Global endometrial ablation technologies

CONTEMPORARY MANAGEMENT OF ABNORMAL UTERINE BLEEDING

0889-8545 J00 $15.00 + .00

GLOBAL ENDOMETRIAL ABLATION TECHNOLOGIES Jay M. Cooper, MD, and Marvin L. Erickson, MD

Twenty percent of women worldwide are affected by menorrhagia, a condition defined as excessive uterine bleeding, equating to more than 80 mL per menstrual cycle." More than one third of the 700,000 hysterectomies performed each year in the United States are for symptomatic menorrhagia, with 35% to 50% of the uterine specimens demonstrating no histologic abnormality> In England, 73,000 to 90,000 hysterectomies per year are performed for abnormal uterine bleeding, with no histologic abnormality found." Because of the cost, risks, and complications of hysterectomy and the fact that 20% of uterine specimens show no pathologic condition that accounts for the bleeding, it has been theorized that a large proportion of hysterectomies performed for abnormal uterine bleeding may not be necessary. These data raise the question of the validity of extirpative surgery for excessive uterine bleeding. Perhaps lesser procedures that allow for uterine conservation might be equally effective and be associated with less risk and cost. A number of technologies have been developed, and many others are under investigation, that selectively destroy the endometrial lining while preserving the uterus. Such procedures are intended to provide long-term treatment of abnormal uterine bleeding. This article discusses, contrasts, and compares multiple modalities of global endometrial ablation technology. The gold standard for endometrial ablation is hysteroscopically directed thermal ablation. It is Widely accepted as safe, effective, and durable. Despite its documented safety and efficacy and the ready availability of reliable instrumentation to perform the procedure, endometrial ablation has not been adopted overwhelmingly by the gynecologic community. A reasonable explanation for the lack of widespread use of resection and ablation is the procedures' perceived risks and technical difficulty. To overcome these obstacles, less skill-intensive technologies have been developed for the destruction or ablation of the endome-

From the Department of Obstetrics and Gynecology, University of Arizona, School of Medicine, Phoenix Baptist Hospital (JMC); and St. Joseph's Hospital and Medical Center and Maricopa Medical Center, Phoenix Integrated Residency in Obstetrics and Gynecology (MLE), Phoenix, Arizona

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trial lining. Included among these technologies are modalities that use heat, cold, microwaves, light, chemicals, lasers, and radiofrequency energy. After a device has been invented, developed, and clinically evaluated, Food and Drug Administration (FDA) approval must be obtained before the device may be marketed in the United States. FDA APPROVAL OF ABLATION DEVICES

The application process for endometrial ablation devices is quite laborious. It requires the submission of an investigational device exemption application. An applicant must provide the following information to the agency: • • • • • •

Device design, description, and performance information Labeling information Manufacturing summaries Sterilization capabilities Commercialization and environmental impact summaries Summaries of all prior investigations, including adequate in vitro and animal testing safety data • Clinical testing information, including (1) safety and feasibility studies demonstrated on prehysterectomy patients; (2) effectiveness and feasibility studies, including presubmission 6-month follow-up data; and (3) a pre market approval (PMA) investigational study intended to demonstrate saiety and efficacy, which is both prospective and randomized, that allows comparison of the investigational procedure with electrosurgical reaction ablation. The study must be conducted at several centers, with at least 10 patients assigned to both the investigational and control procedures. Twelve-month follow-up data are required before FDA approval is considered, although a PMA application may be submitted after 6 months.

