Photodynamic therapy for endobronchial malignant disease: a prospective fourteen-year study.

BACKGROUND: After intravenous injection, the photosensitizer dihematoporphyrin either is selectively retained in tumor cells. This photosensitizer absorbs 630 nm wavelength light energy and produces a singlet oxygen that destroys the tumor. Photodynamic therapy was performed on endobronchial tumors with the use of light generated by an argon dye laser system delivered through cylinder diffusing tip quartz fibers passed through the biopsy channel of a flexible endoscope. OBJECTIVES: Our objectives were to determine factors affecting survivals, benefits, and complications. METHODS: From 1982 to May 1996, photodynamic therapy was performed on 175 patients with endobronchial tumors. Sixteen had stage I disease, 9 stage II, 42 stage IIIA, 64 stage IIIB, and 44 stage IV. All were followed up until death or November 1996. RESULTS: Multivariate analysis of survival of the effects of age, sex, race, histologic features, Karnofsky Performance Status, and clinical stage showed the clinical stage (p < 0.0001) to be the most statistically significant factor. Sixteen patients with stage I disease had a 93% 5-year disease-related estimated survival. Median (months) survivals were as follows: stage I = not reached; stage II = 22.5; stage IIIA = 5.7; stage IIIB = 55; and stage IV = 5.0. Performance status does become significant when it reaches 50 but was not significant for stages I or II. CONCLUSIONS: Photodynamic therapy may be considered as an alternative treatment for patients under consideration for surgical treatment for stage I carcinoma in whom the risk of surgery is high. The length of palliation for patients with noncurative disease was equal to or better than that reported historically for most other treatment regimens.

Nd:YAG laser and photodynamic therapy for esophageal and endobronchial tumors under general and local anesthesia. Effects on arterial blood gas levels.

STUDY OBJECTIVE: Our objective was to determine the respiratory and acid-base metabolism response to endoscopic laser surgery for obstructive tumors, as related to the duration and different types of endoscopy, anesthesia, and laser treatment. DESIGN: The design was a case-control, cohort analytic, nonrandomized controlled survey of case series before and after endoscopic procedures. SETTING: A referral-based surgery and oncology practice at one hospital's laser center. PATIENTS: We studied a sequential sample of 82 patients in the age range from 35 to 92 years, with malignant and benign, primary and metastatic, partially and completely obstructing esophageal (15 patients) and endobronchial (67 patients) tumors. INTERVENTIONS: A total of 229 diagnostic, laser treatment, and follow-up endoscopic procedures was performed under general or local anesthesia (46 esophagoscopies and 183 bronchoscopies). The latter group consisted of 29 cases of general and 154 cases of local topical anesthesia. The last group involved 37 diagnostic and toilet bronchoscopies, 86 cases of YAG-laser tumor ablation, and 31 cases of PDT. MEASUREMENTS AND MAIN RESULTS: Direct-reading electrode measurements of arterial blood, sampled before and immediately after the endoscopic procedure, revealed statistically significant (p less than 0.001) increases in PaCO2 (200 of 229 cases) and decreases in pH (195 of 229 cases) and PaO2 (215 of 229 cases). These findings were similar after bronchoscopy and esophagoscopy, general and local anesthesia (only the decrease in pH was less pronounced in the latter case), and explorative endoscopies and different laser treatments and did not correlate with the total duration of the procedure within the wide time range of 7 to 210 minutes. The initial preoperative level of PaCO2 was considerably higher and the level of PaO2 was significantly lower in patients with endobronchial tumors, as compared to patients with esophageal cancer. A strong, inverse linear relationship was found between the perioperative changes in PaO2 and its initial level and between PaCO2 and pH changes. CONCLUSIONS: The PDT for esophageal and endobronchial malignancies is no more harmful for acid-base metabolism and respiratory functions than YAG-laser tumor ablation or any other common, nonlaser endoscopic procedure.

Pathogenesis of acute ischemic mitral regurgitation in three dimensions.

