Gunter Thomas

Phase I study of debulking surgery and photodynamic therapy for disseminated intraperitoneal tumors

PURPOSE Phase I study designed to determine the maximum tolerated dose of intraoperative photodynamic therapy (PDT) at laparotomy/debulking surgery in patients with refractory or recurrent, disseminated intraperitoneal tumors. METHODS AND MATERIALS Patients received dihematoporphyrin ethers (DHE) 1.5-2.5 mg/kg by i.v. injection prior to surgery. Patients resected to < or = 5 mm of residual disease underwent laser light delivery to all peritoneal surfaces. RESULTS Fifty-four patients entered the study. Thirty-nine underwent resection and light delivery/PDT. PDT dose was escalated by increasing DHE from 1.5 to 2.5 mg/kg, shortening the interval between DHE injection and surgery from 72 to 48 hr, and increasing the light dose. Initially, 630 nm red light alone was used. In this group, PDT of 2.8-3.0 J/cm2 induced small bowel edema and resulted in 3 small bowel perforations after bowel resection or enterotomy. Further light dose escalation, however, was achieved by switching to less penetrating 514 nm green light to the bowel/mesentery. In later patients, whole peritoneal PDT was supplemented with boost doses of 10-15 J/cm2 red light or 5-7.5 J/cm2 green light to high risk areas. Small bowel complications were not seen after switching to less penetrating green light. Dose limiting toxicities occurred in 2 of 3 patients at the highest light dose of 5.0 J/cm2 green light with boost. These patients had pleural effusions that required thoracentesis and postoperative respiratory support for 7-9 days, while one had a gastric perforation. At potential follow-up times of 3.8-43.1 months (median 22.1 months), 30/39 patients are alive and 9/39 are free of disease. CONCLUSION The maximum tolerated dose of intraoperative PDT following debulking surgery performed 48 hr after intravenous administration 2.5 mg/kg DHE is 3.75 J/cm2 of 514 nm green light to the entire peritoneal surface with boosts to 5.0-7.5 J/cm2 of 514 nm green light or 10-15 J/cm2 of 630 nm red light to sites of gross disease encountered at surgery.

Intrapleural Photodynamic Therapy: Results of a Phase I Trial

AbstractBackground: The management of pleural neoplasms, specifically mesothelioma, remains difficult. We performed a phase I trial in 54 patients with isolated hemithorax pleural malignancy to determine (a) the feasibility of intraoperative, intrapleural photodynamic therapy after debulking surgery; (b) the influence of light dose/sensitizer interval on postoperative morbidity in order to define the photodynamic therapy (PDT) maximal tolerated dose (MTD); and (c) whether first order dosimetry could be applied to this complex geometry. Methods: Cohorts of three patients were given escalating intraoperative light doses of 15–35 J/cm2 48 h after i.v. delivery of 2.0 mg/kg Photofrin II (Quadra Logic Technologies, Vancouver, British Columbia, Canada), and then escalating light doses of 30–32.5 J/cm2 after a 24-h sensitizer/operation interval. Twelve patients could not be debulked to the prerequisite 5 mm residual tumor thickness. The remaining 42 patients underwent 19 modified pleuropneumonectomies, five lobectomy-pleurectomies, and 18 pleurectomies. Intrapleural PDT was delivered using 630 nm light from two argon pump-dye lasers, and real-time and cumulative light doses were monitored using seven uniquely designed, computer-interfaced photodiodes. Results: There was one 30-day mortality from intraoperative hemorrhage. In the 48-h sensitizer/operation group (n=33), possible PDT-related complications included an empyema with late hemorrhage in one of three patients at 17.5 J/cm2 and a bronchopleural fistula at 35 J/cm2. At each of these light doses, three additional patients were treated without complication. Two patients subjected to 24-h sensitizer dosing and 32.5 J/cm2 developed esophageal perforations after pleuropneumonectomy at identical sites. The MTD was declared as 30 J/cm2 light with a 24-h dosing interval when none of the six patients (three original, three repeat) at that level developed toxicity. Conclusions: These data demonstrate that resection and intrapleural PDT can be performed safely with currently available sensitizers and lasers. Phase II and III trials are now warranted at this MTD in a homogeneous population of patients with pleural malignancies.

