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Endometrial ablation by means of photodynamic therapy with photofrin II
Endometrial ablation by means of photodynamic therapy with photofrin II Nayantara Bhatta, MD: R. Rox Anderson, MD,"' b Thomas Flotte, MD:' b Isaac Schiff, MD:' b Tayyaba Hasan, PhD: and N.S. Nishioka, MD·' b
Boston, Massachusetts OBJECTIVE: Photodynamic therapy is a technique in which tissue is irradiated with light after the use of a photosensitizing drug that produces singlet oxygen, which has a cytotoxic effect. The feasibility of using photodynamic therapy with photofrin "for endometrial ablation was studied. STUDY DESIGN: Fifty-eight rabbits were studied. Preferential uptake of photofrin " by endometrial tissue, compared with the myometrium, was established by drug extraction and fluorescence microscopy after administration of photofrin II intravenously. Dosimetry for endometrial ablation was established by administering photofrin " in 1, 2, 5, and 10 mg/kg doses and laser light (630 nm) at radiant exposures of 100 and 200 J/cm 2 • Histologic examination was performed at 24 hours, 5 days, and 10 days after treatment. There were two control groups. One group received laser light but no photofrin II, and the other received photofrin II without laser light. RESULTS: The concentration of photofrin " was three times higher in the endometrium than in the myometrium at doses of 1 and 2 mg/kg. Fluorescence microscopy of frozen sections of endometrium and myometrium showed a predominantly perivascular fluorescence from photofrin II. A dose of 1 and 2 mglkg and a flow of 100 J/cm2 was adequate for endometrial ablation in rabbits. At 24 hours after treatment there was extensive hemorrhage and evidence of cell death in the entire endometrium and mild hemorrhage in 10% to 50% of the inner circular layer of the myometrium. At 5 days after treatment necrosis of the entire endometrium and the inner half of the myometrium was seen, but the outer half of the myometrium and the serosa were normal. There were no cases of uterine perforation. Similar results were seen at 10 days after treatment, except for the additional presence of inflammatory cells. Neither control group (drug without light, light without drug) showed any injury to the endometrium at 24 hours. CONCLUSION: We conclude that endometrial ablation can be effectively achieved in rabbits by means of photodynamic therapy with photofrin " without significant complications. (AM J OBSTET GVNECOL 1992; 167: 1856-63.)
Key words: Photodynamic therapy, endometrial ablation, photofrin Endometrial ablation with the Nd :YAG laser was first reported by Goldrath et al. 1 in 1981 as a substitute for hysterectomy in patients with chronic menorrhagia from benign causes refractive to medical therapy. The procedure is performed under direct visualization through a hysteroscope and requires 60 to 120 minutes 2 to complete. The uterine cavity is distended with irrigating fluid to maintain a dear visual path. Hypervolemia and pulmonary edema' as a result of fluid overload have been reported after this procedure. Gas was used to cool down the fiber tip; this has caused death from gas embolism.4 Moreover, the laser irradiation is delivered at extremly high power through an optical fiber, which could perforate the uterus and From the Vincent Gynecology Service, Wellman Laboratories of Photomedicine, Massachusetts General Hospital, a and Haroard Medical S chool. h Presented at the Thirty-ninth Annual Meeting of the Society for Gynecologic Investigation, San Antonio, Texas, March 18-21, 1992. Reprint requests: N. Bhatta, MD, Wellman 2, Massachusetts General Hospital, Boston, MA 02114.
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produce thermal injury to adjacent bowel. 5 The overall success rate has been reported to be 52%2 to 95%.6 Failures are usually related to technical limitations that prevent all areas of the endometrium from being destroyed. Photodynamic therapy with a hematoporphyrin derivative is based on the preferential uptake and retention by certain tissues, such as neoplastic, inflammatory, traumatized, and embryonic tissues." 8 Irradiation of the porphyrin-containing tissue with light of appropriate wavelength leads to formation of singlet molecular oxygen, cytotoxicity, and destruction of the tissues. 9 • 10 In this fashion tissues that preferentially retain photosensitizing drugs can be destroyed with relatively little damage to surrounding tissues. Well-vascularized tissue that is well oxygenated tends to take up more photofrin II, therefore making it a good target tissue for photodynamic therapy. We postulated that endometrium might retain photosensitizers preferentially over myometrium, making it possible to selectively destroy the endometrium after irradiation with an appropriate wavelength of laser
Endometrial photodynamic ablation
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Red Light
Blue Light
,---------------,
ARGON LASER
__
m_J
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DYE LASER
l__________________ ~MIRROR
"--_______-'-5;4~,;;lL-----....Jr-----.30~;,;-----r FIBER
"
~ COUPLER \
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Fig. 1. Laser light delivery to rabbit uterus.
light. This might allow endometrial ablation to be performed without a hysteroscope, fluid irrigation, or high-powered lasers. Additionally, because the laser light would be delivered in a diffuse manner, the chances of residual untreated endometrium remaining after the procedure might be reduced. If successful, the procedure might even be done in the office. As a first step toward testing this hypothesis, we performed experiments to determine whether preferential uptake and retention of the photofrin by endometrium occurred. We then performed in vivo animal experiments to determine the optimal laser and photosensitizer doses for endometrial ablation.
Material and methods Photosensitizer. Freeze-dried photofrin pommer sodium (Lederle, Pearl River, N.Y.), a preparation of hematoporphyrin derivative enriched for diporphyrin and oligoporphyrin ethers (or esters), was stored in the dark at -70 C. A concentration of 2.5 mg/ml solution for injection into the animals was obtained by dissolving 15 mg of photofrin II in 6 ml of 5% dextrose. Laser. A dye laser (model CR-599; Coherent, Palo Alto, Calif.) containing DCM dye (catalog No. 06490; Exciton, Dayton, Ohio) was pumped by the 514.5 nm emission of a continuous-wave, argon-ion laser (model Innova 100; Coherent). The dye laser emission was tuned to 630 nm. Laser energy was delivered through a quartz fiber 400 or 600 Ilm in diameter to a cylindric intrauterine radiator described below, providing flow of 100 and 200 ]/cm2. Laser Iight-delivery system. A disposable cylindric diffusing fiberoptic tip 2 cm in length was constructed 0
by removing the cladding and spraying it with white paint. This allowed relatively uniform light emission from the side of the fiber. The cylindric tip fiber was placed in a balloon dilatation catheter (Dc/6-2!7!75; Medi-Tech, Watertown, Mass.), which provided a contour for the uterus (Fig. I). The balloon was distended with 5 ml of water to conform to the rabbit uterine cavity. This allowed the balloon to fit inside the uterine cavity loosely without causing any pressure on the uterine wall. The length of the balloon used in these experiments was 3.5 cm. The uniformity of the light through the cylindric tip fiber was measured with a photovolt detector with an isotropic ball-tip fiber every 1 mm on the cylindric fiber. Animals. Fifty-eight female virgin New Zealand White rabbits weighing 3 to 3.5 kg were studied. Rabbits have a double uterus that continues into the fallopian tube on either side. The endometrium is present in folds. The thickness of the endometrium varied from 40 to 950 Ilm and the thickness of the myometrium varied from 500 to 1000 Ilm (Fig. 2). The animals were anesthetized with ketamine (50 mg/kg) and xylazine (2 mg/kg) administered intramuscularly. Experimental design. The study was performed in three phases. In the first phase the goal was to establish the preferential uptake of photofrin II by the endometrium. This was established by extraction of photofrin II from the separated endometrium and myometrium (six animals) and by fluorescence microscopy of fresh-frozen sections (four animals). In the second phase of the study experiments were performed (22 animals) to demonstrate that laser-irradiated endometrial ablation of photofrin II-rich endometrium could be achieved
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Fig. 2. Histologic features of normal uterus. A, Low-power photomicrograph illustrating endometrium (E), circular (C) and longitudinal (L) layers of myometrium, vascular plexus (arrowheads) between two muscular layers, lumen (asterisk), and glands (arrow). (Hematoxylin and eosin. Original magnification x 115.) B, High-power photomicrograph of myometrium at junction of inner circular (C) and outer longitudinal (L) muscular layers. Arrowheads, Vascular plexus. (Hematoxylin and eosin. Original magnification x 200.) C, High-power photomicrograph of endometrium illustrating epithelium and connective tissue. Lumen (asterisk) and glands (arrows) are noted. (Hematoxylin and eosin. Original magnification x 200.)