Changes in the geometric and intravalvular relationships between subunits of the ovine mitral valve were measured before and after acute posterior wall myocardial infarction in three dimensions by means of sonomicrometry array localization. In 13 sheep, nine sonomicrometer transducers were attached around the mitral anulus and to the tip and base of each papillary muscle. Five additional transducers were placed on the epicardium. Snares were placed around three branches of the circumflex coronary artery. One to 2 weeks later, echocardiograms, dimension measurements, and left ventricular pressures were obtained before and after the coronary arteries were occluded. Data were obtained from seven sheep. Coronary occlusion infarcted 32% of the posterior left ventricle and produced 2 to 3+ mitral regurgitation by Doppler color flow mapping. Multidimensional scaling of dimension measurements obtained from sonomicrometry transducers produced three-dimensional spatial coordinates of each transducer location throughout the cardiac cycle before and after infarction and onset of mitral regurgitation. After posterior infarction, the mitral anulus enlarges asymmetrically along the posterior anulus, and the tip of the posterior papillary muscle moves 1.5 +/- 0.3 mm closer to the posterior commissure at end-systole. The posterior papillary muscle also elongates 1.9 +/- 0.3 mm at end-systole. The left ventricle enlarges asymmetrically and ventricular torsion along the long axis changes. The development of postinfarction mitral regurgitation appears to be the consequence of multiple small changes in ventricular shape and contractile deformation and in the spatial relationship of mitral valvular subunits.

Photodynamic therapy to treat tumors of the extrahepatic biliary ducts. A case report.

The poor survival rate of patients with extrahepatic bile duct tumors is well documented. Over the course of 4 years, we treated a white woman with diabetes diagnosed with histologically proven adenocarcinoma of the common bile duct with six injections of dihematoporphyrin ether followed by seven photodynamic therapy treatments to the biliary duct. As of July 1989, the patient was still alive, was not jaundiced, and had a Karnofsky performance status of 70. No changes occurred in any blood chemistry value from the time of injection to the time of photodynamic therapy. Of the transient elevations of some blood chemistry values and the white blood cell count, which occurred within 24 to 48 hours after photodynamic therapy, only those of alanine aminotransferase, aspartate aminotransferase, and amylase were significant.

Photodynamic therapy for cutaneous and subcutaneous malignant neoplasms.

Twenty-seven patients with cutaneous and subcutaneous malignant neoplasms were treated with photodynamic therapy. Therapy was administered to 248 areas during a total of 72 separate treatment sessions after patients received a total of 45 injections of sensitizer. Seven patients had basal cell carcinoma, three had squamous cell carcinoma, three had malignant melanoma, one had liposarcoma, and 12 had breast cancers. One patient had Bowen's disease. Treatment was given either by surface radiation or interstitially. One month after treatment, 48 (67%) of the treatment sessions resulted in a complete response (no clinical evidence of tumor), and 19 (26%) resulted in a partial response (greater than 50% reduction in the number or size of tumors). Fifteen patients were examinable 12 months after treatment, and in this group, 31 treatment sessions were evaluated as a complete response one month after therapy, 15 (48%) of which retained this status at one year after treatment. By comparing the ability of different light-delivery instrumentation, it was concluded that the Yellow Springs radiometer (Yellow Springs Instruments, model 65A, Yellow Springs, Ohio) provided the most reliable spot power density readings. Straight-tipped fibers are nonhomogeneous and can result in overtreatment of the central area with necrosis and pain and in undertreatment of the periphery.

Photodynamic therapy for esophageal tumors.

Between 1982 and 1987, 40 patients with esophageal tumors (19 adenocarcinomas, 19 squamous carcinomas, and two melanomas) in whom conventional treatments were unsuccessful were treated with photodynamic therapy (PDT) after injection with either hematoporphyrin derivative or dihematoporphyrin ether. Patients underwent endoscopy again two to three days and one month after PDT and as needed when symptoms recurred. At one month, the average minimal diameter opening of 28 assessable tumors increased from 6 to 9 mm. Of the 35 patients who could be evaluated one month after PDT, the average improvement in food intake was from a liquid to a soft diet. Average survival time (from time of first treatment) was 7.7 months (n = 17) for adenocarcinoma, 5.8 months (n = 12) for squamous cell carcinoma, and 25 months (n = 2) for melanoma. Two patients with stage I adenocarcinoma were alive with no evidence of disease at 11 and 23 months. One patient with stage I squamous cell cancer died 18 months after PDT, with recurrence of tumor above the treated area noted eight months after treatment. One patient with stage I melanoma died of a synchronous colon cancer 31 months after PDT, with no evidence of residual melanoma.

