Journal of Photochemistry and Photobiology B: Biology 141 (2014) 20–25

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Clinical outcome of photodynamic therapy in esophageal squamous cell carcinoma Eunjue Yi a, Chan Kyu Yang b, Chosun Leem a, Youngsoo Park c, Ji-Eun Chang a, Sukki Cho a,b, Sanghoon Jheon a,b,⇑ a b c

Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Gyeonggi, Republic of Korea Department of Thoracic and Cardiovascular Surgery, College of Medicine, Seoul National University, Seoul, Republic of Korea Department of Internal Medicine, Seoul National University Bundang Hospital, Gyeonggi, Republic of Korea

a r t i c l e

i n f o

Article history: Received 21 May 2014 Received in revised form 25 August 2014 Accepted 2 September 2014 Available online 16 September 2014 Keywords: Photodynamic therapy Esophageal neoplasms Palliative care

a b s t r a c t The aim of this study was to evaluate the feasibility and safety of photodynamic therapy (PDT) as a curative treatment option or as palliative therapy for esophageal squamous cell carcinoma. Medical records of patients who received PDT for esophageal squamous cell carcinoma, including carcinoma in situ, were reviewed retrospectively. Survival analysis was performed using the Kaplan–Meier method. A total of 31 cases were treated with PDT between 2003 and 2013. Treatment was for palliative purposes in 11 cases (35.5%) and for therapeutic purposes in 20 cases (64.5%). We achieved 15 cases (48.4%) of complete remission and 16 (51.6%) cases of partial remission during the follow-up period. There were 6 fatalities, 5 of which were related to disease progression. Complications, including benign strictures, occurred in 11 cases (35.5%) but there was only 1 complication-related death. Recurrence occurred in 2 patients with complete remission. Overall survival was 31.9 months for patients with complete remission and 28.2 months for those with partial remission. Disease-free survival of patients with complete remission was 21.9 months. Our data suggest that photodynamic therapy is a reasonable palliative treatment option with acceptable complication rates for esophageal cancer and could be performed for therapeutic purposes in cases of early esophageal cancer. Ó 2014 Elsevier B.V. All rights reserved.

1. Introduction Photodynamic therapy (PDT) is an endoscopic procedure involving selective uptake of a photosensitizer by proliferative, especially malignant, cells that allows targeted cytotoxic effects when light of a specific wavelength is applied. PDT requires 3 components: a tumor-specific photosensitizer, oxygen, and a light source [1]. Separately, none of these are harmful, but the combination of these three components initiates a serial photochemical reaction that rapidly causes significant cytotoxicity. The first step of PDT is administration of the photosensitizer, which usually has a tetrapyrrole structure. Subsequent irradiation

⇑ Corresponding author at: Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, 166, Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 463-707, Republic of Korea. Tel.: +82 31 787 7133; fax: +82 31 787 4050. E-mail address: [email protected] (S. Jheon). http://dx.doi.org/10.1016/j.jphotobiol.2014.09.001 1011-1344/Ó 2014 Elsevier B.V. All rights reserved.

with light of an appropriate wavelength corresponding to the absorption band of the photosensitizers results in the generation of singlet oxygen and induces cell death via 3 phenomena: apoptosis, necrosis, and autophagy [2,3]. The first clinical use of PDT was in 1978 for patients with metastatic skin cancers [4]. Since then, photodynamic therapy has become increasingly applied in anticancer therapy. It appears to be a reasonable option for the treatment of malignant and premalignant non-melanoma skin lesions, and also for Barrett’s esophagus and unresectable cholangiocarcinoma [1,5]. PDT is very attractive therapeutic modality that has many advantages. It is a minimally invasive technique with few deleterious effects on normal tissue. It has negligible systemic effects and can be applied in combination with other therapeutic modalities. It has also been reported to yield a survival benefit and an improvement in quality of life. Clinical applications of PDT for esophageal cancer have been reported in high-grade dysplasia and Barrett’s esophagus, for early

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esophageal cancer in inoperable patients, and in palliative treatment for obstructive lesions. Although PDT was approved by the Food and Drug Administration as a drug-device almost 2 decades ago [1], it remains underutilized clinically and its full effectiveness has not yet been fully elucidated, especially for therapeutic purpose in early esophageal cancer. In this study we analyzed the results of 31 sessions of PDT for esophageal cancer in order to gain insight into its indications in this disease entity.