without significant damage to the outer muscular and serosa of the uterus. Appropriate light and photofrin II dose determinations were made. Histologic studies were performed in 20 animals to determine the effect after 24 hours and 5 days and to assess possible undesirable regrowth of the endometrium at 10 days. There were two control groups. In one control group six animals were not given photofrin II, but the uterine cavity was irradiated with laser light (100 J/cm 2 ) to exclude any thermal effect in the endometrial ablation. This control consisted of the second uterine horn of the animals of the experimental group (i.e., each animal had an irradiated and a control unirradiated uterine horn). Drug extraction (six animals). Three animals received I mg/kg of photofrin II and three received 2 mg/kg by
direct injection into the ear vein. The uterus was removed 24 hours later by laparotomy. The uterus was opened longitudinally and the endometrium was dissected away from the myometrium with a pair of fine scissors. The myometrium was further scraped to obtain the remaining endometrial tissue. The wet tissue weight was measured, and the tissue samples were frozen at -70 C. For extraction tissue samples were homogenized (model PT 10/35 homogenizer, Brinkmann Instruments, Westbury, N.Y.) in 0.1 mol/L sodium hydroxide, then centrifuged at 17,000 revolutions/min (Sorvall RC-5B refrigerated superspeed centrifuge, Du Pont) for 20 minutes. The fluorescence of the supernatant was measured with a spectrofluorometer (Fluorolog 2, Spex Industries, Edison, N.J.) and compared with that of a standard solution of photofrin II after a 0
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Table I. Concentration of photofrin in endometrium and myometrium 24 hours after injection Photofrin dose (mg/kg body weight) 1 mg/kg
Photofrin concentration in tissue (Jl{i/gm)
Endometrium
Mean ± SE
3.71 ± 0.51
I
standard curve with known photofrin II concentrations was generated. The emission spectrum for photofrin II was scanned from 590 to 750 nm with an excitation wavelength of 400 nm. Background correction was not obtained. Photofrin II concentration was expressed as micrograms per gram. The statistical analysis was performed with the two-tail t test. Fluorescence microscopy (jour animals). Rabbit uteri were examined 24 hours after intravenous injection of photofrin II at doses of 0, 1, 5, and 10 mg/kg body weight. Frozen sections 7 fLm thick were viewed under epiillumination with an epiillumination fluorescence microscope (Zeiss, Oberkochen, Germany) illuminated with a 50 W mercury lamp. Specimens were examined with a Zeiss BP405/8 exciter filter (405 nm with a band width of 8 nm), chromatic beam splitter FT420 (Zeiss), and barrier filter LP590 (Zeiss). Laparotomy technique. A laparotomy was performed through a midline incision, and the two uterine horns were exposed. Part of one uterine horn was ligated and removed for the control study (photofrin II given but not laser light irradiation). In the second uterine horn a port of entry was made approximately 3.5 cm above the cervical end, by formation of a small opening. The balloon catheter was inserted through this opening into the uterine cavity for irradiation (Fig. 1). The balloon catheter was secured in place with a stay suture. The aim was to achieve uniform distribution of the light to the entire surface of the uterine cavity. Other abdominal organs were shielded from the light delivered to the uterus. The abdominal cavity was closed in two layers. Uterine specimens were collected by a second laparotomy, and the animals were killed after the procedure. Specimens were placed in a 10% formalin solution for later histologic examination. Dosimetry study (22 animals). The aim was to estimate the minimum dose of photofrin II effective for endometrial ablation at a flow of 100 and 200 J/cm 2 • Animals were given photofrin II in doses of 0.5, 1, 2, 5, or 10 mg/kg and irradiated after 24 and 48 hours with 100 or 200 J/cm 2 (one animal in each group). In addition, amounts of 0.5 and 1 mg/kg were given to one animal each and the uterine cavity was irradiated 4 hours later at 100 J/cm 2 to assess acute effects on endometrial ablation. Endometrial ablation (20 animals). Photofrin II
2 mg/kg Myometrium
Endometrium
1.04 ± 0.34
10.26 ± 1.31
I
Myometrium 3.54 ± 0.5
doses of 1 (seven animals), 2 (10 animals), and 4 (three animals) mg/kg and a light dose of 100 J/cm 2 were administered 24 hours later. The uterus was obtained by laparotomy at intervals of 1, 5, and 10 days after treatment.
Results Photofrin II extraction. The concentration of the dye in the endometrium was three to four times higher than that in the myometrium 24 hours after injection of the dye (Table I). The difference was statistically significant (p < 0.01). Fluorescence microscopy. Animals that did not receive photofrin II showed no fluorescence. Animals that received photofrin II had findings consistent with the extraction data. Qualitatively, there was more fluorescence in the endometrium than in the myometrium. The patterns of fluorescence in these two tissues were different. In the myometrium fluorescence was predominantly perivascular, whereas in the endometrium (Fig. 3) fluorescence was both perivascular and interstitial. The interstitial fluorescence was most intense in the subepithelial locations. The epithelium demonstrated some fluorescence but less than that of the subjacent connective tissue. Dosimetry study. Light irradiation (100 J/cm2) 4 hours after photofrin II injection did not have any effect on the endometrium or the myometrium. In contrast, there was hemorrhage and cell death of the endometrium when the same flow was given at 24 and 48 hours after photofrin II injection. There was no noticeable difference in the macroscopic and microscopic appearance of the two groups. Therefore an interval of 24 hours for laser irradiation after photofrin II injection was selected for further experiments. Laser irradiation was performed at two separate flows, 100 and 200 J/cm2. Interestingly, there was no apparent difference in the damage to the endometrium or myometrium at these flows. At the highest photofrin II doses of 5 and 10 mg/kg, damage to the surrounding organs (bladder, loop of intestine, fallopian tube, and upper part of vagina) was noted. The damage appeared as erythema or petechial hemorrhage. In contrast, the experiments were performed with 1, 2, and 4 mg/kg body weight doses of photofrin II. Endometrial ablation. Examination of the abdomi-
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Table II. Results of endometrial ablation at three different doses at intervals of 1, 5, and 10 days Photofrin dose (mg/kg body weight) 1 mg
2 mg
4mg
Animal No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Results 1 day ++++ ++++ ++++
++++ ++++ ++++
I
5 days
++++ ++++
++++ ++++ ++++ 0
J
10 days
0 0
++++ ++++ 0 + + + +E + + + +E + + + +E
+ + + +, Full-thickness endometrial ablation; 0, no endometrial ablation; E, extensive damage to myometrium.
