Global status of clinical photodynamic therapy: the registration process for a new therapy.

The clinical use of photodynamic therapy (PDT) has been ongoing for over a decade. However, attempts to apply for approval of the therapy from boards of health for general use began only in 1989. The unique nature of PDT and the resultant changes in the normal drug registration process, as well as steps which are being taken to approve PDT for the treatment of endobronchial lung cancer, superficial bladder cancer and esophageal cancer are described. The current clinical status of PDT in these indications is also reviewed.     

Lasers for the treatment of intraocular tumors

Lasers are used extensively in ophthalmology for a variety of conditions, including many choroidal and retinal tumors. With technologic advances, current therapy attempts not only to maximize survival with globe-salvaging treatment, but also to preserve vision. Each neoplasm has different indications for primary and adjuvant therapy, as well as differing laser treatment protocols. Additionally, there are numerous laser applications available for use, including laser photocoagulation, transpupillary thermotherapy (TTT), and photodynamic therapy (PDT). The current review outlines the basic principles of laser treatment for intraocular tumors, focusing on the indications, treatment protocols, efficacy, and safety, while also presenting the latest advances in intraocular tumor treatment.     

Sequential photodynamic therapy (PDT) and high dose brachytherapy for endobronchial tumour control in patients with limited bronchogenic carcinoma

BACKGROUND: Bulky endobronchial tumours in patients with lung cancer are difficult to treat. Brachytherapy and photodynamic therapy (PDT) are variably effective, and the combination of these treatments is not often recommended. However, cell culture studies and animal studies indicate a possible synergistic effect of combining PDT with ionising radiation. We assessed the safety and effectiveness of combined brachytherapy and PDT in patients with bulky endobronchial lung cancer. METHODS: Patients with histologically proven non-small cell bronchogenic carcinoma and bulky endobronchial tumours were treated using a combination of PDT (Photofrin, 2 mg/kg) and brachytherapy. Six weeks after PDT, brachytherapy was applied with five fractions of 4 Gy at weekly intervals. Follow up was performed with standard and autofluorescence bronchoscopy and tissue biopsies every 3 months. RESULTS: Thirty two patients were treated. Tumours were extensive with lengths ranging from 10 to 60 mm along the bronchus and estimated volumes ranging from 40 to 3500 mm3. At a mean follow up of 24 months, 26 patients were free of residual tumour and local recurrence. The remaining patients received a second treatment with PDT, brachytherapy, Nd:YAG laser coagulation, or external beam radiation. Distant metastases (lung, lymph node) developed in two of the six patients. Currently, all 32 patients are well. There is no evidence of residual or local recurrent endobronchial cancer in 28 patients and none had severe complications. CONCLUSION: The combination of PDT and brachytherapy for treating patients with lung cancer and extensive endobronchial tumour is safe and, in this study, had excellent therapeutic efficacy.     

Endobronchial photodynamic therapy for the treatment of lung cancer.

After 2 decades of basic research and clinical experience with endobronchial photodynamic therapy, clear indications for its use have arisen. PDT for the treatment of superficial NSCLC is a viable alternative for patients with inoperable lung cancer. Although early indications are that it may be used to spare operable patients an aggressive surgical procedure, this application still should be considered investigational. The standard of care remains surgical resection in the operable patient. PDT may be considered for the palliation of obstructing lesions of the tracheobronchial tree; however, the risk for prolonged sensitivity to sunlight limits its broad application in this patient population. As better screening techniques are introduced, the role of PDT will expand in the future management of superficial lung cancers. Future developments include new photosensitizers with decreased duration of sun sensitivity and greater choice of wavelength to affect depth of penetration, better dosimetry systems for more consistent light delivery and reporting of results, and better light delivery systems for more homogenous distribution of light.     