2. Patients and methods Medical records of patients with esophageal cancer who underwent photodynamic therapy in our institute between 2003 and 2013 were reviewed retrospectively. Candidates for PDT were selected as follows: (1) patients with early esophageal cancers who could not receive surgery because of comorbidities or who refused surgery; (2) patients with recurrent cancer or unresectable tumor requiring palliative surgery; (3) patients requiring emergency alleviation of severe pain or obstruction. All patients underwent routine laboratory blood tests and careful physical examination. Enhanced chest computed tomography (CT) and positron-emission tomography CT were performed for cancer evaluation and detection of metastasis. Endoscopic examination including endoscopic ultrasound (EUS) was essential for the assessment of staging and pathology. PDT consists of two stages: administration of photodynamic therapy and irradiation with light of an appropriate wavelength. The administrated dose of photosensitizer was 2 mg/kg. After a waiting period of 24–48 h after the administration of photosensitizer via an intravenous route, the patients underwent endoscopic tumor ablation with a light diffusion catheter (Xcell PDT Balloon with Fiber Optic Diffuser, Cook Endoscopy, Winston-Salem, NC, USA) using a tunable laser (DiomedÒ 630 PDT Laser System, Diomed, Ltd., Cambridge, UK). Although various kinds of photosensitizers were used, in most cases we used Photofrin (Pinnacle Biologics, Bannockburn, IL, USA). Other options were chosen if Photofrin caused any adverse reactions. Patients were given 200–400 J per session, with treatment duration of 500–700 s. Patients underwent assessment by endoscopy 2 days after the first treatment. Mechanical debridement of necrotic tissue was performed if necessary. Dilatation of the esophageal lumen to prevent or eliminate stenosis and additional laser irradiation was also performed if necessary. All patients were recommended to avoid sunlight for 4 to 6 weeks after the final PDT. If the patient had no complaints they were given soft food beginning. Follow-up endoscopy was performed at 1, 3, and 6 months after the first PDT. Chest CT was also performed 6 months after PDT. Treatment results were categorized into 3 groups: complete remission (CR), defined as no evidence of disease on follow-up chest CT or endoscopy 6 months after PDT; partial remission (PR), in which tumor regressed or was still observed in the tumor bed or there was regrowth after remission; or no response, defined as up to 50% of the tumor remaining or an increase in tumor size after PDT. We evaluated treatment response in each case. Local recurrence was defined as emergence of tumor regrowth after complete or partial remission on follow-up endoscopy or chest CT. Survival and complication rates were calculated using Kaplan–Meier survival analysis. SPSS 20.0 (IBM, New York, NY, USA) was used for statistical analysis.

3. Results 3.1. Patient characteristics A total of 31 cases were analyzed. 2 were female, and the rest were male. The median follow-up period was 26.0 months. Average age at the time of treatment was 65.1 (±9.71) years. PDT was performed 26 times (83.9%) for primary lesions and 5 times (16.1%) for recurrent lesions. Information on patients is summarized in Table 1, and the treatment modalities that patients received before PDT are categorized in Table 2. 3.2. Treatment results CR was achieved in 15 (48.4%) of the 31 cases. One patient could have reached CR after 4 sessions of PDT. Two patients in the CR group had recurrences during the entire follow-up period. No patients in the CR group died during the follow-up period. PR was observed in 16 (51.6%) cases. Two of these patients should have received surgery because of residual tumor. Six patients with PR died during the follow-up period (19.4%): 4 from cancer progression, 1 from PDT complications, and the other from aspiration pneumonia. The overall complication rate was 35.5% (11 cases). The most common complication was benign stricture, which occurred in 6 cases (19.4%). Two of these patients needed stent insertion for their stricture. One patient died as a result of esophageal perforation after PDT, which was the only complication-related death. Local recurrence was observed in 9 patients (29.0%). Among the PR cases, there were 7 cases of recurrence, defined as regrowth of tumor in follow-up examination. Of those 7 patients, 4 died of cancer progression. For treatment of recurrence, 2 patients received surgery and 6 received recurrent PDT. Two of the patients with CR showed recurrence, but none died of cancer progression. One patient received endoscopic mucosal resection (EMR) and other received radiation therapy for treatment of recurrence (Table 3).