Fig. 3. Fluorescence photomicrographs of uterus 24 hours after intravenous injection of photofrin II. A, Myometrium demonstrates predominantly perivascular localization of fluorescence (arrowheads). (Original magnification x 260.) B, Endometrium (E) demonstrates more fluorescence than in myometrium (M) and pattern is predominantly interstitial. (Original magnification x 130.)
nal organs at 1 day, 5 days, and 10 days after treatment did not show any damage to adjacent organs. One day after treatment the uterus appeared edematous and darker because of hemorrhage. At 5 and 10 days the uterus was slightly darker and still somewhat edematous but much less than on day 1. In several cases the uterus was found to be slightly adherent to the fallopian tube. There was no serosal damage, and the uterus was intact in all animals. At 10 days dark vaginal discharge was noted. Histologic examination. Twenty-four hours after treatment with 2 mg/kg photofrin II and flow of 100 J/cm 2 there was extensive hemorrhage in the endometrium with damage to the epithelium and the blood vessels. The myometrium showed some hemorrhage in the inner circular layer of the muscle, and the extent of injury was well demarcated. Five days after treatment there was necrosis of the entire endometrium (Fig. 4). The epithelium had sloughed, the blood vessels and
cells in the connective tissue were eosinophilic, and there was pyknotic loss of the nuclei. The extravasated red blood cells seen at 24 hours were no longer apparent. Occasional inflammatory cells were present. The inner 10% to 50% of the myometrium showed coagulative necrosis, and the outer 50% of the myometrium and the serosa were viable. At 10 days after treatment histologic examination showed results remarkably similar to those at 5 days after treatment. The only difference was the presence of a few more scattered inflammatory cells. Treatment with 1 mg/kg photofrin II and 100 J/cm 2 demonstrated similar results. Treatment with 4 mg/kg photofrin II and 100 J/cm 2 demonstrated more extensive damage at 10 days after treatment compared with 1 and 2 mg/kg doses. The serosa was intact along with 20% viable myometrium, whereas the remainder of the myometrium and the entire endometrium were necrotic. Of the 20 animals treated at 100 J/cm 2 , four showed no response to treatment. Both of the animals received 1 mg/kg photofrin II and, when examined 10 days after treatment, showed no response. The other two received 2 mg/kg photofrin II and were examined 5 and 10 days after treatment. It is unclear why these animals showed no response, although the reason for no response in these four animals could be insufficient laser light delivery to the uterus from some technical problem. The unirradiated control uterine horn showed no
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Fig. 4. Photomicrographs of uterus 5 days after treatment with 2 mg/kg photofrin II and 100 ]/cm 2 laser light delivered 24 hours after photofrin II injection. A, Low-power photomicrograph illustrates necrosis of endometrium (E) and portion of myometrium (C). Necrotic vessels (asterisk) and occluded vessels (arrowheads) are noted. (Hematoxylin and eosin. Original magnification x 115.) B, High-power photomicrograph of myometrium showing necrosis of inner circular layers (C) of myometrium and viability of outer longitudinal layers of myometrium. Arrowheads, Occluded vessels. (Hematoxylin and eosin stain. Original magnification x 200.) C, High-power photomicrograph of endometrium demonstrating sloughing of epithelium and necrosis. Asterisk, Lumen; arrow, necrotic vessels. (Hematoxylin and eosin stain. Original magnification x 200.)
damage to the endometrium or the myometrium. The control uterine horn that was irradiated with 100 J/cm 2 laser light but received no photofrin II also showed no damage to the entire endometrium or the myometrium. These data are summarized in Table II.
Comment Photodynamic therapy is a treatment modality that destroys tissue when light provides the activated energy for a toxic photochemical reaction. Most photodynamic action typically requires three components: photosensitizer, oxygen, and light. Oxygen is required because excited (singlet) oxygen acts as an intermediate. The potential for minimal normal tissue toxicity because of selective sequestration of photofrin II within tumors has prompted treatment of skin, II bladder,12 head and neck, 1:1 brain 14 and esophagus 15 tumors.
The use of photodynamic therapy in gynecologic cancers, although not extensive, has been encouraging. High-power photodynamic fluorescence has been reported in both dysplasia and cervical carcinomas. 16 Primary and recurrent vaginal cancers I? 18 and cervica l9 and ovarian tumors 20. 21 have been treated by photodynamic therapy. Apart from tumors, photodynamic therapy has been investigated in rabbit endometrial transplants as a model for treatment of endometriosis. 22 • 23 Our study is apparently the first to examine the use of photodynamic therapy to perform endometrial ablation as an alternative to hysterectomy in women with uncontrolled benign uterine bleeding. There are > 600,000 hysterectomies performed each year in the United States. 2 ' The main indications are leiomyomas and dysfunctional uterine bleeding; such abnormal bleeding accounts for 18% to 40% of the
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hysterectomies. 25 . 26 The complications of hysterectomy, apart from accompanying physical, social, and psychologic effects, are 0.1 % mortality and up to 30% morbidity.24 In 1981 Goldrath et al. l introduced Nd:YAG laser destruction of the endometrium lining as an alternative to hysterectomy. Laser ablation of the endometrium is designed to provide treatment for patients who have significant menorrhagia. Endometrial ablation by laser is performed through a hysteroscope by means of a touch technique,' a nontouch technique!7 or a combination of the twO."8 Recently electrocoagulation of the endometrium has been successfully performed with ball-end resectoscope."9 Technically it is difficult to reach the entire surface of the uterine cavity, and as a result incomplete destruction of the endometrium occurs. In addition, there is a considerable amount of endometrial fragments, bubbles, and other debris, which interferes with the view. Several methods are used to clear the hysteroscopic view. The cervix can be dilated beyond the diameter of the hysteroscope to allow rapid egress of fluid and debris from the cavity. The disadvantage of this method is that it requires a large volume of fluid that must be infused and then collected and does not allow good distention of the uterine cavity. Irrigating hysteroscopes or a separate irrigating catheter have been described. 30 Besides the technical difficulties, postoperative complications of bleeding, fluid retention, uterine perforation, and pulmonary edema from fluid overload have been reported. 3 - 5 Overall, hysteroscopic endometrial ablation is a technically difficult procedure and has a considerable complication rate. In this study we have demonstrated that photofrin II is taken up and retained preferentially by the endometrium. The photofrin II concentration was observed to be predominantly located in the stromal part of the endometrium. Manyak et al. 31 have also shown photofrin II fluorescence in the rabbit endometrial cell. Effective endometrial photodynamic ablation was achieved with a light dose of 100 J/cm2 and a drug dose of 1 to 2 mg/kg body weight. A photofrin II dose of 4 mg/kg resulted in more extensive and more reliable damage to the myometrium. No endometrial ablation was obtained in four cases at a dose of 1 to 2 mg/kg body weight. It is possible that the optimum dose to achieve endometrial ablation in the rabbit model at a radiant exposure of 100 J/cm 2 is > 2 mg and < 4 mg/kg body weight. This theory was not examined in this study. Notably, no complications were noted in any animals. When the uterus was examined at 5 and 10 days after treatment, there was evidence of complete necrosis of the endometrium. Fifty percent of the myometrium next to the endometrium (circular layer) was also damaged. Potential advantages of endometrial photodynamic
