Photodiagnosis and Photodynamic Therapy (2006) 3, 266—271

Clinical study of Photofrin photodynamic therapy for the treatment of relapse nasopharyngeal carcinoma Li-bo Li MD ∗, Rong-cheng Luo, Wang-jun Liao, Ming-jiang Zhang, Yu-ling Luo, Jing-xia Miao Oncology Department of Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China

KEYWORDS Nasal pharyngeal cancer; Nasal obstruction; Photofrin; Photodynamic therapy; Chemotherapy

Summary Objectives: To evaluate the clinical response and adverse effects of Photofrin photodynamic therapy (PDT) in patients with relapse nasal pharyngeal cancer. Methods: Thirty patients with relapse nasal pharyngeal cancer were randomly divided into PDT group and chemotherapy group. In PDT group, patients received intravenous administration of Photofrin (2 mg/kg b.w.) and 48 h later light (200—300 J/cm) was delivered by a 630 nm diode laser through a cylinder diffuser under endoscopic assistance. Two days after PDT the necrotic tissues were removed and newly identified sites were subject to another round of light irradiation. In chemotherapy group, the routine cisplatin and 5-fluorouracil (DDP/5-FU) remedy was used. Endoscopic and radiological examinations were performed during 6 months follow-up. The Karnofsy Score was used to evaluate the quality of life. Results: The local response and nasal cavity obstruction remission rate in PDT group were better than that in chemotherapy group. The Karnofsy Score was also improved in PDT group. Conclusion: This pilot study suggests that Photofrin PDT is effective and safe in treatment of advanced nasal pharyngeal cancer and management of nasal obstruction. © 2006 Published by Elsevier B.V.

Introduction In some areas of China the morbidity and the mortality of nasopharyngeal carcinoma (NPC) are high. Radiotherapy is the most common treatment with approximately 50% 5-year survival. However, ∗ Corresponding author. Tel.: +86 20 72787738; fax: +86 20 87726110. E-mail address: libo@fimmu.com (L.-b. Li).

1572-1000/$ — see front matter © 2006 Published by Elsevier B.V. doi:10.1016/j.pdpdt.2006.09.004

radiotherapy is associated with a number of severe side effects. Advanced NPC is very difficult to treat, especially the relapse patients after radiotherapy. Those patients cannot endure the complication and adverse reaction of repeat radiotherapy. Therefore, most patients might receive chemotherapy. But the effectiveness of chemotherapy is not guaranteed. Photodynamic therapy (PDT) is a relatively new technology in the treatment of cancer and

PDT of nasopharyngeal carcinoma associated with only minor side effects. The principle of PDT is that the photosensitizer can be concentrated in the tumor tissue and excited by light and the subsequent photodynamic reaction can generate cytotoxic reactive oxygen species (ROS) and lead to the death of cancer cells [1—3]. Several Chinese groups started to explore the feasibility of PDT for the treatment of NPC since the early 1980s. Those NPC PDT procedures involved multiple sessions of treatment using domestic photosensitizers and patient response was encouraging. The 3- and 5-year survivals were reported as 44.6 and 25.4%, respectively [4—7]. Early studies conclude that PDT could improve survival and is feasible for localized primary and recurrent NPC. In China, the majority of clinical investigations use domestically produced hematoporphyrin derivatives (HpD) as the PDT photosensitizer and gold or copper vapour laser as the PDT light source [2,4]. Clinical PDT using Photofrin and diode laser has not been reported in China before. Photofrin and Diomed 630 laser were introduced into China in the early 2000s. Since then, they have been used in several newly established PDT Centres for treating various tumors including advanced and relapse NPC. In order to evaluate the efficacy of Photofrin PDT for the treatment of NPC, we compared PDT with chemotherapy in a small group of patients who had failed radiotherapy. This manuscript will summarize the preliminary results of this pilot study.

Material and method Patient data A total of 30 relapse NPC patients were randomly divided into two groups. The PDT group included 13 males and 2 females (28—70 years old and the average age of 52 years old). The chemotherapy group included 11 males and 4 females (34—72 years old and the average age of 55 years old). All the patients were classified as stage IV and had local relapse after sufficient dose of radiotherapy. Previous radiotherapy dose was one or two courses of 6000 cGy. Some patients had adjunctive chemotherapy after radiotherapy and before local relapse. The scheme was PF: cisplatin (total DDP 80 mg/m2 , d1—d5 V.D.) and 5-fluorouracil (5-Fu) (500 mg/m2 , d1—d5, V.D.). The intervals between radiotherapy and PDT or chemotherapy were 6—12 months. All patients had lymph metastasis and/or bone metastasis, but their main complaints were local symptoms, such as nasal cavity obstruction, pain, and

267 hypoacusis. All patients were examined by a UV-240 electric endoscope and diagnosed by histopathologic examination. There were eight patients in each group who had nasal cavity obstruction. During the course of this study, patients also used some Chinese herb medicines which might enhance antitumor immunity.