A controlled trial of Nd-YAG laser vs photodynamic therapy for advanced malignant bronchial obstruction

A prospective randomized study was set up to evaluate the efficacy of photodynamic therapy (PDT) compared with Neodymium Yttrium Aluminium Garnet (Nd-YAG) laser used endoscopically in patients with stage III inoperable lung cancer and substantial (>50%) endobronchial luminal obstruction: of the 26 patients in the study 11 were allocated to Nd-YAG laser treatment (Group I) and 15 to PDT (Group II). Patients were assessed clinically, radiologically, functinally and endoscopically before and at 1 monthly intervals after treatment for 3 months, then 3 monthly when applicable. Age, sex, pulmonary function and mean percentage of bronchial luminal opening before treatment were comparable in the two groups, and not statistically different. At 1 month after treatment all patients had subjective amelioration of their symptoms and objectively responded to treatment by a substantial increase in bronchial luminal opening. There was however a significantly greater improvement in the PDT (Group II) than the Nd-YAG laser treatment Group I (p<0.0006). The bronchial disobliteration was attended by improvement in pulmonary function which again was significantly greater in Group II (PDT) than in Group I (Nd-YAG). It was concluded that endoscopic PDT in patients with extensive lung cancer and major airway obstruction is more effective than Nd-YAG laser treatment.     

Laser treatment of obstructive endobronchial tumors: factors which determine response

To investigate whether computerized tomography (CT) and radionuclide quantitative ventilation-perfusion lung scan add any useful information to a carefully performed endoscopic examination in determining the response of patients with obstructive endobronchial tumors to laser treatment, the findings in 40 patients treated with photodynamic therapy (PDT) or the Nd:YAG laser were analysed. Endoscopic laser treatment was found to be most effective when the tumor was polypoid in appearance bronchoscopically, with little or no submucosal invasion or peribronchial extension seen on CT. When bronchoscopy and CT showed increasing submucosal and/or peribronchial disease, the immediate and long-term response to treatment was poorer. CT provided valuable information regarding the extent of the peribronchial involvement and airway distortion which were often underestimated by bronchoscopy alone. Reduction of regional perfusion out of proportion to ventilation on scintigraphy in the involved lung zone was found to be associated with extensive peribronchial involvement. We conclude that the addition of CT and radionuclide quantitative ventilation-perfusion lung scan to bronchoscopic examination is useful in predicting the response of patients with obstructive endobronchial tumors to laser treatment. Whether PDT or YAG laser is more effective in relieving endobronchial obstruction by tumor awaits a randomized controlled trial.     

Survival after photodynamic therapy to non-pulmonary metastatic endobronchial tumors

BACKGROUND: For the past 15 years we have used photodynamic therapy (PDT) to treat endobronchial tumors. Unfortunately patients who have non-primary lung cancer metastatic to bronchi and who have failed other treatment regimens may not be offered endobronchial tumor management. Thirteen patients with endobronchial tumors metastatic from non-pulmonary primaries were treated with PDT. We: 1) evaluated the effects of PDT on the tumor, the quality of life, and the length of survival; and 2) compared their survival after PDT to that of 27 patients with stage IV primary endobronchial tumors treated with PDT after they failed all other treatment regimens. MATERIALS AND METHODS: Photodynamic therapy was performed using 630-nm light delivered through cylinder diffusing tip quartz fibers passed through the biopsy channel of a flexible bronchoscope after intravenous injection of the photosensitizer dihematoporphyrin ether. One to two days after PDT bronchoscopy was repeated and necrotic tissue was mechanically removed and, if necessary, that site or other new sites were treated. Two days after this another bronchoscopy was performed and the necrotic tissue was mechanically removed. Bronchoscopy was repeated one month after PDT and periodically thereafter as needed to re-treat symptomatic residual tumor. The percent obstruction of the bronchus due to tumor was estimated before and at the end of each bronchoscopy. Clinical effects were evaluated using Wilcoxon signed rank tests for scaled parameters of dyspnea, cough, hemoptysis, and Karnofsky Performance Status (KPS) before and one month after PDT. All patients were followed until their death. RESULTS: The mean percent obstruction due to metastatic non-pulmonary tumors at 38 different endobronchial treated sites decreased from 85% to 13% at discharge after PDT. The 72% mean decrease of obstruction was statistically significant using the Wilcoxon signed rank test (P < .0001). There was a statistically significant improvement in the level of dyspnea (P = .012), hemoptysis (P = .028), cough (P = .027), and KPS (P = .020). Kaplan-Meier survival curves and Mann-Whitney U rank tests showed the median survival of stage IV primary tumor patients (4 months) vs. metastatic tumor patients (14 months) was statistically significant (P = .008). CONCLUSION: PDT of endobronchial metastatic tumors effectively decreased the amount of endobronchial obstruction, and improved the quality of life.     