Endometrial ablation technologies include the following: 1. Hot water thermal balloon: Thermachoice (Gynecare, Menlo Park, CA), Caviturm (Wallsten, Morges, Switzerland) 2. Radiofrequency thermal balloon (Vesta [Valleylab, Boulder, CO]) 3. Hydrothermal ablation (BEl, Hackensack, NJ) 4. Bipolar three-dimensional device (Novasure [Novacept, Palo Alto, CAl) 5. Microwave 9.2 GHz applicator (Microsulis, Waterloo, WK) 6. Laser interstitial hyperthermy, ELITT (Gynelase [ESC, Needham, MAl) 7. Cryoablation: First Option (CryoGen, San Diego, CA), Soprano (Gynecare) UiERINE THERMAL BALLOONS FlUid-Filled Thermal Balloon

Thermal balloons have been developed to provide for automated global ablation of the endometrial cavity accomplished without visual control. Of the hot water uterine thermal balloons, two have received extensive clinical investigation: Thermachoice and Caviturm, The Thermachoice apparatus consists of a handpiece with catheter and controller unit. The catheter is 16 em long and 4.5 mm in diameter with a latex

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balloon at its distal end. The balloon catheter, connected to the handpiece, is inserted blindly though the cervix to the uterine fundus. The balloon is filled with 5% dextrose in water so as to produce intrauterine pressures that range between 90 and 190 nun Hg. Once balloon pressure is stabilized at 180 nun Hg, activation of the controller unit is initiated by depressing a button on the proximal end of the catheter. A preset 8-minute cycle is undertaken with the balloon temperature maintained at 87° ± 5° C. The controller unit is designed to self-terminate automatically if pressure drops to less than 45 rum Hg or rises to more than 210 mrn Hg. Complications of the procedure are infrequent; however, Significant postprocedural cramping pain can last 24 hours. Endometritis rarely has been reported. Patients are usually discharged within 4 hours of the procedure. Procedural success, defined as reduction of menstrual blood flow to eumenorrhea or less, was reported in 87% of patients in the pivotal FDA study, which compared the thermal hot water balloon with roller-ball endometrial ablation. Only 10% of patients required a subsequent procedure (i.e., repeat ablation or hysterectomy)." Two-year follow-up data report durable success of uterine balloon therapy (UBT) as 89.1% compared with roller-ball at 90.4%. Success was defined as absence of menorrhagia. Although amenorrhea was achieved in only 13.3% of UBT patients compared with 22.1% of roller-ball patients, there was no statistical difference noted in patient satisfaction. Eighty-six percent of UBT patients and 86.7% of roller-ball patients claimed satisfaction. Adverse events at 2 years included 15 hysterectomies (4 in the UBT group, 11 in the roller-ball group), with 6 hysterectomies being performed for intractable menorrhagia (2 in the UBT group, 4 in the roller-ball group)." The Caviturm technology is similar to that of Thermachoice. It differs in that the balloon is Silastic rather than latex. The balloon has an impeller within it to circulate the warm fluid so as to ensure consistent temperatures throughout the treatment cycle." The device has not been used in the United States at the time of this writing. RADIOFREQUENCY THERMAL BALLOON

A radiofrequency thermal device by Valleylab has 12 electrodes mounted on the surface of an expandable Silastic balloon. A specially designed controller is connected to an electrosurgical generator so as to deliver 45 W of electrosurgical energy to the electrodes. The electrodes then achieve and maintain a preselected temperature of 70° to 75° C. A computer-controlled cycle provides for a 1- to 2-minute warm-up and a 4-minute therapy at the preselected temperature. The computer controller switches individual thermistor-controlled electrodes on and off four times per second to maintain a homogeneous tissue temperature. Individual thermistors control temperature precisely at each of the 12 electrodes. This allows the device to account for local perfusion differences and ensure adequate tissue treatment in all areas of the uterine cavity. Lower temperatures of 72° C are intentionally reached in the cornual regions, where the potential for extrauterine thermal damage is greater. Cervical dilation to 8 mm is required to accommodate insertion of the collapsed device in its protective sheath. Once deployed, the balloon is filled with 10 to 15 cc of air to form-fit the uterine cavity.3 Data submitted as part of the pivotal FDA study demonstrated a 40% amenorrhea rate at 3- and 6-month follow-up and a reported 2% failure rate

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(which required another procedure or hysterectomy). Patient satisfaction in excess of 80% was noted in both the control and investigational arms of the study (FDA panel submission, October, 1998).

