 12 cases; three-session, 12 cases; ≥ four-session, 16 cases). The intervals between each session were 4—6 weeks. However, it is not clear whether the multi-session was designed for the previously untreated region of larger tumor or some regions received the repeated treatment.
78 Therapeutic effects were evaluated by ultrasound and CT scans, histopathologic examination of post-PDT biopsy, and laboratory analysis. Based on published data therapeutic responses were summarized as follows: at 7—15 days post-PDT Bmode sonography showed many hypoechoic spots or patches in treated areas. Honeycomb appearance was seen in treated areas in some patients. At one month the sonographic scan showed a slight signal enhancement in treated area and tumor boundary remained visible and size became smaller. CT scan confirmed tumor necrosis and the reduction of tumor mass. The histopathologic examination indicated a mix of necrosis, inflammation and fibrosis in the treated area. No damage was detected in the surrounding normal tissue. One patient underwent resection 1 month post-PDT. Histopathologic examination showed larger areas of tumor necrosis. Infiltration of numerous lymphocytes and macrophages was seen in the adjacent non-irradiated liver tissue [128]. Post-PDT AFP examination showed various degrees of decrease in AFP levels. In their 1996 paper, they reported short-term therapeutic effects of the first 30 patients (28 hepatocellular carcinomas, 2 adenocarcinomas) [47,48]. Amongst them 25 patients were evaluated and all of them showed partial response (48%) or stable (52%). Long-term follow up of 70 patients (up to 5 years) showed that multiple treatments might prolong survival [57]. Amongst them 1-year survival rate was 10% in one-session group (n = 30), 50% in two-session group (n = 12), 75% in three-session group (n = 12), and 92% in ≥four-session group (n = 16). It is arguable that whether (advanced) liver cancer is a suitable PDT indication. Nevertheless, the preliminary results of this single hospital study demonstrated that PDT was effective and safe for the treatment of inoperable large primary and recurrent liver cancers. Multiple treatments could improve survival. They concluded that interstitial PDT might become an effective modality for the palliative treatment of liver cancer and to improve the quality of life for an extended period. However, further investigation is needed in order to determine if PDT is a useful modality.
Port-wine stains PDT Port-wine stains PDT study outside China is still limited and the clinical outcomes are controversial [129]. A combination modality of photothermal and photodynamic therapy has recently been proposed [130]. However, Chinese have been pursuing PWS PDT for over a decade. In the early 1990s, inspired by the emerging facts of anti-vascular nature of antitumor PDT [131], the Chinese started
Z. Huang to explore the feasibility of utilizing vascular targeting PDT to eliminate abnormal blood vessels of port-wine stains (PWS, capillary vascular malformations). Firstly, they used an ex vivo human vein model of the umbilical cord to demonstrate the strong absorption of HpD by vascular endothelium cells. Then, they established an in vivo animal model using chicken comb to demonstrate that HpD-PDT could selectively destroy micro-vessels in the dermis and spare surrounding normal epidermal tissues [132]. These clinicians may not have been aware, but PWS PDT had been proposed as early as 1985 and similar studies had already been done outside China [133,134]. Anyway, encouraged by these promising pre-clinical discoveries, the first Chinese clinical study was quickly launched in Chinese People’s Liberation Army (PLA) General Hospital (known as Beijing 301 Hospital) in early 1991. A total of 20 lesions in 19 subjects (3—45 years old) were treated. They described PWS as a pink, purple, thicker or nodular lesion. In their pilot study, there were 11 thicker or nodular lesions, although the location and size were not specified, and 4 were already subjected to other therapies. In this experimental study, BHpD was given at dosages of 0.8—5 mg/kg and the area of light irradiation was 1—50 cm2 . Light fluences of 50—550 J/cm2 were delivered by argon ion laser (514.5 nm) or dye laser (630 nm). Although not being specified, the choice of light source was possibly based on the depth of lesion. Drug—light intervals and length of followup were not reported. Therapeutic responses were examined visually and recorded in five grades: (I) excellent (complete blanching, become normal skin), (II) good (marked blanching, thicker lesion become flat), (III) fair (significant blanching, thicker lesion become flat moderately), (IV) poor (slight blanching, thicker lesion become flat slightly) and (V) no change (no change). Nevertheless, except for one failed case and three needing second treatment, good-to-excellent responses were observed [107]. This study was then expanded to another 20 or so subjects and promising clinical outcomes convinced Chinese physicians that PDT was a safe and highly selective modality for effectively bleaching PWS [108]. A year later, the same hospital tested another domestic photosensitizer, namely PSD-007 (a code name for Photocarcinorin—–a mixture of 7 different porphyrins), and a KTP laser (532 nm) in 50 lesions (6 pink, 35 purple and 9 thicker) of 50 subjects (1—50 years old). The majority of lesions (44/50) were located on the face. In this study the photosensitizer was given at a fixed dose level of 5 mg/kg and light administered in a dose escalating fashion ranging from 90 to 540 J/cm2 at the light fluence