December 1992 Am J Obstet Gynecol
ablation include no need for a hysteroscope at the time of laser light irradiation; no need for fluid irrigation during the procedure, thereby reducing the complications associated with fluid overload; reduced chances of perforation; and potentially a reduced chance of incomplete destruction of the endometrium with laser light irradiation in a diffuse manner. The thicker myometrial wall (approximately 3 cm) of the human uterus would be an advantage for photodynamic therapy because it would shield other surrounding organs in the pelvis and thus prevent any photochemical damage. The rabbit is a poor model for extrauterine damage from photodynamic therapy because of its thin uterine wall. The procedure could be performed in the office with the patient under paracervical block, without the need for general anesthesia. We conclude that endometrial ablation with photodynamic therapy can be successfully performed and may have applications in clinical practice. We thank W. Farinelli for his expert technical support, Kevin Schomacker, PhD, for suggestions and expert discussions, M. Goetschkes for her careful work in preparing the histologic samples, and Lederle, Pearl River, N.Y., for supplying the photofrin. REFERENCES 1. Goldrath MH, Fuller TA, Segal S. Laser photovaporization of the endometrium for the treatment of menorrhagia. AM J OBSTET GYNECOL 1981;140:14-9. 2. Davis JA. Hysteroscopic endometrial ablation with the neodymium-YAG laser. Br J Obstet Gynaecol 1989;96: 928-32. 3. Goldrath MH. Hysteroscopic laser surgery. In: Baggish MS, ed. Basic and advanced laser surgery in gynecology. Norwalk, Connecticut: Appleton-Century-Crofts, 1985: 357. 4. Catastrophic injury secondary to the use of coaxial gascooled fibers and artificial sapphire tips for intrauterine surgery: a report of five cases. Lasers Surg Med 1989;9: 581-4. 5. Loffer FD. Laser ablation of the endometrium. Obstet Gynecol Clin North Am 1988;15:77-89. 6. Goldrath MH. Hysteroscopic laser ablation of the endometrium. In: Sharp F,JordanJA, eds. Gynaecological laser surgery. Proceedings of the Fifteenth Study Group of the Royal College of Obstetricians and Gynaecologists, London, 1985. New York: Perinatology Press, 1985:25365. 7. Figge FHJ, Weiland GS, Manganiello LO]. Cancer detection and therapy: affinity of neoplastic, embryonic and traumatized tissue for porphyrins and metalloporphyrins. Proc Soc Exp Bioi Med 1948;68:640. 8. Selman SH, Goldblatt PJ, KlauningJE, Keck RW, KreimerBirnbaum M. Localization of hematoporphyrin derivative in injured bladder mucosa. J Urol 1958;133:1104. 9. Dougherty TJ. Photosensitization of malignant tumors. Semin Surg Oncol 1986;6:380. 10. Manyak MJ, Russo A, Smith PD, Glatstein E. Photodynamic therapy. J Clin Oncol 1986;2:24. 11. Tomio L, Calzavara F, Zorat PL, et al. Photoradiation therapy for cutaneous and subcutaneous malignant tumors using hematoporphyrin. In: Doiron DR, Gomer q, eds. Porphyrin localization and treatment of tumors. New York: Alan R Liss, 1984:829-41.
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12. Hisazumi H, Misaki T, Miyoshi N. Photoradiation therapy of bladder tumors. J Urol 1983;130:685-7. 13. Wile AG, Novotny J, Mason GR, Passay V, Berns MW. Photoradiation therapy of head and neck cancer. In: Doiron DR, Gomer CJ, eds. Porphyrin localization and treatment of tumors. New York: Alan R Liss, 1984:681-93. 14. Laws ERJr, Cortese DA, Kinsey JH, Eagan RT, Anderson RE. Photoradiation therapy in the treatment of malignant brain tumors: a phase I (feasibility) study. Neurosurgery 1981 ;9:672-8. 15. Hayata Y, Kato H, Okitsu H, Kawaguchi M, Konaka C. Photodynamic therapy with hematoporphyrin derivative in cancer in the upper gastrointestinal tract. Surg Oncol 1985;1:1-11. 16. Kyriazis GA, Balin H, Lipson RL. Hematoporphyrin-derivative-f1uorescence test colposcopy and colpophotography in the diagnosis of atypical metaplasia, dysplasia, and carcinoma in situ of the ceIVix uteri. AM J OBSTET GYNECOL 1973;1l7:375-80. 17. Corti L, Tomio L, Maluta S, et al. The recurrence in gynecologic cancer treated with photodynamic therapy. Photochem Photobiol 1987;46:949-52. 18. Soma H, Akiya K, Nurahara S, Kato H, Hayata Y. Treatment of vaginal carcinoma with laser photoirradiation following administration of hematoporphyrin derivative. Ann Chir Gynaecol 1982;71:133-6. 19. Gray MJ, Lipson RL, Maeck JVC, Parker L, Romeyn D. Use of hematoporphyrin derivative in detection and management of ceIVical cancer. AM J OBSTET GYNECOL 1967; 99:766-71. 20. Tochner Z, Mitchell JB, Harrington FS, Smith PD, Russo D, Russo A. Treatment of intraperitoneal ovarian ascitic tumor with hematoporphyrin derivative and laser light. Cancer Res 1985;45:2983-7. 21. Delaney TF, Sindelar W, Pass HI, et al. Initial experience with photodynamic therapy for peritoneal carcinomatosis [Abstract]. In: Proceedings of the International Conference of Photodynamic Therapy and Medical Laser Appli-
22.
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24. 25. 26.
27. 28.
29. 30. 31.
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cations, London, England, July 1988. Dorchester, England: Dorsett Press, 1988. Manyak MJ, Nelson LM, Solomon D, Russo A, Thomas GF, Stillman RJ. Photodynamic therapy of rabbit endometrial transplants: a model for treatment of endometriosis. Fertil Steril 1989;52: 140-4. Petrucco OM, Sathananden M, Petrucco MF, et al. Ablation of endometriotic implants in rabbits by hematoporphyrin derivative photoradiation therapy using the gold vapor laser. Lasers Surg Med 1990;10;344-8. Easterday CL, Grimes DA, Riggs JA. Hysterectomy in the United States. Obstet Gynecol 1983;62:203-12. Lee NC, Dicker RC, Rubin GL, Ory HW. Confirmation of the preoperative diagnoses for hysterectomy. AM J OBSTET GYNECOL 1984;150:283-7. Pokras R, Hufnagel VG. Hysterectomies in the United States 1965-1984. Hyattsville, Maryland: Centers for Disease Control, National Center for Health Statistics, 1987: 1-32; DHHS publication no (PHS)87-1753. (Vital and health statistics; series 13; no 92). Loffer FD. Hysteroscopic endometrial ablation with the Nd:YAG laser using a non-touch technique. Obstet Gynecol 1987;69:679-82. Lomano JM. Dragging technique versus blanching technique for endometrial ablation with Nd:YAG laser in the treatment of chronic menorrhagia. AM J OBSTET GYNECOL 1988;159:152. Vancaillie TG. Electrocoagulation of the endometrium with the ball-end resectoscope. Obstet Gynecol 1989;74: 425-7. Baggish MS, Baltoyannis P. New technique for laser ablation of the endometrium in high-risk patients. AMJ OBSTET GYNECOL 1988;159:287-92. Manyak MJ, Nelson LM, Solomon D, DeGraffW, Stillman RJ, Russo A. Fluorescent detection of the rabbit endometrial implants resulting from monodispersed viable cell suspensions. Fertil Steril 1990;54:356-9.