Treatment protocols In PDT group (n = 15), Photofrin (Axcan, Canada) was dissolved to 2.5 mg/ml by 5% glucose injection fluid before use and administered intravenously at a dose level of 2 mg/kg b.w. The IV infusion tube was rinsed in order to ensure a correct dose. Prior to light irradiation local anesthesia was performed by spraying lidocaine. A customer-made shield was used to protect the epiglottis during light irradiation. The light of 200—300 J/cm was delivered by a diode laser (Diomed 630, DIOMED, UK) through a cylindrical diffuser 48 h after Photofrin injection. The length of the diffuser (1—5 cm) was chosen according to the lesion size. Under endoscopic assistance, the diffuser tip was placed in the center of the nasal cavity to the best of the operator’s observation. PDT light irradiation was carried out in 1—3 continuous segments. The light irradiation for each segment lasted 12 min. The irradiated segments partly overlapped and had a margin at least 0.5 cm beyond cancer lesion to ensure that the cancer lesion was fully covered. Patients were asked to avoid sunlight for 4—6 weeks after Photofrin injection. After 48 h of the first treatment, PDT-induced necrotic tissues were removed by biopsy forceps under endoscope guidance. At this time, the deep-seated and newly exposed cancer lesions were re-treated after cleaning out the necrotic tissue. Later the treated areas were cleaned repeatedly if necessary. One patient underwent another session of PDT treatment 1 month later. In the chemotherapy group (n = 15), patients received the following regimen: cisplatin (Sandong Qilu Pharmaceutical LTD), total DDP 80 mg/m2 , divided into d1—d5, and V.D. 5-Fu (Jiangsu Nantong Pharmaceutical Ltd.), 500 mg/m2 , d1—d5, and V.D. Patients were given anti-vomiting treatment as needed. One cycle of treatment lasted 4 weeks. Two cycles of chemotherapy were given in all chemotherapy group patients. All patients had nausea, vomiting, and leukocyte diminution. But all could endure the toxicity during the chemotherapy. No dose reduction was considered because the chemotherapy dose was considered as a normal level to Asian patients.

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Evaluation Patient response was evaluated by endoscopic and radiological examinations (CT or MRI) at 1 month, 3 months and half a year after the completion of treatment. The national evaluation criterion was adopted to evaluate short-term clinical responses [8]. Complete response (CR): the tumor disappears completely for over 1 month, and negative by pathology biopsy. Significant response (SR): the product of the tumor biggest diameter and upright diameter (or the height of the tumor) is reduced by over 50% for 1 month. Minor response (MR): the tumor shrinkage is less than 50% and lasts for 1 month. No response (NR): the tumor has no change or accretion. In addition, the quality of life was also evaluated by Karnofsky Score (KS). All patients were followed up for at least half a year.

Statistical analysis Statistical analysis was performed using statistical software (SPSS for Windows, Version 10.0). The 2 -test was used to compare PDT efficacy, cavity obstruction improvement and Karnofsky Score between PDT group and DDP/5-FU group. P < 0.05 was considered to be statistically significant.

Results Short-term response and symptom improvement In this pilot study, relapse NPC patients who had failed radiotherapy were treated with Photofrin PDT. Short-term response and symptom improvement were compared with chemotherapy. Preliminary evaluation indicated that there was significant difference between the two groups in both local short-term response and symptom improvement. Local response was evaluated by endoscopic and radiological examinations at 1 and 3 months after the completion of treatment. Although neither group showed complete response, 80% patients in PDT group showed significant response, which was six-fold higher than that of chemotherapy group. There was a statistical significance (P = 0.001) in

Table 1

Table 2 Cavity obstruction improvement (cases%) before and after treatment

Photofrin PDT DDP/5FU

N

Improved

No change

P

8 8

7 (87.5) 2 (25.0)

1 (12.5) 6 (75.0)

0.041

Pearson Chi-square (2 ) = 6.349, v = 1, P = 0.041.

Table 3

Karnofsky Score before and after treatment

N Mean KS before treatment (range) Mean KS after treatment (range) No. of improvement (cases%) No. of no change (cases%) P Pearson Chi-square

Photofrin PDT

DDP/5FU

15 45 (30—60)

15 40 (30—50)

70 (60—80)

50 (40—60)

14 (93.3)

5 (33.3)

1 (6.7)

9 (60.0)

0.02

(2 ) = 10.641,

v = 1, P = 0.02.

the overall clinical response between PDT and Chemotherapy (Table 1). Each group had eight patients having obstructed nasal cavity. PDT could effectively debulk the tumor mass and improve the obstruction symptom. Preliminary data indicated that there was a statistical significance (P = 0.041) in obstruction improvement between PDT group and chemotherapy group (Table 2). Figs. 1 and 2 show representative endoscopic images taken from two patients before and after PDT. Both patients received two courses of radiotherapy. One patient (55 years old male) underwent single course treatment of 300 J/cm and obstructed nasal cavity remained open 6 months after PDT. Another patient (57 years old male) underwent twocourse PDT (300 J/cm each) at an interval of 1 month. The nasal cavity remained open during 2 years of follow-up but the patient died of lung metastasis. The quality of life before and after treatment was also evaluated by the Karnofsky Score. Majority of patients showed improvement in the Karnofsky Score after PDT treatment (Table 3). The mean score increased from 45 to 70 in PDT group

Clinical response (cases%)

Photofrin PDT DDP/5FU

N

CR

SR

MR

15 15

0 (0) 0 (0)

12 (80.0) 2 (13.3)

2 (13.3) 6 (40.0)

Pearson Chi-square (2 ) = 13.393, v = 1, P = 0.001.