Photodynamic therapy in China rate of 50—100 mW/cm2 . The area of light irradiation ranged from 3 to 85 cm2 . Although the effectiveness did not correspond well with the delivered light dose, fair-to-excellent responses were seen in 94% (47/50) of the lesions after a single treatment and these improvements remained unchanged at 1-year follow up. No scarring or skin damage was observed and temporary skin pigmentation induced by the treatment caused little cosmetic concern [109]. Interestingly, in the following year, they treated another 57 lesions in 50 subjects (2—47 years old) using the same photosensitizer (4—5 mg/kg) and a copper vapor laser (510.6 and 578.2 nm), hoping that the copper vapor laser would improve the efficacy of PWS PDT [110]. Light was delivered at dose levels of 160—360 J/cm2 at the light fluence rate of 70—100 mW/cm2 . The lesions (4 pink, 48 purple and 5 thickening or nodules) were mainly located on the face (52/57). The area of light irradiation ranged from 3 to 64 cm2 . All lesions showed responses to a single treatment. Fair-to-excellent responses were seen in 98% (56/57) of the lesions. Again, it is not clear whether light doses were assigned to lesions in a random fashion or based on the nature of the lesion. Therefore, it is impossible to correlate the results with the light dose retrospectively. Drug—light intervals were not specifically reported in the articles but one could speculate that light might be applied immediately after the completion of drug infusion. Nevertheless, in both studies more than half of the lesions had already undergone radioisotope, laser or cryosurgery therapies prior to PDT. In addition to original PWS lesion scarring, abnormal pigmentation induced by previous treatment often co-existed. But the authors claimed that their effect on PDT efficacy was minimal. Based on these studies, pink and purple lesions showed 100% and 57—75% good-to-excellent responses, respectively. Thicker and nodular lesions also showed significant and non-reversible response, which indicates the destruction of the abnormal micro-vessels. In an effort to further prove PDT-mediated vascular acting effect, another study was launched in the same hospital to measure skin blood perfusion in normal and PWS areas in 56 subjects before and after PDT [111]. There was no mention in this article on what photosensitizer and laser were used for this study. Using a laser Doppler flowmeter, blood perfusion rate was measured at the same area (2 cm2 ) before and after PDT. A reduction of blood flow in PWS area was noticeable at 30 min after PDT and blood flow continued to decrease at 6 and 24 h after PDT. Long-term follow-up (3—12 months) showed marked reduction in the blood perfusion in the treated area although values were
79 still higher than the contralateral normal control. In this article authors only presented perfusion data (e.g., mean, maximal and minimal values) in four separate groups based on the clinical outcome—– excellent (11), good (25), fair (13) and poor (7). Difference in blood perfusion rate was statistically significant in PWS areas before and after PDT in all groups. But there was no statistically significant difference between treated and untreated normal areas in excellent and good response groups. There were statistically significant differences between treated and untreated normal areas in fair and poor response groups. These results further demonstrate that the mechanism of PWS PDT is mediated through the impact on the microcirculation. Later they conducted a similar study on 28 lesions of 24 subjects [114] using HpD instead. Their results showed that a marked decrease in blood perfusion was seen after PDT in all lesions and the difference between before and after PDT was statistically significant even at six months after PDT. Lin et al. [113] (the Ninth People’s Hospital of Shanghai) reported their similar study in the Journal of Plastic and Reconstructive Surgery in 1997. Using PSD-007 (4—7 mg/kg) and a copper vapor laser (578 nm, 40—90 mW/cm2 ), they treated a total of 130 subjects (3—65 years old). Five children less than 6 years old required general anesthesia. They classified PWS lesions into three groups: ordinary (flat, pink to purple), dilated (thicker, nodular) and post-treatment (scar, abnormal pigmentation). They retrospectively followed 118 subjects (82 ordinary, 18 dilated and 18 post-treatment) for a minimum of 6 months. Overall 98% lesions (116/118) showed fair-to-excellent responses. Poor response was seen in post-treatment group involving hypertropic scars. However, other hospitals reported that in their trial of 80 subjects (2½—65 years old) all subjects experienced a varying degree of PDTrelated pain and younger subjects (