Boston, Massachusetts OBJECTIVE: Photodynamic therapy is a technique in which tissue is irradiated with light after the use of a photosensitizing drug that produces singlet oxygen, which has a cytotoxic effect. The feasibility of using photodynamic therapy with photofrin "for endometrial ablation was studied. STUDY DESIGN: Fifty-eight rabbits were studied. Preferential uptake of photofrin " by endometrial tissue, compared with the myometrium, was established by drug extraction and fluorescence microscopy after administration of photofrin II intravenously. Dosimetry for endometrial ablation was established by administering photofrin " in 1, 2, 5, and 10 mg/kg doses and laser light (630 nm) at radiant exposures of 100 and 200 J/cm 2 • Histologic examination was performed at 24 hours, 5 days, and 10 days after treatment. There were two control groups. One group received laser light but no photofrin II, and the other received photofrin II without laser light. RESULTS: The concentration of photofrin " was three times higher in the endometrium than in the myometrium at doses of 1 and 2 mg/kg. Fluorescence microscopy of frozen sections of endometrium and myometrium showed a predominantly perivascular fluorescence from photofrin II. A dose of 1 and 2 mglkg and a flow of 100 J/cm2 was adequate for endometrial ablation in rabbits. At 24 hours after treatment there was extensive hemorrhage and evidence of cell death in the entire endometrium and mild hemorrhage in 10% to 50% of the inner circular layer of the myometrium. At 5 days after treatment necrosis of the entire endometrium and the inner half of the myometrium was seen, but the outer half of the myometrium and the serosa were normal. There were no cases of uterine perforation. Similar results were seen at 10 days after treatment, except for the additional presence of inflammatory cells. Neither control group (drug without light, light without drug) showed any injury to the endometrium at 24 hours. CONCLUSION: We conclude that endometrial ablation can be effectively achieved in rabbits by means of photodynamic therapy with photofrin " without significant complications. (AM J OBSTET GVNECOL 1992; 167: 1856-63.)
Key words: Photodynamic therapy, endometrial ablation, photofrin Endometrial ablation with the Nd :YAG laser was first reported by Goldrath et al. 1 in 1981 as a substitute for hysterectomy in patients with chronic menorrhagia from benign causes refractive to medical therapy. The procedure is performed under direct visualization through a hysteroscope and requires 60 to 120 minutes 2 to complete. The uterine cavity is distended with irrigating fluid to maintain a dear visual path. Hypervolemia and pulmonary edema' as a result of fluid overload have been reported after this procedure. Gas was used to cool down the fiber tip; this has caused death from gas embolism.4 Moreover, the laser irradiation is delivered at extremly high power through an optical fiber, which could perforate the uterus and From the Vincent Gynecology Service, Wellman Laboratories of Photomedicine, Massachusetts General Hospital, a and Haroard Medical S chool. h Presented at the Thirty-ninth Annual Meeting of the Society for Gynecologic Investigation, San Antonio, Texas, March 18-21, 1992. Reprint requests: N. Bhatta, MD, Wellman 2, Massachusetts General Hospital, Boston, MA 02114.
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produce thermal injury to adjacent bowel. 5 The overall success rate has been reported to be 52%2 to 95%.6 Failures are usually related to technical limitations that prevent all areas of the endometrium from being destroyed. Photodynamic therapy with a hematoporphyrin derivative is based on the preferential uptake and retention by certain tissues, such as neoplastic, inflammatory, traumatized, and embryonic tissues." 8 Irradiation of the porphyrin-containing tissue with light of appropriate wavelength leads to formation of singlet molecular oxygen, cytotoxicity, and destruction of the tissues. 9 • 10 In this fashion tissues that preferentially retain photosensitizing drugs can be destroyed with relatively little damage to surrounding tissues. Well-vascularized tissue that is well oxygenated tends to take up more photofrin II, therefore making it a good target tissue for photodynamic therapy. We postulated that endometrium might retain photosensitizers preferentially over myometrium, making it possible to selectively destroy the endometrium after irradiation with an appropriate wavelength of laser
Endometrial photodynamic ablation
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Red Light
Blue Light
,---------------,
ARGON LASER
__
m_J
1857
DYE LASER
l__________________ ~MIRROR
"--_______-'-5;4~,;;lL-----....Jr-----.30~;,;-----r FIBER
"
~ COUPLER \
FIBER
Fig. 1. Laser light delivery to rabbit uterus.
light. This might allow endometrial ablation to be performed without a hysteroscope, fluid irrigation, or high-powered lasers. Additionally, because the laser light would be delivered in a diffuse manner, the chances of residual untreated endometrium remaining after the procedure might be reduced. If successful, the procedure might even be done in the office. As a first step toward testing this hypothesis, we performed experiments to determine whether preferential uptake and retention of the photofrin by endometrium occurred. We then performed in vivo animal experiments to determine the optimal laser and photosensitizer doses for endometrial ablation.
Material and methods Photosensitizer. Freeze-dried photofrin pommer sodium (Lederle, Pearl River, N.Y.), a preparation of hematoporphyrin derivative enriched for diporphyrin and oligoporphyrin ethers (or esters), was stored in the dark at -70 C. A concentration of 2.5 mg/ml solution for injection into the animals was obtained by dissolving 15 mg of photofrin II in 6 ml of 5% dextrose. Laser. A dye laser (model CR-599; Coherent, Palo Alto, Calif.) containing DCM dye (catalog No. 06490; Exciton, Dayton, Ohio) was pumped by the 514.5 nm emission of a continuous-wave, argon-ion laser (model Innova 100; Coherent). The dye laser emission was tuned to 630 nm. Laser energy was delivered through a quartz fiber 400 or 600 Ilm in diameter to a cylindric intrauterine radiator described below, providing flow of 100 and 200 ]/cm2. Laser Iight-delivery system. A disposable cylindric diffusing fiberoptic tip 2 cm in length was constructed 0
by removing the cladding and spraying it with white paint. This allowed relatively uniform light emission from the side of the fiber. The cylindric tip fiber was placed in a balloon dilatation catheter (Dc/6-2!7!75; Medi-Tech, Watertown, Mass.), which provided a contour for the uterus (Fig. I). The balloon was distended with 5 ml of water to conform to the rabbit uterine cavity. This allowed the balloon to fit inside the uterine cavity loosely without causing any pressure on the uterine wall. The length of the balloon used in these experiments was 3.5 cm. The uniformity of the light through the cylindric tip fiber was measured with a photovolt detector with an isotropic ball-tip fiber every 1 mm on the cylindric fiber. Animals. Fifty-eight female virgin New Zealand White rabbits weighing 3 to 3.5 kg were studied. Rabbits have a double uterus that continues into the fallopian tube on either side. The endometrium is present in folds. The thickness of the endometrium varied from 40 to 950 Ilm and the thickness of the myometrium varied from 500 to 1000 Ilm (Fig. 2). The animals were anesthetized with ketamine (50 mg/kg) and xylazine (2 mg/kg) administered intramuscularly. Experimental design. The study was performed in three phases. In the first phase the goal was to establish the preferential uptake of photofrin II by the endometrium. This was established by extraction of photofrin II from the separated endometrium and myometrium (six animals) and by fluorescence microscopy of fresh-frozen sections (four animals). In the second phase of the study experiments were performed (22 animals) to demonstrate that laser-irradiated endometrial ablation of photofrin II-rich endometrium could be achieved
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Fig. 2. Histologic features of normal uterus. A, Low-power photomicrograph illustrating endometrium (E), circular (C) and longitudinal (L) layers of myometrium, vascular plexus (arrowheads) between two muscular layers, lumen (asterisk), and glands (arrow). (Hematoxylin and eosin. Original magnification x 115.) B, High-power photomicrograph of myometrium at junction of inner circular (C) and outer longitudinal (L) muscular layers. Arrowheads, Vascular plexus. (Hematoxylin and eosin. Original magnification x 200.) C, High-power photomicrograph of endometrium illustrating epithelium and connective tissue. Lumen (asterisk) and glands (arrows) are noted. (Hematoxylin and eosin. Original magnification x 200.)