Laser applications in oral surgery and implant dentistry

Lasers have been used for many years in oral surgery and implant dentistry. In some indications, laser treatment has become state of the art as compared to conventional techniques. This article is a comprehensive review of new laser applications in oral surgery and implant dentistry. One of the most interesting developments over the last years was the introduction of the 9.6-μm CO₂ laser. It has been shown in the recent literature that the use of this new device can preserve tissue with almost no adverse effects at the light microscopic level. In contrast, modifications of approved CO₂ laser therapies of premalignant lesions resulted in higher recurrence rates than the conventional defocused laser technique. However, several studies indicate that other wavelengths such as Nd–YAG (λ = 1,064 nm) or diode lasers (λ = 810 nm) may be also of value in this field. In many other indications, the use of lasers is still experimental. Intraoperatively used photodynamic therapy or periimplant care of ailing implants with the CO₂ laser seems to be more of value than conventional methods. However, further studies are required to assess standard protocols. Over the past years, research identified some new indications for laser treatment in oral surgery and implant dentistry. Moreover, well-known laser applications were defined as state of the art. Nevertheless, further studies are required for laser treatment in oral surgery and implant dentistry. This work was presented in part as a keynote lecture at the 10th Anniversary Meeting of the International Society for Lasers in Dentistry, Berlin/Germany, May 18–20, 2006.     

Pulmonary resection after successful downstaging with photodynamic therapy

Photodynamic therapy (PDT) is a treatment option for lung cancer that involves the administration of a photosensitizing agent and selective, bronchoscopic delivery of light to tumor tissue that has retained the agent. Currently, PDT is used either to treat microinvasive endobronchial nonsmall cell lung cancer (NSCLC) or to palliate patients with completely or partially obstructing endobronchial NSCLC. Herein is a case of PDT that successfully downstaged an obstructing endobronchial NSCLC, thereby enabling a complete resection. At 9 months postoperatively, the patient was treated for a chest wall recurrence with no evidence of disease in the airway or mediastinum.     

Repeated applications of photodynamic therapy on <Emphasis Type="Italic">Candida glabrata</Emphasis> biofilms formed in acrylic resin polymerized

Previous studies have been suggested that photodynamic therapy (PDT) can be used as an adjuvant treatment for denture stomatitis. In this study, we evaluated the effects of multiple sessions of PDT on Candida glabrata biofilms in specimens of polymerized acrylic resin formed after 5 days. Subsequently, four applications of PDT were performed on biofilms in 24-h intervals (days 6–9). Also, we evaluated two types of PDT, including application of laser and methylene blue or light-emitting diode (LED) and erythrosine. The control groups were treated with physiological solution. The effects of PDT on biofilm were evaluated after the first and fourth application of PDT. The biofilm analysis was performed by counting the colony-forming units. The results showed that between the days 6 and 9, the biofilms not treated by PDT had an increase of 5.53 to 6.05 log (p?=?0.0271). Regarding the treatments, after one application of PDT, the biofilms decreased from 5.53 to 0.89 log. When it was done four applications, the microbial reduction ranged from 6.05 log to 0.11 log. We observed that one application of PDT with laser or LED caused a reduction of 3.36 and 4.64 compared to the control groups, respectively (p?=?0.1708). When it was done four applications of PDT, the reductions achieved were 1.57 for laser and 5.94 for LED (p?=?0.0001). It was concluded that repeated applications of PDT on C. glabrata biofilms showed higher antimicrobial activity compared to single application. PDT mediated by LED and erythrosine was more efficient than the PDT mediated by laser and methylene blue.     