HYDROTHERMAL ABLATION

Hydrothermal ablation is accomplished by instilling into the uterine cavity free-flowing normal saline superheated to 80° to 90° C (Fig. 1). The fluid flows into the uterus through an insulated sheath under direct hysteroscopic visualization. Cervical dilation to 8 mm is required to allow for insertion of a standard hysteroscope with the specially designed insulated sleeve. Room temperature physiologic saline is first infused into the uterine cavity and the uterus is flushed then distended to allow visual confirmation of proper intrauterine placement and to assess potential intracavitary pathologic conditions not previously diagnosed. The system then warms the constantly circulating fluid to a preset temperature of 90° C thus triggering a lO-minute treatment cycle." The system has been designed so intrauterine pressure never exceeds 55 mm Hg, well below the 70 to 75 mm Hg opening pressure of the fallopian tubes, to ensure that fluid does not pass into the peritoneal cavity. The procedure is monitored continuously and aborted automatically if there is any fall in intrauterine pressure or a loss of 10 mL of fluid, whlch could indicate leakage of superheated fluid into the vagina or the peritoneal cavity. The ablation procedure is not adversely affected by anomalies of the uterine cavity, including septa, separate cornua, fibroids, or polyps. At the temperatures achieved, more than 80° C, full-thickness irreversible endometrial damage or destruction is achieved, I Hydrothermal abla-

Figure 1. Hydrothermal ablation control box and insulated hysteroscope (BEl, Hackensack, NJ).

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Figure 2. Novasure radiofrequency constant power generator and hand-held three-dimensional bipolar ablation device (Novacept, Palo Alto, CAl.

tion is the only global automated ablation technology that allows real-time, hysteroscopic surveillance of the uterine cavity. The hydrothermal ablation technology is currently undergoing evaluation as part of a phase 3 FDA clinical investigation. Six-month safety and efficacy data will be available in mid-2000. THREE·DIMENSIONAL BIPOLAR ABLATION

Novasure is a disposable, three-dimensional, fan-sh aped, exp andable bipolar device composed of a porous metallic membrane draped over a metallic skeleton (Fig. 2). Once introduced into the uterine cavity, it is deployed from its protective plastic sheath. Suction created by the generator device draws the uterine lining into close contact with the device array before the ablation procedure is initiated. The Novasure gener ator delivers constant power up to 180 W at 500 kHz to the bipolar device to provide for a controlled and contoured depth of ablation. The generator automatically calculates the power delivery required, from the uterine length and cornua to cornua width dimensions. During the ablation procedure, sucti on removes steam and moisture from the tissue to allow for extensive dessication of the tissue . The generator terminates the procedure when a preset impedance limit of SOw is reached , which indicates ade quate depth of tissue destruction. The predetermined and tapered depth of ablation is characterized by a deeper tissue destruction in the main body of the uterus and a more shallow depth of destruction in both the cornual area and near the cervical os. Treatment times vary from 40 to 120 seconds depending on endometrial tissue thickness. Preliminary studies in extirpated uteri indica te that depths

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of ablation of 4 to 4.5 mm in the uterine corpus and 2.2 to 2.9 mm in the cornua and lower uterine corpus are achieved. Using serosal surface thermocouples in prehysterectomy patients, no significant increase in temperature was noted during the ablation procedures," The safety and efficacy of the Novasure procedure is being currently evaluated in a multisite phase ill clinical trial. Preliminary results based on I-year follow-up data from phase II feasibility studies indicate that 97% of the women treated with the Novasure procedure experience an improvement in their men-