without significant damage to the outer muscular and serosa of the uterus. Appropriate light and photofrin II dose determinations were made. Histologic studies were performed in 20 animals to determine the effect after 24 hours and 5 days and to assess possible undesirable regrowth of the endometrium at 10 days. There were two control groups. In one control group six animals were not given photofrin II, but the uterine cavity was irradiated with laser light (100 J/cm 2 ) to exclude any thermal effect in the endometrial ablation. This control consisted of the second uterine horn of the animals of the experimental group (i.e., each animal had an irradiated and a control unirradiated uterine horn). Drug extraction (six animals). Three animals received I mg/kg of photofrin II and three received 2 mg/kg by
direct injection into the ear vein. The uterus was removed 24 hours later by laparotomy. The uterus was opened longitudinally and the endometrium was dissected away from the myometrium with a pair of fine scissors. The myometrium was further scraped to obtain the remaining endometrial tissue. The wet tissue weight was measured, and the tissue samples were frozen at -70 C. For extraction tissue samples were homogenized (model PT 10/35 homogenizer, Brinkmann Instruments, Westbury, N.Y.) in 0.1 mol/L sodium hydroxide, then centrifuged at 17,000 revolutions/min (Sorvall RC-5B refrigerated superspeed centrifuge, Du Pont) for 20 minutes. The fluorescence of the supernatant was measured with a spectrofluorometer (Fluorolog 2, Spex Industries, Edison, N.J.) and compared with that of a standard solution of photofrin II after a 0
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Table I. Concentration of photofrin in endometrium and myometrium 24 hours after injection Photofrin dose (mg/kg body weight) 1 mg/kg
Photofrin concentration in tissue (Jl{i/gm)
Endometrium
Mean ± SE
3.71 ± 0.51
I
standard curve with known photofrin II concentrations was generated. The emission spectrum for photofrin II was scanned from 590 to 750 nm with an excitation wavelength of 400 nm. Background correction was not obtained. Photofrin II concentration was expressed as micrograms per gram. The statistical analysis was performed with the two-tail t test. Fluorescence microscopy (jour animals). Rabbit uteri were examined 24 hours after intravenous injection of photofrin II at doses of 0, 1, 5, and 10 mg/kg body weight. Frozen sections 7 fLm thick were viewed under epiillumination with an epiillumination fluorescence microscope (Zeiss, Oberkochen, Germany) illuminated with a 50 W mercury lamp. Specimens were examined with a Zeiss BP405/8 exciter filter (405 nm with a band width of 8 nm), chromatic beam splitter FT420 (Zeiss), and barrier filter LP590 (Zeiss). Laparotomy technique. A laparotomy was performed through a midline incision, and the two uterine horns were exposed. Part of one uterine horn was ligated and removed for the control study (photofrin II given but not laser light irradiation). In the second uterine horn a port of entry was made approximately 3.5 cm above the cervical end, by formation of a small opening. The balloon catheter was inserted through this opening into the uterine cavity for irradiation (Fig. 1). The balloon catheter was secured in place with a stay suture. The aim was to achieve uniform distribution of the light to the entire surface of the uterine cavity. Other abdominal organs were shielded from the light delivered to the uterus. The abdominal cavity was closed in two layers. Uterine specimens were collected by a second laparotomy, and the animals were killed after the procedure. Specimens were placed in a 10% formalin solution for later histologic examination. Dosimetry study (22 animals). The aim was to estimate the minimum dose of photofrin II effective for endometrial ablation at a flow of 100 and 200 J/cm 2 • Animals were given photofrin II in doses of 0.5, 1, 2, 5, or 10 mg/kg and irradiated after 24 and 48 hours with 100 or 200 J/cm 2 (one animal in each group). In addition, amounts of 0.5 and 1 mg/kg were given to one animal each and the uterine cavity was irradiated 4 hours later at 100 J/cm 2 to assess acute effects on endometrial ablation. Endometrial ablation (20 animals). Photofrin II
2 mg/kg Myometrium
Endometrium
1.04 ± 0.34
10.26 ± 1.31
I
Myometrium 3.54 ± 0.5
doses of 1 (seven animals), 2 (10 animals), and 4 (three animals) mg/kg and a light dose of 100 J/cm 2 were administered 24 hours later. The uterus was obtained by laparotomy at intervals of 1, 5, and 10 days after treatment.
Results Photofrin II extraction. The concentration of the dye in the endometrium was three to four times higher than that in the myometrium 24 hours after injection of the dye (Table I). The difference was statistically significant (p < 0.01). Fluorescence microscopy. Animals that did not receive photofrin II showed no fluorescence. Animals that received photofrin II had findings consistent with the extraction data. Qualitatively, there was more fluorescence in the endometrium than in the myometrium. The patterns of fluorescence in these two tissues were different. In the myometrium fluorescence was predominantly perivascular, whereas in the endometrium (Fig. 3) fluorescence was both perivascular and interstitial. The interstitial fluorescence was most intense in the subepithelial locations. The epithelium demonstrated some fluorescence but less than that of the subjacent connective tissue. Dosimetry study. Light irradiation (100 J/cm2) 4 hours after photofrin II injection did not have any effect on the endometrium or the myometrium. In contrast, there was hemorrhage and cell death of the endometrium when the same flow was given at 24 and 48 hours after photofrin II injection. There was no noticeable difference in the macroscopic and microscopic appearance of the two groups. Therefore an interval of 24 hours for laser irradiation after photofrin II injection was selected for further experiments. Laser irradiation was performed at two separate flows, 100 and 200 J/cm2. Interestingly, there was no apparent difference in the damage to the endometrium or myometrium at these flows. At the highest photofrin II doses of 5 and 10 mg/kg, damage to the surrounding organs (bladder, loop of intestine, fallopian tube, and upper part of vagina) was noted. The damage appeared as erythema or petechial hemorrhage. In contrast, the experiments were performed with 1, 2, and 4 mg/kg body weight doses of photofrin II. Endometrial ablation. Examination of the abdomi-
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Table II. Results of endometrial ablation at three different doses at intervals of 1, 5, and 10 days Photofrin dose (mg/kg body weight) 1 mg
2 mg
4mg
Animal No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Results 1 day ++++ ++++ ++++
++++ ++++ ++++
I
5 days
++++ ++++
++++ ++++ ++++ 0
J
10 days
0 0
++++ ++++ 0 + + + +E + + + +E + + + +E
+ + + +, Full-thickness endometrial ablation; 0, no endometrial ablation; E, extensive damage to myometrium.