Endoscopic laser treatment for bronchogenic carcinoma

The use of laser therapy for endobronchial lesions has met with general enthusiasm. From published series it is difficult to determine specific indications for its use, based upon patients' complaints, locations of tumor, and any concomitant therapies. Most reports do not provide sufficient information to permit adequate comparisons regarding improvement in symptoms and long-term efficacy. Exophytic lesions of the trachea and mainstem bronchi are most amenable to therapy by laser, and improvement in symptoms correlates best with improved patency of large airways. In most patients the major portion of the endobronchial debulking procedure can be performed quickly and safely by physically coring out the exophytic tumor mass with the rigid end of the bronchoscope. A large biopsy forceps can help accomplish this with very little bleeding. The laser can then remove any remaining tumor and produce hemostasis by coagulation of the tumor bed. The major purpose of laser therapy is to lessen or completely relieve symptoms of airway obstruction. Laser therapy to obstructed lobar or segmental bronchi rarely reduces symptoms unless they are associated with post-obstructive pneumonia. When the obstruction is longstanding, laser ablation may fail to establish airway patency. Hemoptysis from exophytic lesions can usually be well controlled. Treatment of lesions that produce extrinsic compression of the trachea or bronchi is of little value. At present, laser therapy is one of several treatments available for neoplastic endotracheal or endobronchial obstruction. Other local therapies include external-beam irradiation, cryotherapy, electrocoagulative therapy, and intraluminal brachytherapy with insertion of afterloading catheters. Most of these modalities are available in large oncologic centers, and it will take the better part of the next decade to identify specific indications for each of these therapies individually and in combination. Currently, Nd:YAG therapy has an established role in the palliative treatment of obstructive endobronchial disease. Response rates to therapy with relief of obstruction are in the range of 80 to 85 per cent. Nd:YAG therapy is easy, quick, and, with proper caution, safe. In the majority of cases it must be repeated on one or several occasions. Photodynamic therapy is now being critically evaluated for the treatment of similar lesions.     

Endobronchial photodynamic therapy for lung cancer

BACKGROUND AND OBJECTIVE: Endobronchial photodynamic therapy (PDT) is a minimally invasive technique for the palliation of major airway obstruction from lung cancer, and for the treatment of endobronchial microinvasive lung cancer. STUDY DESIGN: Results of reported clinical trials were compared, and the author's preliminary results with second generation photosensitizers were also reviewed. RESULTS: A review of the clinical experience with endobronchial PDT is provided. Potential advantages of PDT include the duration of palliation achieved through the delayed cellular effects of PDT within tumor. Side-effects from FDA-approved photosensitizer (Photofrin, Porfimer sodium, Axcan Scandipharm, Montreal, Quebec) include skin photosensitivity. HPPH (2-[1-hexyloxyethyl]-2 devinyl pyropheophorbide) is an example of a second-generation photosensitize that shows promise in the treatment of lung cancer, and appears to be free from significant skin photosensitivity. CONCLUSION: PDT is an effective tool for the palliation of endobronchial lung cancers which obstruct the central airways and is also effective for the treatment of central microinvasive carcinoma and carcinoma in situ of the central airways.     

The outpatient-procedure effectiveness of laser treatments in oncology

The outpatient procedure of CO₂ laser surgery has been recently integrated into the routine activity of the National Cancer Institute, Milan. Specific operative protocols that are codified for laser outpatient selection after adequate staging by pathology are presented. Specific indications for gynecologic disease (preneoplastic disorders, CIN, VAIN, and VIN), and general-surgery neoplastic disorders (soft tissue sarcomas, lip and oral cavity lesions, breast lesions) are described. Details of the safety procedures, rules of application, laser instrumentation accessories and wattages, both with vaporization and excisional technique, are reported. An overall rate of 30% out of the 4,000 cases treated yearly are selected for laser treatment procedures on the basis of the evaluation of real advantages. The general advantages of laser surgical applications such as reduction of bleeding and postoperative pain, early and late complications; no-touch method; and patient acceptability—have been emphasized in the routine outpatient procedures. Reduction of the total costs and of the waiting list for hospitalization by the new procedures are finally considered.     

