Lasers in Surgery and Medicine 39:647–653 (2007)
Performance of a Dedicated Light Delivery and Dosimetry Device for Photodynamic Therapy of Nasopharyngeal Carcinoma: Phantom and Volunteer Experiments H.J. Nyst, MD,1 R.L.P. van Veen, PhD,2* I.B. Tan, MD,1 R. Peters, PhD,3 S. Spaniol, PhD,4 D.J. Robinson, PhD,2 F.A. Stewart, PhD,5 P.C. Levendag,6 and H.J.C.M. Sterenborg, PhD2 1 Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Department of Head and Neck Oncology and Surgery, Amsterdam, The Netherlands/Academic Medical Center, Department of Otolaryngology Amsterdam, The Netherlands 2 ErasmusMC, Center of Optical Diagnosis and Therapy, Rotterdam, The Netherlands 3 ErasmusMC, Department of Prosthesis, Rotterdam, The Netherlands 4 Biolitec AG, R&D, Bonn, Germany 5 Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Department of Experimental Therapy, Amsterdam, The Netherlands 6 ErasmusMC, Radiotherapy, Rotterdam, The Netherlands
The objective of this study was to develop a light delivery and measurement device for photodynamic therapy (PDT) in the nasopharyngeal cavity, which achieves a homogeneous and reproducible fluence rate distribution to a target area and provides proper shielding of predefined risk areas. Materials and Methods: A flexible silicone applicator was developed, incorporating light delivery and dosimetry fibers. The applicator can be inserted through the mouth and fixed in the nasopharyngeal cavity. Tissue optical phantoms were prepared on the basis of optical properties measured in vivo using diffuse reflectance spectroscopy (DRS). The fluence rate over the length of the applicator surface was measured in air, in tissue optical phantoms and in five healthy volunteers. Results: The fluence rate distribution over the applicator surface in air and tissue optical phantom was found to be more homogeneous (SD/mean 3.8% and 18.3%, respectively) than the fluence rate distribution in five volunteers (SD/mean ranging from 19% up to 52%). The maximum observed fluence rate build-up in the nasopharynx varied between subjects and ranged from a factor of 4.1–6.9. Shielding of the risk area such as the soft palate and tongue was effective. Conclusions: In air and in tissue optical phantoms the fluence rate distribution of the device was highly homogeneous. The observed inter-subject and intra-subject variations in fluence rate in healthy volunteers originated from differences in optical properties and nasopharyngeal geometry. Light delivery based on a single tissue surface measurement will not be adequate. In situ dosimetric measurements are required to determine the light fluence delivered to a geometrically complex site such as the nasopharynx. These observations should be taken in consideration when developing light applicators for PDT of the nasopharynx and other non-uniform surfaces. Lasers Surg. Med. 39:647–653, 2007. ß 2007 Wiley-Liss, Inc. ß 2007 Wiley-Liss, Inc.
Key words: applicator; nasopharyngeal cavity; nasopharynx; nasopharyngeal carcinoma; fluence rate; photodynamic therapy; light delivery device INTRODUCTION We are investigating the use of photodynamic therapy (PDT) as an alternative or additional treatment modality for nasopharyngeal carcinoma (NPC). The few published studies treating NPC using PDT demonstrate variable clinical outcome. In all but one of these studies, in situ light dosimetry was not employed and treatment parameters varied considerably between patients [1–3]. In general, light delivery was based on manually positioning an optical fiber through an endoscope [4,5]. The only reference in the literature to a systematic approach to light delivery is from Lofgren et al. [6]. They developed a rigid light delivery system for Photofrin-PDT, which was inserted through the nose into the nasophanryngeal cavity. A beam deflector at the distal end of the system directed the light upward onto the nasopharynx. Five patients were treated, again with variable results. The variable outcome of tumor response probably contributed to the premature cessation of PDT for NPC. The therapeutic effect of PDT depends on a combination of parameters that include drug dose, drug-light interval, and light fluence rate. These parameters have been extensively investigated in pre-clinical models and a small number of stage I clinical trials aimed at optimising PDT. A homogeneous and reproducible fluence rate delivery during *Correspondence to: R.L.P. van Veen, Center for Optical Diagnostics and Therapy, Department of Radiation Oncology, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail:
[email protected] Accepted 25 July 2007 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/lsm.20536