Palliation of esophageal malignancy with photodynamic therapy.

Sixteen patients with esophageal malignancies received photodynamic therapy after 3 mg of hematoporphyrin derivative (Photofrin I) or 2 mg of Photofrin II per kilogram of body weight was injected intravenously two to six days prior to treatment. A tunable dye argon laser system delivered 630 nm light through quartz fibers passed through the biopsy channel of a gastroscope. All patients obtained improvement in swallowing, usually from total obstruction or clear liquids only to a regular diet within three weeks and with new techniques, at least liquids within three days of treatment. Karnofsky Performance Status (KPS) and esophageal grades were measured before treatment, 1 month following treatment, and periodically until death. Ten patients died an average of 3.7 months after initial treatment (range, 0.6 to 19 months). Six patients are alive at 11, 10, 5, 2.5, 2 months, and 1 month after treatment. The median survival of 12 patients treated more than 6 months ago was 6.5 months and of 9 patients with an initial KPS higher than 30, 8.1 months.

Effect of light dose on the photodynamic destruction of endobronchial tumors.

The effects of various light power densities (milliwatts per centimeter of diffusing fiber [mW/cf]) and light doses (joules per centimeter of diffusing fiber [J/cf]) on the effectiveness of photodynamic therapy to endobronchial and tracheal tumors were evaluated at 46 different sites. All patients had squamous cell carcinoma or adenocarcinoma. They received 2 mg/kg body weight dihematoporphyrin ether intravenously 2 days before treatment bronchoscopy. Only one light treatment was delivered to the site. Patients were treated with diffusing cylinder light tips and underwent toilet bronchoscopy 2 days after photodynamic therapy. The percentage of obstruction was estimated before and after treatment and before and after toilet bronchoscopy. There was no difference between the effects resulting from power densities of 400 and 500 mW/cf, nor were there differences in the reactions between squamous cell carcinoma and adenocarcinoma. The amount of tumor that could be removed at the end of the treatment bronchoscopy, the amount of reobstruction by secretions and exudate seen at toilet bronchoscopy, and the final percent decrease in obstruction at the end of toilet bronchoscopy were proportional to the light dose. Because the final percentage decrease in obstruction plateaued at light doses of 400 to 500 J/cf and there was no statistically significant difference between 400 and 500 J/cf, we recommend using a power density of 500 mW/cf and a light dose of 400 J/cf during photodynamic therapy.

Photodynamic therapy for esophageal malignancy: a prospective twelve-year study.

BACKGROUND: We wanted to determine factors affecting survival rates of benefits to, and complications in patients with esophageal cancer treated with photodynamic therapy. METHODS: From 1982 to January 1994, we used photodynamic therapy to treat 77 patients with esophageal carcinoma and evaluated survival to July 1994. All patients had failed, refused, or were ineligible for surgical intervention, ionizing radiation therapy, or chemotherapy. RESULTS: The only significant variable affecting survival was clinical stage. Median survival after photodynamic therapy was as follows: all patients, 6.3 months (mean survival, 9.2 months); stage I, not reached; stage II, 12 months; stage III, 6.2 months; and stage IV, 3.5 months. For stages III and IV, a Karnofsky performance status of 70 or higher had a significant effect. For stage III, the median survival was 6.3 months when the Karnofsky performance status was equal to or greater than 70 and 3.5 months when it was less than 70. For stage IV, the median survival was 5.5 months when the Karnofsky performance status was equal to or greater than 70 and 2.5 months when it was lower than 70. Seven stage I patients with no treatment prior to photodynamic therapy had an estimated 5-year survival rate of 62%. Three patients with stage I invasive adenocarcinoma and Barrett's mucosa diagnosed when they underwent endoscopy for dysphagia were alive with no evidence of disease 17, 44, and 59 months after photodynamic therapy. CONCLUSIONS: Photodynamic therapy for esophageal carcinoma caused minimal complications and no procedure-related deaths. Photodynamic therapy can be considered an alternative treatment for patients with Barrett's esophagus with severe dysplasia or patients with stage I carcinoma who are under consideration for operation but are high surgical risks. The length of palliation for patients having "noncurative" treatment was equal to or better than that reported historically for most other treatment regimens.

Photodynamic therapy: a review.