Fig. 3. Fluorescence photomicrographs of uterus 24 hours after intravenous injection of photofrin II. A, Myometrium demonstrates predominantly perivascular localization of fluorescence (arrowheads). (Original magnification x 260.) B, Endometrium (E) demonstrates more fluorescence than in myometrium (M) and pattern is predominantly interstitial. (Original magnification x 130.)
nal organs at 1 day, 5 days, and 10 days after treatment did not show any damage to adjacent organs. One day after treatment the uterus appeared edematous and darker because of hemorrhage. At 5 and 10 days the uterus was slightly darker and still somewhat edematous but much less than on day 1. In several cases the uterus was found to be slightly adherent to the fallopian tube. There was no serosal damage, and the uterus was intact in all animals. At 10 days dark vaginal discharge was noted. Histologic examination. Twenty-four hours after treatment with 2 mg/kg photofrin II and flow of 100 J/cm 2 there was extensive hemorrhage in the endometrium with damage to the epithelium and the blood vessels. The myometrium showed some hemorrhage in the inner circular layer of the muscle, and the extent of injury was well demarcated. Five days after treatment there was necrosis of the entire endometrium (Fig. 4). The epithelium had sloughed, the blood vessels and
cells in the connective tissue were eosinophilic, and there was pyknotic loss of the nuclei. The extravasated red blood cells seen at 24 hours were no longer apparent. Occasional inflammatory cells were present. The inner 10% to 50% of the myometrium showed coagulative necrosis, and the outer 50% of the myometrium and the serosa were viable. At 10 days after treatment histologic examination showed results remarkably similar to those at 5 days after treatment. The only difference was the presence of a few more scattered inflammatory cells. Treatment with 1 mg/kg photofrin II and 100 J/cm 2 demonstrated similar results. Treatment with 4 mg/kg photofrin II and 100 J/cm 2 demonstrated more extensive damage at 10 days after treatment compared with 1 and 2 mg/kg doses. The serosa was intact along with 20% viable myometrium, whereas the remainder of the myometrium and the entire endometrium were necrotic. Of the 20 animals treated at 100 J/cm 2 , four showed no response to treatment. Both of the animals received 1 mg/kg photofrin II and, when examined 10 days after treatment, showed no response. The other two received 2 mg/kg photofrin II and were examined 5 and 10 days after treatment. It is unclear why these animals showed no response, although the reason for no response in these four animals could be insufficient laser light delivery to the uterus from some technical problem. The unirradiated control uterine horn showed no
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Fig. 4. Photomicrographs of uterus 5 days after treatment with 2 mg/kg photofrin II and 100 ]/cm 2 laser light delivered 24 hours after photofrin II injection. A, Low-power photomicrograph illustrates necrosis of endometrium (E) and portion of myometrium (C). Necrotic vessels (asterisk) and occluded vessels (arrowheads) are noted. (Hematoxylin and eosin. Original magnification x 115.) B, High-power photomicrograph of myometrium showing necrosis of inner circular layers (C) of myometrium and viability of outer longitudinal layers of myometrium. Arrowheads, Occluded vessels. (Hematoxylin and eosin stain. Original magnification x 200.) C, High-power photomicrograph of endometrium demonstrating sloughing of epithelium and necrosis. Asterisk, Lumen; arrow, necrotic vessels. (Hematoxylin and eosin stain. Original magnification x 200.)
damage to the endometrium or the myometrium. The control uterine horn that was irradiated with 100 J/cm 2 laser light but received no photofrin II also showed no damage to the entire endometrium or the myometrium. These data are summarized in Table II.
Comment Photodynamic therapy is a treatment modality that destroys tissue when light provides the activated energy for a toxic photochemical reaction. Most photodynamic action typically requires three components: photosensitizer, oxygen, and light. Oxygen is required because excited (singlet) oxygen acts as an intermediate. The potential for minimal normal tissue toxicity because of selective sequestration of photofrin II within tumors has prompted treatment of skin, II bladder,12 head and neck, 1:1 brain 14 and esophagus 15 tumors.
The use of photodynamic therapy in gynecologic cancers, although not extensive, has been encouraging. High-power photodynamic fluorescence has been reported in both dysplasia and cervical carcinomas. 16 Primary and recurrent vaginal cancers I? 18 and cervica l9 and ovarian tumors 20. 21 have been treated by photodynamic therapy. Apart from tumors, photodynamic therapy has been investigated in rabbit endometrial transplants as a model for treatment of endometriosis. 22 • 23 Our study is apparently the first to examine the use of photodynamic therapy to perform endometrial ablation as an alternative to hysterectomy in women with uncontrolled benign uterine bleeding. There are > 600,000 hysterectomies performed each year in the United States. 2 ' The main indications are leiomyomas and dysfunctional uterine bleeding; such abnormal bleeding accounts for 18% to 40% of the
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hysterectomies. 25 . 26 The complications of hysterectomy, apart from accompanying physical, social, and psychologic effects, are 0.1 % mortality and up to 30% morbidity.24 In 1981 Goldrath et al. l introduced Nd:YAG laser destruction of the endometrium lining as an alternative to hysterectomy. Laser ablation of the endometrium is designed to provide treatment for patients who have significant menorrhagia. Endometrial ablation by laser is performed through a hysteroscope by means of a touch technique,' a nontouch technique!7 or a combination of the twO."8 Recently electrocoagulation of the endometrium has been successfully performed with ball-end resectoscope."9 Technically it is difficult to reach the entire surface of the uterine cavity, and as a result incomplete destruction of the endometrium occurs. In addition, there is a considerable amount of endometrial fragments, bubbles, and other debris, which interferes with the view. Several methods are used to clear the hysteroscopic view. The cervix can be dilated beyond the diameter of the hysteroscope to allow rapid egress of fluid and debris from the cavity. The disadvantage of this method is that it requires a large volume of fluid that must be infused and then collected and does not allow good distention of the uterine cavity. Irrigating hysteroscopes or a separate irrigating catheter have been described. 30 Besides the technical difficulties, postoperative complications of bleeding, fluid retention, uterine perforation, and pulmonary edema from fluid overload have been reported. 3 - 5 Overall, hysteroscopic endometrial ablation is a technically difficult procedure and has a considerable complication rate. In this study we have demonstrated that photofrin II is taken up and retained preferentially by the endometrium. The photofrin II concentration was observed to be predominantly located in the stromal part of the endometrium. Manyak et al. 31 have also shown photofrin II fluorescence in the rabbit endometrial cell. Effective endometrial photodynamic ablation was achieved with a light dose of 100 J/cm2 and a drug dose of 1 to 2 mg/kg body weight. A photofrin II dose of 4 mg/kg resulted in more extensive and more reliable damage to the myometrium. No endometrial ablation was obtained in four cases at a dose of 1 to 2 mg/kg body weight. It is possible that the optimum dose to achieve endometrial ablation in the rabbit model at a radiant exposure of 100 J/cm 2 is > 2 mg and < 4 mg/kg body weight. This theory was not examined in this study. Notably, no complications were noted in any animals. When the uterus was examined at 5 and 10 days after treatment, there was evidence of complete necrosis of the endometrium. Fifty percent of the myometrium next to the endometrium (circular layer) was also damaged. Potential advantages of endometrial photodynamic
