Phase II clinical study of photodynamic therapy using mono-l-aspartyl chlorin e6 and diode laser for early superficial squamous cell carcinoma of the lung

doi:10.1016/S0169-5002(03)00242-3

Lung Cancer

Volume 42, Issue 1, October 2003, Pages 103-111

https://doi.org/10.1016/S0169-5002(03)00242-3 Get rights and content

Abstract

Photofrin is the most commonly used photosensitizer for photodynamic therapy (PDT). The major side effect of Photofrin is cutaneous photosensitivity. A second generation photosensitizer, mono-l-aspartyl chlorin e6 (NPe6) has shown anti-tumor efficacy and rapid clearance from skin. Therefore, we conducted a phase II clinical study to investigate the anti-tumor effects and safety of NPe6 in patients with early superficial squamous cell carcinoma of the lung. Enrollment criteria consisted of endoscopically evaluated early stage lung cancer with normal chest X-ray and CT images, no lymph node or distant metastasis. Tumors were located no more peripherally than subsegmental bronchi, the peripheral margin had to visible, and the tumor size had to not more than 2 cm in diameter. The histologic type of the tumor had to squamous cell carcinoma. Laser irradiation (100 J/cm²) using a diode laser was performed at 4 h after administration of NPe6 (40 mg/m²). Among 41 patients with 46 lesions, 40 with 45 lesions were eligible for safety evaluation, and 35 patients with 39 lesions were judged as eligible for efficacy evaluation. No serious adverse drug reactions were observed. Disappearance of skin photosensitivity was recognized within 2 weeks in 28 of 33 patients (84.8%) and in all the other seven patients first tested at 15–18 days. Complete response (CR) was seen in 84.6% of lesions (82.9% of patients). This study demonstrated excellent anti-tumor effects and safety, especially low skin photosensitivity in patients with early stage lung cancer. PDT using the second generation photosensitizer NPe6 and a diode laser will likely become a standard modality of PDT for central type early superficial squamous cell carcinoma of the lung.

Introduction

Photodynamic therapy (PDT) is a form of cancer treatment which offers palliative therapy for advanced cancer with obstructive tumors and the possibility of curing minimally invasive disease when treated in its earliest stages. PDT is a two stage process with the first stage consisting of an injection of a photosensitizer. Photofrin (porfimer sodium) is the most commonly used photosensitizer for this process. The major side effect of Photofrin itself is cutaneous photosensitivity, which lasts approximately 4–6 weeks [1]. Photofrin is mostly cleared from a variety of tissues at 24–72 h following a period of time after injection. However, this photosensitizer is retained in tumor, skin, and organs of the reticuloendothelial systems [2]. In the second and final stage of the tumor is illuminated with 630 nm red light emanating from a laser. Tumor selectivity in treatment occurs through a combination of selective retention of photosensitizer, selective delivery of light, and drug/light dose selection such that normal tissues are relatively spared [3]. However, the effectiveness of PDT is known to be limited because the maximal therapeutic depth of penetration by activating light is no more than 2 cm. Therefore, the main application of PDT for lung cancer to obtain complete remission is for carcinoma in situ or early invasive squamous cell carcinoma [4].

Because of the skin photosensitivity of Photofrin, many investigators have shown interest in the synthesis of new photosensitizers, which possess lower skin photosensitivity for use in PDT. Among those photosensitizers, mono-l-aspartyl chlorin e6 (NPe6) is considered as a promising photosensitizer. This compound has shown anti-tumor efficacy with laser irradiation in a murine tumor model and rapid clearance from skin [5]. We performed a phase I clinical study using NPe6 and a diode laser for bronchogenic early superficial squamous cell carcinoma from April 1995 to December 1996. When the results were analyzed in eight eligible patients (eight lesions), the rate of complete response (CR) was 87.5% (7/8), and neither particularly serious adverse reactions nor abnormal clinical laboratory findings were noted [6]. Therefore, we conducted a phase II clinical study to investigate anti-tumor effects and the safety of NPe6 in patients with endoscopically evaluated early stage lung cancer using the same dosage shown to be safe and effective in the previous phase I clinical study.

Section snippets

Patients and methods

The type of study was nation-wide multi-center study funded by Ministry of Health and Welfare. This study was designed as an open-labeled clinical trial. A total of ten institutions were enrolled in this study from October 1997 through March 2000.

Results

Among 41 patients (46 lesions) registered, one patient refused to receive NPe6. Therefore, NPe6 was given to 40 patients (45 lesions, Table 1). All except one were male, and the median age was 67 years old. Performance status was 0 or 1 in all except one patient. The histological type was squamous cell carcinoma in all patients and all were carcinomas in situ (CIS) or early invasive carcinomas. There were 19 clinical stage 0 (CIS) cases (23 lesions), and 21 stage I cases (22 lesions). Fifteen

Discussion

PDT was first applied clinically for endoscopically early stage lung cancer at our institution using an argon dye laser combined with a tumor-specific photosensitizer, hematoporphyrin derivative (HpD) in March 1980 [10], and subsequently Kato et al. reported the first case of 5-year disease-free survival in a case of early stage lung cancer treated only by PDT [11]. In 1988, a multicentric study on PDT for early stage lung cancer performed by the PDT cancer group of the Ministry of Health and

Acknowledgements

The authors wish to thank Professor J.P. Barron of the International Medical Communications Center of Tokyo Medical University for his review of the manuscript.

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Phase II clinical study of photodynamic therapy using mono-l-aspartyl chlorin e6 and diode laser for early superficial squamous cell carcinoma of the lung

Abstract

Introduction

Section snippets

Patients and methods

Results

Discussion

Acknowledgements

Chest

Chest

Chest

Eur. J. Cancer

J. Photochem. Photobiol. B

J. Photochem. Photobiol. B

J. Photochem. Photobiol. B

Cutaneous phototoxic occurrence in patients receiving Photofrin

Lasers Surg. Med.

Distribution and elimination of Photofrin II in mice

Photochem. Photobiol.

The theory of photodynamic therapy dosimetry: consequences of photodestruction of sensitizer

Photochem. Photobiol.

Photodynamic therapy with a diode laser for implanted fibrosarcoma in mice employing mono-l-aspartyl chlorin E6

Photochem. Photobiol.