Photodynamic therapy for chest wall recurrence in breast cancer

Photodynamic therapy is the use of a sensitizer (dihematoporphyrin ethers) which is preferentially retained in tumor cells and activated by subsequent light delivery resulting in a selective tumoricidal effect. Between 1986 and 1989, we treated 20 patients with photodynamic therapy for chest wall recurrence of breast cancer. Responses were seen (20% complete response, 45% partial response, 35% no response), but the duration of response was short (average 2.5 months). Complications, in decreasing frequency, included pain, ecchymoses, blistering, ulceration and necrosis in the area of tumor involvement on the chest wall. One patient required skin flap reconstruction for full thickness necrosis. A limitation to this mode of therapy is that the sensitizer currently used is activated by light at a wavelength of 630 nm. This light can penetrate to a tissue depth of only 0.5 to 1.0 cm; thus, deeper disease cannot be treated. Future research must focus on the development of a clinically useful photosensitizer that can be activated by light at longer wavelengths and thereby achieve deeper tissue penetration. This would greatly expand the patient population for which this therapy is useful.

Phase I trial of photo dynamic therapy in the treatment of recurrent superficial transitional cell carcinoma of the bladder

Abstract Objectives A Phase I trial of photodynamic therapy (PDT) in the treatment of superficial transitional cell carcinoma (TCC) of the bladder was performed. Methods Twenty patients with recurrent superficial TCC of the bladder after receiving a mean of 2.6 (range 1 to 6) courses of intravesical therapy were treated with PDT. The photosensitizer Photofrin II dose was 1.5 or 2.0 mg/kg. A 630-nm intravesical red laser was used to activate the photosensitizer 2 days after administration of Photofrin II. A 0.01 % intralipid solution was used as a bladder-filling medium to scatter light and achieve more homogeneous light distribution. Light doses from 5.1 to 25.6 J/cm 2 (total dosage 1500 to 5032 J) were used to illuminate the bladder. Results Twenty patients underwent 21 treatments with PDT. Complications included asymptomatic reflux in 4 patients. One other patient, treated at the highest total light dose, experienced bladder contraction and fibrosis. Nine patients (45%) had no tumor evident at cystoscopy, on random biopsies, or in urinary cytology at the 3-month evaluation after treatment. Four patients remained without recurrent disease for 23 to 56 months. Sixteen of 20 (80%) patients experienced recurrence, and 8 of the 16 underwent cystectomy. Conclusions An intravenous photosensitizer dose of 1.5 mg/kg Photofrin II followed by light energy in the range of 13 J/cm 2 (total light dose 2500 to 3250 J) was defined as a safe treatment parameter and resulted in tumor responses. With present technologies, administration of PDT requires careful dosimetry.

Threshold for Lens Damage During Q switched Nd:YAG Laser Iridectomy: A Study of Rhesus Monkey Eyes

Clinical and pathologic examinations were performed after 18 iridectomies had been created in six eyes of three rhesus monkeys using increasing Q-switched neodymium (Nd):YAG laser energy, pulses per burst, and number of bursts. Treatment parameters bracketed the threshold for lens damage during iridectomy. Iridectomy with one or two bursts of one or two Q-switched pulses at 5 to 6.2 mJ per pulse was achieved without lens damage. Slight increase of pulse energy or an increase to three pulses per burst (without pulse energy increase) caused local damage to the underlying lens. Marked increase of any of the treatment parameters caused slightly larger iridectomies and slightly larger, localized damage of the underlying lens. Synechiae developed between the monkey posterior iris surface at the iridectomy and the damaged area in 80% of the lens lesions. In monkeys, the small pulsed laser iridectomies created with pulses of energies up to 6.5 mJ became occluded during the healing process.