December 1992 Am J Obstet Gynecol
ablation include no need for a hysteroscope at the time of laser light irradiation; no need for fluid irrigation during the procedure, thereby reducing the complications associated with fluid overload; reduced chances of perforation; and potentially a reduced chance of incomplete destruction of the endometrium with laser light irradiation in a diffuse manner. The thicker myometrial wall (approximately 3 cm) of the human uterus would be an advantage for photodynamic therapy because it would shield other surrounding organs in the pelvis and thus prevent any photochemical damage. The rabbit is a poor model for extrauterine damage from photodynamic therapy because of its thin uterine wall. The procedure could be performed in the office with the patient under paracervical block, without the need for general anesthesia. We conclude that endometrial ablation with photodynamic therapy can be successfully performed and may have applications in clinical practice. We thank W. Farinelli for his expert technical support, Kevin Schomacker, PhD, for suggestions and expert discussions, M. Goetschkes for her careful work in preparing the histologic samples, and Lederle, Pearl River, N.Y., for supplying the photofrin. REFERENCES 1. Goldrath MH, Fuller TA, Segal S. Laser photovaporization of the endometrium for the treatment of menorrhagia. AM J OBSTET GYNECOL 1981;140:14-9. 2. Davis JA. Hysteroscopic endometrial ablation with the neodymium-YAG laser. Br J Obstet Gynaecol 1989;96: 928-32. 3. Goldrath MH. Hysteroscopic laser surgery. In: Baggish MS, ed. Basic and advanced laser surgery in gynecology. Norwalk, Connecticut: Appleton-Century-Crofts, 1985: 357. 4. Catastrophic injury secondary to the use of coaxial gascooled fibers and artificial sapphire tips for intrauterine surgery: a report of five cases. Lasers Surg Med 1989;9: 581-4. 5. Loffer FD. Laser ablation of the endometrium. Obstet Gynecol Clin North Am 1988;15:77-89. 6. Goldrath MH. Hysteroscopic laser ablation of the endometrium. In: Sharp F,JordanJA, eds. Gynaecological laser surgery. Proceedings of the Fifteenth Study Group of the Royal College of Obstetricians and Gynaecologists, London, 1985. New York: Perinatology Press, 1985:25365. 7. Figge FHJ, Weiland GS, Manganiello LO]. Cancer detection and therapy: affinity of neoplastic, embryonic and traumatized tissue for porphyrins and metalloporphyrins. Proc Soc Exp Bioi Med 1948;68:640. 8. Selman SH, Goldblatt PJ, KlauningJE, Keck RW, KreimerBirnbaum M. Localization of hematoporphyrin derivative in injured bladder mucosa. J Urol 1958;133:1104. 9. Dougherty TJ. Photosensitization of malignant tumors. Semin Surg Oncol 1986;6:380. 10. Manyak MJ, Russo A, Smith PD, Glatstein E. Photodynamic therapy. J Clin Oncol 1986;2:24. 11. Tomio L, Calzavara F, Zorat PL, et al. Photoradiation therapy for cutaneous and subcutaneous malignant tumors using hematoporphyrin. In: Doiron DR, Gomer q, eds. Porphyrin localization and treatment of tumors. New York: Alan R Liss, 1984:829-41.
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12. Hisazumi H, Misaki T, Miyoshi N. Photoradiation therapy of bladder tumors. J Urol 1983;130:685-7. 13. Wile AG, Novotny J, Mason GR, Passay V, Berns MW. Photoradiation therapy of head and neck cancer. In: Doiron DR, Gomer CJ, eds. Porphyrin localization and treatment of tumors. New York: Alan R Liss, 1984:681-93. 14. Laws ERJr, Cortese DA, Kinsey JH, Eagan RT, Anderson RE. Photoradiation therapy in the treatment of malignant brain tumors: a phase I (feasibility) study. Neurosurgery 1981 ;9:672-8. 15. Hayata Y, Kato H, Okitsu H, Kawaguchi M, Konaka C. Photodynamic therapy with hematoporphyrin derivative in cancer in the upper gastrointestinal tract. Surg Oncol 1985;1:1-11. 16. Kyriazis GA, Balin H, Lipson RL. Hematoporphyrin-derivative-f1uorescence test colposcopy and colpophotography in the diagnosis of atypical metaplasia, dysplasia, and carcinoma in situ of the ceIVix uteri. AM J OBSTET GYNECOL 1973;1l7:375-80. 17. Corti L, Tomio L, Maluta S, et al. The recurrence in gynecologic cancer treated with photodynamic therapy. Photochem Photobiol 1987;46:949-52. 18. Soma H, Akiya K, Nurahara S, Kato H, Hayata Y. Treatment of vaginal carcinoma with laser photoirradiation following administration of hematoporphyrin derivative. Ann Chir Gynaecol 1982;71:133-6. 19. Gray MJ, Lipson RL, Maeck JVC, Parker L, Romeyn D. Use of hematoporphyrin derivative in detection and management of ceIVical cancer. AM J OBSTET GYNECOL 1967; 99:766-71. 20. Tochner Z, Mitchell JB, Harrington FS, Smith PD, Russo D, Russo A. Treatment of intraperitoneal ovarian ascitic tumor with hematoporphyrin derivative and laser light. Cancer Res 1985;45:2983-7. 21. Delaney TF, Sindelar W, Pass HI, et al. Initial experience with photodynamic therapy for peritoneal carcinomatosis [Abstract]. In: Proceedings of the International Conference of Photodynamic Therapy and Medical Laser Appli-
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cations, London, England, July 1988. Dorchester, England: Dorsett Press, 1988. Manyak MJ, Nelson LM, Solomon D, Russo A, Thomas GF, Stillman RJ. Photodynamic therapy of rabbit endometrial transplants: a model for treatment of endometriosis. Fertil Steril 1989;52: 140-4. Petrucco OM, Sathananden M, Petrucco MF, et al. Ablation of endometriotic implants in rabbits by hematoporphyrin derivative photoradiation therapy using the gold vapor laser. Lasers Surg Med 1990;10;344-8. Easterday CL, Grimes DA, Riggs JA. Hysterectomy in the United States. Obstet Gynecol 1983;62:203-12. Lee NC, Dicker RC, Rubin GL, Ory HW. Confirmation of the preoperative diagnoses for hysterectomy. AM J OBSTET GYNECOL 1984;150:283-7. Pokras R, Hufnagel VG. Hysterectomies in the United States 1965-1984. Hyattsville, Maryland: Centers for Disease Control, National Center for Health Statistics, 1987: 1-32; DHHS publication no (PHS)87-1753. (Vital and health statistics; series 13; no 92). Loffer FD. Hysteroscopic endometrial ablation with the Nd:YAG laser using a non-touch technique. Obstet Gynecol 1987;69:679-82. Lomano JM. Dragging technique versus blanching technique for endometrial ablation with Nd:YAG laser in the treatment of chronic menorrhagia. AM J OBSTET GYNECOL 1988;159:152. Vancaillie TG. Electrocoagulation of the endometrium with the ball-end resectoscope. Obstet Gynecol 1989;74: 425-7. Baggish MS, Baltoyannis P. New technique for laser ablation of the endometrium in high-risk patients. AMJ OBSTET GYNECOL 1988;159:287-92. Manyak MJ, Nelson LM, Solomon D, DeGraffW, Stillman RJ, Russo A. Fluorescent detection of the rabbit endometrial implants resulting from monodispersed viable cell suspensions. Fertil Steril 1990;54:356-9.