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clinical PDT plays a vital role in preventing under- or overtreatment [7]. Previous attempts to perform PDT in the nasopharynx may in part have been hampered by inadequate and non-reproducible light delivery due to the difficulty of accessing the nasopharyngeal cavity; this may be a significant factor in the unsatisfactory response obtained in the preliminary clinical studies [1–5]. In order to achieve optimal light delivery in the nasopharynx we have developed a flexible silicone applicator that facilitates a controllable and reproducible approach to the delivery and monitoring of light within the nasophanryngeal cavity. Real-time monitoring of the in vivo fluence rate may prove to be an important factor in PDT since the total fluence rate in tissue, especially in hollow organs, is strongly increased due to multiple diffuse reflections of incident light from the tissue surface. This fluence rate build-up varies with the geometrical shape and tissue optical properties (scattering and absorption), and has been reported to be as high as a factor of 7.5 in the bladder [8]. In another study, we have measured fluence rate variations during PDT of Barrett’s oesophagus [9]. The results showed a dramatic variation between patients, with fluence rate build-up factors ranging from 1.5 up to 4. Similar wide variations were seen for in situ measurements of fluence rate in the oral cavity [10]. These results illustrate the importance of developing instrumentation for integrated light delivery and in situ light fluence rate measurement in PDT. Prior to performing a clinical study of NPC-PDT, the performance of the light applicator was investigated. Here we report on the fluence rate distribution in the target area and shielding efficacy evaluated in air, tissue optical phantoms and in healthy volunteers. Inter- and intrasubject variations in fluence rate distribution are evaluated. MATERIALS AND METHODS The Applicator The light applicator and its position with respect to anatomical locations are schematically shown in Figure 1. The NPC-PDT applicator is made out of silicone (type 625, Wacker Chemie, Krommenie, The Netherlands) and consists of two 220 mm long silicone tubes. The inner diameter of the silicone tubing can accommodate standard flexible implant catheters (e.d. 6 mm, i.d. 4 mm, PB, Barendrecht, Holland) (e.d. 6F, Nucletron, Veenendaal, The Netherlands) for improved guidance of miniature (isotropic) fluence rate detectors. Both tubes are interconnected at the proximal end of the applicator by a small silicone bridge, which abuts at the distal side against the nasal septum. The core to core perpendicular distance between the parallel silicon catheters is 17 mm. The distance between the isotropic detector within the same catheter is 2 mm [11]. The bridge of the applicator is perforated with two 5 mm holes to enhance flexibility. A removable flexible black silicone patch is attached as shown in Figure 1A to protect the soft palate and prevent light from entering the oral cavity. In a pilot study we investigated the influence of bending on the emission profile of cylindrical diffusers. A 652 nm 2W
Fig. 1. A: The NPC PDT applicator device and (B) the position of the light application device with respect to the anatomical location. For the experiments, an optical cylindrical diffuser fiber (1) that emits homogeneously and diffusely over a 30 mm or 60 mm length was used. The NPC target area (2) is usually localised along the outer curve of the applicator. The thick black line represents the black silicon patch intended to shield light from critical healthy areas like the soft palate (3). [Figure can be viewed in color online via www.interscience.wiley.com]
diode laser (Ceralas PDT, Biolitec, Bonn, Germany) was used as light source for this study. The diffuser output was set to 5 mW cm1 for the tissue optical phantoms, and to 100 mW cm1 for the volunteers. In both the tissue optical phantoms and in volunteers, a 30 mm long cylindrical diffuser demonstrated a highly in-homogeneous emission profile with a strong peak at the distal part of the diffuser. This effect was the result of bending of the cylindrical diffuser. When the diffuser is bent at the junction between the quartz fiber and flexible fiber, the majority of the photons exit at the transition point. This results in a peak in
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fluence rate profile at the beginning of the diffuser as seen in Figure 2. This phenomenon was not observed in phantoms for diffusers of 60 mm, since the connection between fiber and diffuser is then at the beginning of the bridge and is straight. To overcome the problem of the inhomogeneous fluence rate distribution for short diffuser lengths, for example,