ses.' MICROWAVE ENDOMETRIAL ABLATION

Microwave energy has been used successfully for ablation of the endometrial lining. Based on the dielectric constant of endometrium, Microsulis (Waterloo, UK) has chosen a microwave frequency of 9.2 GHz (Fig. 3). At this ideal frequency, the microwave energy achieved adequate tissue penetration while not exceeding 6 mm," Microwave energy is delivered through an 8-mm intrauterine applicator. Generally no more than 30 W is delivered by the generator by way of a cable to the leading end of the applicator tip. Power delivery is controlled by the surgeon with a foot switch. The intrauterine temperature is monitored continuously by thermocouples on the external surface of the applicator sheath. A computer and video terminal provide for display of continuous temperature graphics. In phase I studies, patients received a general anesthetic. Cervical dilation to 8 mm was achieved after careful sounding of the uterine cavity. The microwave probe was passed to the fundus, the tip was activated, and within several seconds, a temperature of 95° C was achieved. Using the temperature display to monitor the ablation process, the surgeon moves the probe laterally from one uterine cornua to the other. After achieving 95° C at both cornua, the probe is brought back to the midline and withdrawn slowly, maintaining average temperatures of 95° C throughout the entire treatment. The uterine cavity is treated to the level of the internal as, with the cervix being spared. Proper technique is required to ensure thorough and even endometrial destruction, Treatment times vary from 1 to 4 minutes, with a mean of 2 minutes, 12 seconds." Treatment time is dictated both by the size of the uterine cavity and the endometrial thickness. In most cases patients experience little or no postoperative discomfort, allowing them to return home the same day of surgery. A 0% complication rate was reported in the original 70 patients treated." In Great Britain, more than 500 patients have been treated, in whom 3-year followup data are available. A success rate of more than 90% has been achieved. Amenorrhea was reported in 37.2%, light menses or discharge in 26%, and improved menses and patient satisfaction in 21%. Overall satisfaction at 3 years is reported at 83.7% in 36 of 43 women.'? The company plans to initiate a North American phase III clinical investigation sometime in the year 2000. LASER INTERSTITIAL HYPERTHERMY

This endometrial ablation procedure uses a Nd:YAG laser. The technology is borrowed from oncology, in which laser energy is used to treat primary and secondary malignant tumors," Evidence exists that tissues exposed to more than

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Figure 3. Microwave generator providing microwave frequency of 9.2 GHz at 30 Wand hand-held applicator (Microsulis, Waterloo, UK).

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60° C suffer irreversible damage as a result of cytoskeletal and enzymatic protein denaturation. Laser interstitial hyperthermy, ELITT (Gynelase [ESC, Needham, MAl) (Fig. 4), uses new fiberoptic technology and a multifiber device that resembles an intrauterine device (IUD) in its appearance and deployment. The multifiber design allows even circurn1erential diffusion of laser radiation. The two lateral fibers have diffusion lengths of 3 em; the central fiber is 4 em long. Each fiber tip is wrapped with a Teflon bridge. The lateral fibers are fixed together on a sliding handpiece, which allows them to glide freely around the central fiber. Advancement of the lateral fiber sheath results in a triangular device configuration that conforms closely to the uterine cavity. A fiberoptic filament is then advanced to the fibers to supply the energy source for ablation. The device delivers 5 to 7 W per fiber during an exposure time of approximately 300 seconds. The laser beam uses 830 run wavelength laser light in continuous emission mode with an output power of 30 W. Laser light diffuses inside the uterine cavity in all directions. Absorbed light is converted to heat, which causes coagulation of the endometrium. In phase I studies, temperatures inside the uterine cavity were found to reach 102 C after 4 to 5 minutes. At distances of 6 to 7 mm from the device, temperature never exceeded 60° C with as much as 5 minutes of treatment." The procedure was performed without the requirement of hysteroscopic control. Most patients tolerated the procedure well with only local or regional anesthesia required. 0

Figure 4. ELlTT Nd:YAG laser (Gynelase [ESC, Needham, MAJ) providing laser light of 830 nm wavelength at 30 W with hand-held device.