Photodynamic therapy (PDT) in early central lung cancer: a treatment option for patients ineligible for surgical resection

OBJECTIVES: To review the Yorkshire Laser Centre experience with bronchoscopic photodynamic therapy (PDT) in early central lung cancer in subjects not eligible for surgery and to discuss diagnostic problems and the indications for PDT in such cases. METHODS: Of 200 patients undergoing bronchoscopic PDT, 21 had early central lung cancer and were entered into a prospective study. Patients underwent standard investigations including white light bronchoscopy in all and autofluorescence bronchoscopy in 12 of the most recent cases. Indications for bronchoscopic PDT were recurrence/metachronous endobronchial lesions following previous treatment with curative intent in 10 patients (11 lesions), ineligibility for surgery because of poor cardiorespiratory function in 8 patients (9 lesions) and declined consent to operation in 3 patients. PDT consisted of intravenous administration of Photofrin 2 mg/kg followed by bronchoscopic illumination 24-48 h later. RESULTS: 29 treatments were performed in 21 patients (23 lesions). There was no procedure-related or 30 day mortality. One patient developed mild skin photosensitivity. All patients expressed satisfaction with the treatment and had a complete response of variable duration. Six patients died at 3-103 months (mean 39.3), three of which were not as a result of cancer. Fifteen patients were alive at 12-82 months. CONCLUSION: Bronchoscopic PDT in early central lung cancer can achieve long disease-free survival and should be considered as a treatment option in those ineligible for resection. Autofluorescence bronchoscopy is a valuable complementary investigation for identification of synchronous lesions and accurate illumination in bronchoscopic PDT.     

Anti-microbial photodynamic therapy: useful in the future?

Previous chapters in this volume have focused on fundamental principles and clinical applications of PDT. This chapter will attempt to outline emerging areas of research to identify some new applications that may become useful in the future in clinical practise. The worldwide rise in antibiotic resistance has driven research to the development of novel anti-microbial strategies. Cutaneous diseases caused by MRSA are ideally suited to treatment by anti-microbial photodynamic therapy for eradicating localized infections and for modulating wound healing due to the ability to deliver photosensitizer and light with topical application. The use of photosensitizer and light as an anti-microbial agent against periodontal microbial biofilms should also represent an attractive method of eliminating oral bacteria. Suitable light sources, laser light and non-coherent light will be briefly covered. This chapter will focus on some aspects of anti-microbial photodynamic therapy that appear to be promising for dermatological indications and inactivation of pathogenic bacteria within the oral cavity.     

Effect of Photodynamic Therapy on the Mechanical Strength of Healed Rodent Skin Incisions

. A factor that might complicate the use of intraoperative photodynamic therapy (PDT) is a possible adverse effect on normal tissue recovery. In this study, rats with experimental skin incisions received intraoperative PDT (10 mg/kg haematoporphyrin derivative, 180 J/cm² laser light), immediately followed by closure. Healing was evaluated by tensile strength assessment of the incisions 21 days after PDT. No significant differences between the PDT-treated group and control groups were found. We therefore concluded that with respect to healing of skin incisions in rats, intraoperative PDT is not contraindicated. Paper received November 1996; accepted after revision June 1997.     

Current role of laser therapy in thoracic diseases

Conclusions Laser therapy has become an important tool in the thoracic specialists' armamentarium. It has added a new dimension to using the bronchoscope, thoracoscope, and in performing pulmonary resections with a remarkably low rate of complications that is perhaps related to the learning curve of each operator. In addition to the use of thermal effects of laser (mainly with use of Nd:Yag) for tracheobronchial obstruction, pulmonary resection with adequate parenchymal preservation, and treatment of air leaks and bullae, the use of photosensitisers is making it possible to diagnose and treat early lung cancer, palliate unresectable endobronchial carcinoma, reduce extent of lung resection, and control JLTBP with potential for cure. The combined use of Nd:Yag laser and PDT with other modalities like brachytherapy, hyperthermia, and external beam radiation awaits further studies.     