Photodynamic therapy (PDT) of malignant tumours is a new technique for treating cancers. After intravenous injection, a photosensitiser is selectively retained by the tumour cells so after time there is more sensitiser in the tumour than in the normal adjacent tissue. The photosensitiser must be able to absorb the wavelength of light being delivered to it, and the amount of light getting to the photosensitiser depends on the characteristics of the tissue it passes through. When exposed to light with the proper wavelength, the sensitiser produces an activated oxygen species, singlet oxygen, that oxidises critical elements of neoplastic cells. Because there is less sensitiser in the adjacent normal tissue, less reaction occurs to it. Since this is an entirely different process, the use of chemotherapy, ionising radiation or surgery does not preclude the use of PDT. Also, unlike ionising irradiation, repeated injections and treatments can be made indefinitely. Different molecules and atoms absorb different wavelengths of energy. Since the light energy must be absorbed to start the photochemical reaction, the absorption spectrum of the photosensitiser determines the wavelength used to initiate the reaction. However, this can be qualified by the tissue the light has to travel through to get to the photosensitiser. The photosensitiser porfimer sodium has a peak absorption in the area of 405 nm (blue-violet) and a much lower absorption peak at 630 nm (red). However, because the longer red wavelength penetrates tissue deeper than 405 nm, we use the red wavelength, usually delivered from a laser system. This permits coupling of the red light beam to quartz fibres which can then be used with modifications to treat external surface tumours, inserted interstitially directly into large tumours, passed though any endoscope to treat intraluminal tumours, or inserted behind the retina to treat tumours of the retina. Twenty years after the pioneering work of Dr. Thomas Doherty, the US Food and Drug Administration (FDA) has approved the use of porfimer sodium for photodynamic therapy of endobronchial and oesophageal tumours. Research continues towards approval for management of skin cancers and metastatic cutaneous and subcutaneous breast cancers. The realisation that one of the mechanisms of photodynamic therapy is thrombosis of vessels led to the development of verteporfin to treat macular degeneration. Multiple other areas are being investigated as well as new photosensitisers. Photodynamic therapy is an entirely new treatment modality and its development can be likened to that of the discovery of antibiotics. This is just the beginning, and its possible uses are only limited by the imagination.

Photodynamic therapy of endobronchial and esophageal tumors: an overview.

From 1982 to March 1996 we treated 211 patients with endobronchial tumors and 106 patients with esophageal tumors using photodynamic therapy (PDT) in an ongoing study of the efficacy of PDT. This paper is an overview of our results and the evolvement of our current techniques for using PDT.

Photodynamic therapy of skin and esophageal cancers.

We report on 27 patients with cutaneous and subcutaneous malignancies and 40 patients with esophageal tumors treated with photodynamic therapy (PDT). Of those patients treated for skin tumors, seven had basal cell, three squamous cell, three malignant melanoma, one liposarcoma, and twelve had breast cancers. One patient had Bowen's disease. Treatment was given either by surface radiation or interstitially. One month after treatment, 48 (67%) of the treatment sessions resulted in a complete response (no clinical evidence of tumor) and 19 (26%) resulted in a partial response (more than a 50% reduction in the number or size of tumors). Of the 15 patients evaluable 12 months after treatment, 31 treatment sessions were evaluated as complete response 1 month after therapy, 15 (48%) of which retained this status at 1 year posttreatment. Esophageal tumors were as follows: 19 adenocarcinomas, 19 squamous carcinomas, and 2 melanomas. Most patients were reendoscoped 2 to 3 days after PDT and repeat endoscopies were performed 1 month after PDT and as needed when symptoms recurred. The goal of therapy was to improve the patient's ability to swallow. At 1 month, the average length of all tumors decreased from 7.0 to 6.1 cm, and the average minimal diameter opening increased from 6 to 9 mm. Of the 35 patients who were evaluable 1 month after PDT, the average diet grade improved from 16 to 32 (i.e., improvement in food intake from a liquid to a soft diet).

Photodynamic therapy for obstructive esophageal malignancies.