Table 1 Patient characteristics. Variables

Frequency

Age (years) Median follow-up periods (months)

65.1 ± 9.71 26.0 (1.6–105.4)

Gender Male Female

29 2

93.5 6.5

Cancer status CIS T1 T2 T3 T4 Unknown Recurred

7 15 0 1 1 2 5

22.6 48.4 0.0 3.2 3.2 6.5 16.1

Cancer location Upper Mid Lower

6 11 14

19.4 35.5 45.2

Treatment purpose Therapeutic Palliative Emergency

20 11 0

64.5 35.5 0.0

CIS = carcinoma in situ.

%

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Table 2 Treatments underwent before PDT. Treatment modality

T stage

None

Frequency (%) Frequency (%) Frequency (%) Frequency (%) Frequency (%) Frequency (%) Frequency (%)

CCRT CTx. EMR Operation PDT Total

CIS

T1

T3

T4

Unknown

Recurred

4 (12.9) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 3 (9.7) 7 (22.6)

13 (41.9) 0 (0.0) 0 (0.0) 1 (3.2) 0 (0.0) 1 (3.2) 15 (48.4)

0 (0.0) 0 (0.0) 1 (3.2) 0 (0.0) 0 (0.0) 0 (0.0) 1 (3.2)

1 (3.2) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (3.2)

0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (6.5) 2 (6.5)

0 (0.0) 2 (6.5) 1 (3.2) 0 (0.0) 1 (3.2) 1 (3.2) 5 (16.1)

PDT = photodynamic therapy; CCRT = concomitant chemoradiotherapy; CTx. = chemotherapy; EMR = endoscopic mucosal resection; CIS = carcinoma in situ.

Table 3 Treatment performed after PDT. EMR and RT were performed for recurrence after PDT in CR patients. Treatment modalities

None

T stage

Frequency (%) Frequency (%) Frequency (%) Frequency (%) Frequency (%) Frequency (%) Frequency (%) Frequency (%)

CCRT CTx. EMR Operation PDT RT Total

CIS

T1

T3

T4

Unknown

Recurred

4 (12.9) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 3 (9.7) 0 (0.0) 7 (22.6)

11 (35.5) 0 (0.0) 0 (0.0) 1 (3.2) 1 (3.2) 1 (3.2) 1 (3.2) 15 (48.4)

0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.0) 0 (0.0) 0 (0.0) 1 (3.2)

1 (3.2) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (3.2)

0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (6.5) 0 (0.0) 2 (6.5)

0 (0.0) 2 (6.5) 1 (3.2) 0 (0.0) 0 (0.0) 2 (6.5) 0 (0.0) 5 (16.1)

PDT = photodynamic therapy; CCRT = concomitant chemoradiotherapy; RT = radiation therapy; CIS = carcinoma in situ.