Effectiveness of different light sources for 5-aminolevulinic acid photodynamic therapy

Many medical applications, including photodynamic therapy for cancer (PDT), involve the use of lasers. However, the coherence of laser light is not necessary for PDT, and attempts have been made to construct non-coherent light sources for PDT, which are relatively inexpensive, stable and easy to operate, require simple maintenance but differ fundamentally from the lasers in their output characteristics. In the present work we compared two clinically used lamps, CureLight1, which is a broadband source (560–740 nm) based on a filtered halogen lamp, and CureLight2, which is a narrowband source based on light-emitting diodes (LEDs), with respect to several parameters of crucial significance for PDT efficiency in vivo: (a) depth of action in tissues, (b) heating effects, (c) pain generation, (d) photodegradation of PpIX in solution, in cells and in mouse skin and (e) photo-inactivation of cells in vitro. We conclude that CureLight2 (LED), relative to CureLight1 (halogen) has deeper PDT action in tissue, similar efficiency for bleaching PpIX in mouse skin, better efficiency for bleaching PpIX in cells and solutions and good efficiency for inactivating cells in vitro. CureLight2 gives less heating of the tissue and less pain in unsensitised human skin. All these differences are related to difference in the spectra of the lamps. Thus, PDT light sources with emissions that are visually similar have significantly different photobiological properties.     

Non-PDT Uses of lasers in oncology

The use of therapeutic lasers depends on four basic laser-tissue interactions; photothermal, photochemical (PDT), mechanical and ablative. There is no place for mechanical and ablative interactions in oncology; PDT will be the subject of a further review and the subject of this review is therefore the photothermal reaction. Thermal lasers have been in routine use in oncology for the last 10–15 years. These lasers, emitting in the visible or infra-red parts of the spectrum, are used to produce three basic effects; hyperthermia, coagulation and vaporization. Other energy sources beside lasers can also be used to produce these tissue effects but lasers seem to possess certain basic advantages. In comparison with monopolar or bipolar diathermy and heater probes, lasers can deliver more power, more accurately at the target tissue with better control of damage and a wider range of effects. In comparison with microwave and ultrasound therapy, lasers are again more precise and can be used with more compact and accurate delivery devices. In gastroenterological surgery (as opposed to endoscopy), neurosurgery and gynaecology, laser light can be delivered via a handpiece to cut and coagulate. In ENT and also some applications of gynaecology lasers can also be used via a microscope. In endoscopic surgery laser light is delivered through an optical fibre within the endoscope—this for the time being precludes the use of the CO₂ laser for these applications. More recently, the laser fibre can be placed directly within tumour tissue for interstitial thermal therapy of liver metastases, pancreatic tumours and brain tumours. The future use of thermal lasers in oncology depends very much on the results of properly controlled comparative studies against PDT and non-laser thermal devices; in addition their use may well be widened to include some curative procedures; up until now their use has very much been restricted to palliative therapy except where they are used as an adjunctive cutting device alongside conventional curative surgery.This paper is a revised and updated version of a talk given at Lasers in Medicine: Facing 1992, the final meeting of the European Community Concerted Action Programme on Medical Laser Development, in Amsterdam 29 November–1 December 1991.     

PHOTODYNAMIC THERAPY IN THE TREATMENT OF SUBCUTANEOUSLY IMPLANTED HUMAN BLADDER TUMOUR

Photodynamic therapy (PDT) is an experimental treatment modality for malignant tumours. The effect of PDT with haematoporphyrin derivative (HpD) was studied using a human bladder tumour (BL-17) which was implanted subcutaneously (s.c.) into immunodeficient Balb/c nude mice. This model is only suitable for short-term investigation of PDT because of the high mortality that arises due to the immune deficiency of the animals. In a short-term observation (2 weeks post-treatment), HpD sensitized PDT was effective in the control of tumour growth, with 71 % of tumours cured. The effect of PDT was found to be highly dependent on doses of HpD and/or the activating laser light. The comparison of PDT effects of the gold metal vapour laser (GMVL) and argon ion pumped dye laser (AIPDL) indicated that no significant difference exists between these two different laser sources for PDT. The irradiation with laser light alone and the administration of HpD alone had no significant effect on tumour growth.