Endothelial Damage Thresholds for Retrocorneal Q-switched Neodymium:YAG Laser Pulses in Monkeys

Laser pulses were focused within 1 mm of the rhesus monkey corneal endothelium using the Coherent Model 9900 laser at energies of 3, 6, 9, and 12 mJ. Sixteen slightly off-axis pulses were applied with no contact lens on the eye. Corneal damage was studied clinically and by scanning electron microscopy. Q-switched pulses of 12 mJ or less are not likely to damage the cornea if focused more than 0.75 mm from the endothelium. The retrocorneal focal distance for a 50% incidence of endothelial damage for 6, 9, and 12 mJ pulses was found to be less than 0.5 mm. For 3 mJ pulses, it was less than 0.25 mm. The severe early effect of suprathreshold pulses is edema of endothelial cells in a 0.2- to 0.6-mm diameter circular zone surrounding a small central pit through Descemets membrane. At two months, irregular enlargement of endothelial cells surrounding and partially covering the persistent pit exists at sites of severe damage. The extent of the longer-term change is proportional to the severity of the original insult, but in no case was there clinically significant, persistent damage in the healed corneas.

Intrathoracic photodynamic therapy : a canine normal tissue tolerance study and early clinical experience

Surgery with intraoperative photodynamic therapy (PDT) has the potential to improve the treatment of pleural malignancies. Before embarking on such treatment in humans, however, thoracic tissue tolerance to PDT was studied.

Histopathology of Neodymium:YAG Laser Iridectomy in Humans

Fifteen peripheral iridectomy specimens were obtained, with informed consent, from patients with primary narrow angle glaucoma, after previous neodymium:YAG (Nd:YAG) laser iridectomy. The iridectomies were performed three hours to ten weeks after laser application. Iridectomy specimens were examined by scanning and/or transmission electron microscopy. Early effects of the Nd:YAG laser on the iris were mild hemorrhage and fibrinous aggregates. There were no inflammatory cell infiltrates. At later time intervals (up to 2 months post-laser treatment) the holes showed irregular thickness of iris pigment epithelium at the margins, and tissue atrophy limited to the immediate margins of the hole. Elsewhere the iris was structurally intact. The diameter of the holes varied from 60 to 500 microns. The larger holes corresponded to cases that had received more application shots.

Endothelial Damage From Retrocorneal Mode-locked Neodymium:YAG Laser Pulses in Monkeys

Laser pulses were focused 0.85 to 1.60 mm from the rhesus monkey corneal endothelium using a mode-locked laser at 3.3 and 4.5 mJ. Sixteen slightly off-axis pulses were applied with no contact lens on the eye. Corneal damage was studied clinically and by scanning electron microscopy. The retrocorneal distance for a 50% incidence of endothelial damage (LD 50 = lesion distance, 50%) for 3.3 mJ mode-locked pulses was found to be 1.60 mm. All mode-locked pulses of 4.5 mJ focused 0.85 to 1.60 mJ from the endothelium caused damage. In comparison, Q-switched pulses of 12 mJ or less are not likely to damage the cornea if focused more than 0.75 mm from the endothelium. The severe, early effect of mode-locked pulses is edema of endothelial cells in a 0.2- to 0.3-mm diameter circular zone surrounding a 0.1-mm diameter denuded zone with a small central break of Descemets membrane. By two months, mild and moderate lesions heal with little or no distortion of the endothelial mosaic. Irregular enlargement of endothelial cells surrounding and covering the previously denuded area of severe lesions is caused by both mode-locked and Q-switched treatment. In no case was there clinically significant, persistent damage in the healed monkey corneas.

Corneal Opacification in C57BL/6J Mice

Corneal opacities occurring in adult C57BL/6J mice were studied clinically as well as by light and electron microscopy. Grossly, the early stages showed a paracentral opacity with a focus of pigmentation within the opacified area. In later stages, the lesion became vascularized. Light and electron microscopy showed endothelial vacuolization and cell loss in many animals, especially in regions of iridocorneal adhesions. The epithelium overlying areas of endothelial damage showed microcysts and subepithelial bullae. Scanning electron microscopy revealed an altered epithelial surface contour with loss of microvilli, as well as disrupted endothelial cell junctions in affected animals. Iris stroma was atrophic in these cases. The pathogenesis of these changes is uncertain. However, it seems likely that a primary endothelial dysfunction occurs, resulting in secondary stromal and epithelial edema with microcyst formation.