3.3. Survival analysis Overall survival rates and disease-free survival periods are shown in Table 4. There were no significant differences between the complete remission and partial remission categories in terms of overall survival (p = 0.279) or disease-free survival (p = 0.473). Overall survival and disease-free survival curves of PDT patients are shown in Figs. 1 and 2. Progression-free survival periods were calculated for PR patients instead of disease-free survival periods. 4. Discussion PDT was first introduced as a palliative treatment for advanced esophageal cancer. The first application of PDT in esophageal cancer was reported by McCaughan et al. in 1983 [6]. Vignesh et al.

recommend PDT as an effective treatment modality with stents and radiation therapy for patients suffering from dysphagia due to obstructive esophageal cancer [7]. And PDT combined with chemotherapy has been reported superior to chemotherapy alone for advanced esophageal cancer [8]. It has been also adopted as salvage treatment for local failure after chemotherapy or surgery in esophageal squamous cell carcinoma. Although there were some limitations, studies showed feasibility and effectiveness of PDT for locally recurred esophageal cancer after chemotherapy [9,10]. And PDT could be successful as a salvage treatment for in site carcinoma occurred after esophagectomy [11]. Moreover, PDT is also thought to be one of the alternative treatment options for early esophageal cancer [12], especially when the patients have comorbidities. One of the long-term follow-up study

Table 4 Overall survival and disease-free survival periods (months) following PDT.

Total CR PR P-value

Overall survival periods (months)

Disease-free survival periods (progression-free survival periods) (months)

Average (Sd.)

Median (range)

Average (Sd.)

Median (range)

26.7 (±25.42) 31.9 (±18.50) 21.9 (±30.35) 0.279

26.0 (1.6–105.4) 28.4 (5.3–63.0) 4.5 (1.6–105.4)

24.7 (±25.20) 28.2 (±18.30) 21.5 (±30.57) 0.473

19.7 (1.00–105.4) 27.8 (3.0–63.0) 3.9 (1.0–105.4)

Sd. = standard deviation; CR = complete remission; PR = partial remission.

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Fig. 1. Overall survival curve of PDT patients in SNUBH. The average overall survival period of the CR category was 26.6 months and that of the PR category was 24.7 months, but there were no statistically significant differences. The 3-year overall survival rates were approximately 24%.

Fig. 2. Disease-free survival curve of PDT patients in SNUBH. The average disease-free survival period of the PR category was 18.6 months. The 3-year disease-free survival rate of all patients was 20.0%.

of PDT for superficial squamous cell carcinoma revealed that PDT was a potentially curative treatment for selective patients [13,14]. Although esophagectomy has been regarded as a first choice of treatment, it showed 30–40% of morbidity rates and 0–4% of mortality rates. And this could be parts of reasons why we have been looking for other treatment modalities [15]. Endoscopic procedures, including endoscopic mucosal resection (EMR), radiofrequency ablation (RFA), and PDT are attractive candidates for alternation. There have been some reports that demonstrated superiority of other endoscopic treatment modalities over PDT. For Barret’s esophagus, RFA had higher rates of curativeness, lower rates of complication and less cost [16]. However, PDT seems to have advantages over other endoscopic modalities, variability. The effect of PDT could be varied as types of photosensitizer, light sources and wavelength. Equivalent dose of different photosensitizer could result in varying depth of tissue necrosis, and varying light source and wavelength may reveal differences in tissue penetration [12]. Optimization of light dosimetry could reduce complications by controlling penetration to the tissue [17]. Photosensitizer is one of the key components. Photofrin is the oldest and most widely used photosensitizer. Although photofrin PDT was proved to be effective in treatment of esophageal cancer [18], its complications could not be negligible [19]. Several agents have