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Examination of postprocedural pathologic specimens revealed diffuse whitening of the endometrium and superficial layers of the myometrium. Fine superficial traces of carbon were noted in areas that corresponded to the lateral fibers. No changes were noted on the serosal surface of any specimens.' Clinical trials are ongoing in Europe. In a limited number of patients, preliminary data demonstrate an amenorrhea rate of 86% at 6 months and 91% at 12 months. No perforations have been reported; however, two cornual hematomas have been noted." The patent holder plans to submit an application to the FDA to conduct a PMA study. CRYOABLATION

A new cryosurgical technology device has been developed by CryoGen (San Diego, CA) that includes a mixed fluid system, which allows greatly reduced working pressures, and incorporation of a novel, oil-free compressor to circulate the fluid mixture (Fig. 5). The system uses a 55-mm cryoprobe and tip that are inserted into the uterine cavity. Transabdominal ultrasound is used to confirm proper probe placement in the uterus and follow progression of the ice ball during the treatment cycle. When the system is activated and the fluid circulated, probe surface temperatures of - 90 to -110 C are achieved at working pressures of 400 psi or less. The device is inserted alternately into both cornual regions and treatment is initiated. Within 8 to 10 minutes, the endometrial and superficial myometrial tissue is frozen adequately. The hand-held device is then withdrawn and advanced to the opposite cornual region and treatment repeated. It is 0

Figure 5. First Option closed cycle cryoablation unit with 5.5-mm hand-held cryoprobe (CryoGen, San Diego, CAl.

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believed that the cryotherapy is equally destructive to myomas, with symmetry of the frozen area being maintained. A multicenter phase III clinical investigation is currently underway in 10 US and Canadian cities. Preliminary data indicate that a 9- to 12-mm depth of tissue penetration is routinely achieved.' In the phase III study, 43 patients have been followed for 3 months. They report an amenorrhea rate of 56% and hypomenorrheic rate of 30%. Nine percent of women followed for 3 months reported continued menorrhagia. Six-month follow-up data on 12 patients demonstrate amenorrhea in 58% and hypomenorrhea in 41%.4 A competing cryotechnology, the Soprano system (Gynecare) (Fig. 6) is also undergoing a phase III clinical investigation at 10 US sites (Fig. 1). The procedure begins with filling of the urinary bladder with up to 300 mL of fluid. Cervical dilation to 6 mm is followed by the injection of 10 to 15 mL of lubricant into the uterine cavity. The 5-mm diameter cryoprobe is inserted to the top of the uterine cavity. Transabdominal ultrasound scanning is used to confirm proper probe location and monitor progression of the ice ball during a 5-minute therapy. In uteri that have a sounding depth in excess of 9 em, a second "pullback" treatment that lasts 3 minutes is required to ensure adequate treatment of the lower uterine segment. Various global ablation technologies have been proposed as treatment for dysfunctional uterine bleeding or menorrhagia. A comparison of these technologies is shown in Table 1. Many of the devices and technologies are still undergoing development, refinement, and investigation as part of phase II and III clinical trials. Most data are short term. Publication of longer term data, including safety and efficacy parameters, is needed to allow a fair comparison of these technologies. Much of the published data is yet unconfirmed or unreplicated. In evaluating the data available, higher credibility should be given to devices and technologies that have received FDA approval or are currently in FDA-mandated clinical trials.