Objectives Determine factors affecting survival rates, benefits and complications of patients with obstructive esophageal cancer treated with photodynamic therapy (PDT). Methods From 1982 to January 1998, we used PDT to treat 140 patients with obstructive adeno or squamous carcinoma and evaluated survival up to November 1998. All patients had failed, refused, or were ineligible for surgery, ionizing radiation or chemotherapy. The effect of different variables on survival was estimated using multivariate analysis. The Karnofsky Performance Status (KPS), weight, diet and complications were recorded and biopsies and brushings were taken at each endoscopy. At the beginning and end of each endoscopy the minimal diameter open of the esophagus, and the length, thickness and color of the tumor were recorded. Edema, exudate, bleeding, and mucositis were evaluated and recorded on an ordinal scale.Results The only significant variable affecting survival was the clinical stage. The median survival after PDT for all patients was 6.5 months (mean = 13.9). Kaplan-Meier survival after PDT curves were statistically significantly different when stratified by the clinical Stage at the time of PDT (p < 0.0001). Median survival (months) were for: Stage I = 56; Stage II = 12; Stage III = 6.5; Stage IV = 3.5. Analysis of each individual stage showed the KPS was the only confounding variable with a statistically significant effect on survival after PDT and this was only for Stages III and IV. The most significant effect occurred when the KPS was >/= 70. For Stage III the median survival when the KPS was >/= 70 was 7.7 months and for a KPS < 70 it was 5.0 months (p = 0.0001). For Stage IV the median survival when the KPS was >/= 70 was 5.5 months and for a KPS < 70 it was 2.5 months (p = 0.0002). The mean minimum diameter open before PDT was 6.2 mm (median 6.0mm) and at the end of the PDT treatment endoscopy 11.1 mm (median 12.0 mm) for a mean increase in the minimum diameter open of 4.9 mm (median 5.0 mm) This was statistically significant using paired t-tests (p < 0.0001).Conclusions Photodynamic therapy for esophageal carcinoma caused minimal complications and procedure related mortality. Complete obstruction can be relieved by the end of the PDT endoscopy. The length of palliation for "non-curative" patients was equal to or better than that reported historically for most other treatment regimens.

Development of a laser center.

Since Grant Hospital obtained its carbon dioxide laser in December 1981, another CO2 laser and tunable dye, argon, and neodymium:yttrium-aluminum-garnet lasers have been added to its Laser Center. A multidisciplined approach to developing the hospital's Laser Center has been successful, with an average of 100 laser operations performed each month by oncologic surgeons, gynecologists, general surgeons, neurosurgeons, dermatologists, gastroenterologists, otolaryngologists, and urologists. This article relates to the rationale for establishing a laser center and the steps in its development.

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.

The immediate effects of different light doses for photodynamic therapy of endobronchial tumors.

The immediate effects of different power densities and light dosages were determined on 77 sites of endobronchial tumors in 28 patients. All received 2 mg/kg of dihematoporphyrin ether 2 days prior to photodynamic therapy (PDT). Light (630 nm) was delivered with a tunable dye laser system through quartz fibers modified at the delivery end to disperse the light perpendicular to the axis of the fiber. The degree of obstruction, tumor consistency, edema, exudate, bleeding, amount of relief of obstruction, and complications were estimated before and at the end of treatment and toilet bronchoscopy. The authors found no difference in the effect of power densities of 400 mW/CF or 500 mW/CF when compared to the same total light dosage. However, 700 mW/CF produced coagulation of fibrin collection on fibers. By the end of the treatment, bleeding tumors did not bleed enough to prevent removal, although they were bleeding prior to PDT. The only complication during or after the increased light dosages was the formation of exudate. Hard tumors became soft and edematous by the end of the treatment permitting immediate removal of some tumors. At the time of discharge, the authors achieved greater than 50% reduction of obstruction, that is, complete and partial responses, in 64% of the patients with 200 J/CF, 71% with 300 J/CF, 82% with 400 J/CF, 77% with 500 J/CF, and 100% with 700 J/CF. Overall, they observed a 74% response, again, complete and partial response, at discharge.

Clinical experience with CO2 laser vaporization of neoplasm.

The use of the CO2 laser in the treatment of two types of cancer, advanced ovarian carcinoma and tumors of the liver, has proven to be a useful form of adjunctive therapy. It has proven effective in vaporizing ovarian tumors ranging in size from 5 to 20 mm and liver tumors ranging in size from 1 to 4 cm. This modality is preferable to traditional excision-and-repair techniques, which are far more traumatic and may result in considerable loss of blood.