been investigated for substitution. 5-Aminolaevulinic acid (ALA) reported to be more effective and produce lower complication rates [19]. Studies using m-tetraphydroxyphenyl chlorin (mTHPC) showed better results in comparing with photofrin in treatment of esophageal squamous cell carcinoma as well as adenocarcinoma, and Barrett’s dysplasia [20–22]. PDT with 2-(1-hexyloxyethyl)-2devinyl pyropheophorbide-a (HTTP) has been demonstrated to be more effective than that with photofrin of the same dose in the treatment of esophageal squamous cell carcinoma [23]. We used photofrin in spite of these various alternative agents. Certainly, photofrin has many disadvantages for patients; it needs longer periods of isolation from lights, causes more strictures, photosensitivity and risks for recurrence. But 5-ALA has limitation in tissue penetration. HTTP has been still in research stage [24]. mTHPC is still not approved in our country. PDT has also advantages over conventional cancer treatment modalities, such as surgery or chemotherapy. The major advantages are higher selectivity and lower systemic toxicity. Because of limited light penetration, which ranges from a few millimeters up to one centimeter, depending on blood flow in tissue, PDT causes mostly superficial effects, thus it could be ideal in the treatment of superficial diseases, such as pre-malignant conditions, carcinoma in situ or superficial tumors [1,25,26]. The technique can

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also be used in elderly patients and those with significant comorbidities due to its lower toxicity. It can also be an option for patients who refuse surgery or patients with inoperable condition However, in terms of cancer cure, there are a few papers on the risk of recurrence in patients treated with PDT. Most reports recommend regular endoscopic follow-up every 3 months during the first year of treatment. Esophagectomy is therefore preferable for lesions invading the submucosa. (T1b) [15] Beyond stage T1a, rates of lymph node metastasis also increase [26]. Furthermore, some investigators proposed that esophagectomy in high grade dysplasia should be also considered from the aspect of prevention and cure of occult cancer [7]. Complications in esophageal PDT include chest pain, nausea, vomiting, odynophagia, and skin photosensitivity [27]. The uptake of the photosensitizing agents by the skin requires patients to avoid direct sunlight and wear protective clothing, such as sunglasses, hats, long-sleeved shirts, etc. for several weeks to prevent sunburn [28]. More significant complications including death, mediastinitis, esophageal perforation, tracheo-esophageal fistula, and esophageal strictures requiring dilation have also been reported. Five-year survival rates and complete remission rates of more than 60% have been reported [29]. For palliative therapy, PDT has been reported as effective treatment in 85% of cases [30]. Our study obtained a 48.4% complete remission and a 3-year overall survival of 24%. We thought the relatively low survival rates in our study might be due to relatively short follow-up periods partly, because our mean follow-up periods were less than 3 years, and most of the patients (17 cases) received PDT after 2010. However, in the revision of our data, we found that some of patients died very soon after the PDT, only a few months later. Their physical conditions were very poor, and the PDT seemed to be the last chance for releasing symptoms. There were some patients who lived more than 5 years after the treatment of PDT, even with partial remission. Therefore, if we have more data from PDT experiences, these low survival rates might be changed. Complication rates have been reported between 15% and 40% [29,30]. And the complication rates of our study were 25.4%, which we thought was acceptable. Benign stricture was the most commonly observed complications (6 cases, 19.4%). In those patients, two needed stent insertion and one patient received bougienation. This was relatively favorable results, considering the results of EMR or RFA. The complication rates for stricture after EMR has been reported up to be 49.7%, [31], and those of RFA has been reported to be 20% [32]. Although some reports demonstrated the superiority of RFA over PDT [16,32], the lower rates of complications could justified the performance of PDT in esophageal squamous cell carcinoma. The limitations of the present study include its retrospective nature and the relatively small number of patients. PDT has been widely accepted as primary therapy for early esophageal cancer of inoperable patients, it is still unclear to what extent it can be substituted for surgical treatment. Despite many clinical studies reporting the benefits of PDT, evidence of its efficacy based on prospective randomized controlled trials is still lacking. However, randomized controlled studies are difficult to plan because of ethical considerations. Although PDT is a feasible and safe option for selected esophageal cancer patients, we must be careful when we adopt this modality for early esophageal cancer. Surgical resection remains the first choice for such cases to maximize the possibility of cure.

5. Conclusion PDT is a feasible and safe treatment modality for palliative therapy in advanced esophageal cancer with acceptable complication

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