NR 1 (6.7) 7 (46.7)

P 0.001

PDT of nasopharyngeal carcinoma

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Figure 1 Obstruction improvement after single course PDT treatment. (a) Before treatment, the left nasal cavity was obstructed by the relapse tumor. (b) Close view of the obstruction. (c) During PDT laser irradiation. (d) Six months after, the obstructed nasal cavity remained open.

compared to from 40 to 50 only in chemotherapy group. There was a statistical significance (P = 0.02) in the improvement of quality of life between PDT group and chemotherapy group.

Side effects and adverse reactions The Photofrin PDT induced side effects and adverse reactions were tolerable. Since some lesions involved laryngopharynx, these patients had a slight pain in the treatment area. The nasal cavity secretion increased noticeably. These symptoms disappeared after 3—5 days. Only one case had severe laryngopharynx swelling and pain; swallowing and taking food became difficult. The patient needed anodyne and detumescence treatment. It was believed that a possible light exposure of the epiglottis led to the epiglottis swell and function obstacle. The patient resumed normal function after 1 week. One patient accidentally exposed to sunlight and suffered photosensitivity dermatitis on the exposed areas. Localized redness, swelling, and scurf were noticeable. After symptomatic treatment, the patient’s the skin condition settled 1

week later. One case had skin pigmentation on the part of the skin exposed to light. The pigmentation gradually faded away without any treatment. No bone marrow restrain and liver or kidney toxicity were reported. The ECG and thoracic X-ray showed no problem. Most patients in chemotherapy group had nausea, vomiting and leucopaenia and two patients had elevated GPT (glutamic—pyruvic transaminase).

Discussion Chinese clinicians have explored the use of PDT to treat relapse NPC and NPC residual lesions after radiotherapy for years [4—7]. The total effectual rate was reported as high as 89.6% (55.0% CR and 34.6% SR). Their long-term follow-up of 130 patients showed that 3-year survival rate was 44.6% and 5-year survival rate 25.4%. These suggest that PDT is a good adjuvant method for the patients who fail radiotherapy. Our results are basically similar to these (see Table 1). All of our cases were relapse NPC who were treated previously by

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Figure 2 Obstruction improvement after two-course PDT treatment. (a) Before treatment, the right nasal cavity was obstructed by the relapse tumor completely and the tumor lesion extended about 3 cm long. (b) During PDT laser irradiation. (c) Cleaning out necrotic tissues 48 h after the laser irradiation. (d) Two months after the second session PDT, the obstructed nasal cavity was opened up.

radiotherapy and chemotherapy. We observed that the cavity obstructions caused by cancer lesion improved noticeably after PDT. The improvement was seen in 7/8 cases except only 1 case remained no change in PDT group compared with the control group of improvement in 2/8 cases. The improvement of Karnofsky Score was also seen in PDT group, whereas the control group only had minor response in six cases (see Table 2). All of these changes demonstrate that PDT can improve the local symptom and quality of life. Possible mechanisms might be due to the PDT-induced tumor necrosis, mass reduction and growth inhibition [9]. Early preclinical studies showed the effectiveness of PDT for the treatment of nasopharyngeal carcinoma in animal models [10]. Kulapaditharom et al. treated 13 cases of NPC patients with PDT. The median disease free survival (DFS) was 25.8 months in six cases of T1—T2 NPC patients. PDT combined with chemotherapy might prolong survival for 2 years for T3—T4 NPC patients [11]. Tong et al. treated 12 cases of relapse NPC patients with PDT. All the patients showed positive response by CT and MRI examination 6 months after PDT. Three of eight cases received one course PDT treat-

ment maintained DFS for 9—12 months [12]. Limited investigations show that PDT might be a good option for relapse NPC patients. So far we only have results of short-term evaluation and all patients will be followed up for long observation. Nonetheless, compared to other HpD mixtures, Photofrin has advantages of high purity, convenience, good therapeutic effect and little adverse reaction [13,14]. There were more local reactions in PDT group than that in control chemotherapy group. But there was little systemic reaction in PDT group. Only one case had swallowing difficulty which might be caused by epiglottis function obstacle due to laser radiation. The patients resumed normal swallowing after 2 weeks rest. The adverse reactions in chemotherapy group included nausea, vomiting, fatigue and some even could not endure the chemotherapy. In summary, compared to routine chemotherapy, Photofrin PDT for the treatment of advanced relapse NPC is safe and well tolerable without severe complications. For relapse cancer patients PDT can be adopted for those whose condition could not be controlled by routine methods and valetudinarianism. PDT might offer an effective means to

PDT of nasopharyngeal carcinoma manage the nasal obstruction. However, the long term effect and true clinical value of PDT in the treatment of NPC need to be further investigated.

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