Fil:lure 6. Soprano crvoablation unit with hand-held crvonrnha ((.ll/nAr.FlrA MAn In PFlrk

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Table 1. COMPARISON OF VARIOUS ABLATION TECHNOLOGIES Hysteroscopic Control Required

Device

Pretreatment

Thermachoice VestaDUB Hydrothermal ablation Novasure Microwave EUTT First Option/Soprano

Recommended Recommended Recommended

No No Yes

Not required Recommended Recommended Recommended

No No No No; ultrasound guided

y)

~

Applicator Diameter (mm)

Treatment Time (min)

FDA Approval Status

4.5 10

8-12

Approved Investigational Investigational

8 7 8 6 5.5

4 12

2 1-6 7

5-10

Investigational Investigational Investigational Investigational

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References 1. Baggish M, Paraiso M, Breznock EM, et al: A computer-controlled, continuously circulating, hot irrigating system for endometrial ablation. Am J Obstet Gynecol 173(6)1842-1848, 1995 2. Cooper JM: g-D radiofrequency endometrial ablation: Preliminary results. Presented at the 8th Annual Meeting of the European Society for Gynecologic Endoscopy. Stockholm, September 15, 1999 3. Corson SL, Brill AI, Brooks PG, et al: Interim results of the American Vesta trial of endometrial ablation. J Am Assoc Gynecol Laparosc 6:45-49, 1999 4. Dobak J, Yu X, Ghaerzadeh K: A novel closed loop cryosurgical device. Advances in Cryogenic Engineering 43:897-902, 1998 5. Donnez J, Polet R, Mathieu PE, et al: Nd:YAG laser IT multifiber device (the Donnez Device): Endometrial ablation by interstitial hyperthermia. In Donnez J, Nissolle M (eds): Atlas of Laser Operative Laparoscopy and Hysteroscopy. Parthenon, 1995, pp 353-359 6. Donnez J, Polet R, Mathieu PE, et al: Endometrial laser interstitial hyperthermy: A potential modality for endometrial ablation. Obstet Gynecol 87:459-464, 1996 7. Droegemueller W, Makowski E, Macsalka R: Destruction of the endometrium by cryosurgery. Am J Obstet Gynecol 110:467-473, 1971 8. Feldberg ill, Cronin NJ: A 9.2 GHz microwave applicator for the treatment of menorrhagia. IEEE MTT-5 Digest: 755-758, 1998 9. Friberg B, Persson BRR, Willen R, et al: Endometrial destruction by hyperthermia: A possible treatment of menorrhagia. Acta Obstet Gynecol Scand 75:330-335, 1996 10. Goldrath MH, Fuller TA, Segal S: Laser photovaporization of the endometrium for the treatment of menorraghia. Am J Obstet GynecoI140:14-19, 1981 11. Goldrath MH, Varrionuevo M, Husain M: Endometrial ablation by hysteroscopic instillation of hot saline solution. J Am Assoc Gynecol Laparosc 4:235-240, 1997 12. Grainger DA, Tjaden BL: Thermal balloon and roller-ball ablation to treat menorrhagia: Two-year results from a multicenter prospective randomized clinical trial, in press 13. Hodgson DA, Feldberg IB: Microwave endometrial ablation: Development, clinical trial and outcomes at three years. Br J Obstet Gynaecol106:684-694, 1999 14. Hospital Episode Statistics: Finished Consultant Episodes by Diagnosis, Operation and Specialty. London, Her Majesty's Stationary Office, 1995 15. Hullberg L, Hogdahi AM, Nilsson L, et al: Menstrual blood loss: A population study. Acta Obstet Gynecol Scand 45:320-351, 1966 16. Meyer WR, Walsh BW, Grainger DA, et al: Thermal balloon and rollerball ablation to treat menorrhagia: A multicenter comparison. Obstet Gynecol 92:98-103, 1998 17. Phipps J, Lewis BV, Prior MY: Experimental and clinical studies with radiofrequencyinduced thermal endometrial ablation for functional menorrhagia. Obstet Gynecol 76:876-881, 1990 18. Sharp N, Cronin N, Feldberg 1, et al: Microwaves for mennorrhagia: A new fast technique for endometrial ablation. Lancet 346:1003-1004, 1995 19. Sharp N, Feldberg I, Hodgson D, et al: Microwave endometrial ablation. Endoscopic Surgery for Gynecologists 63:630-636, 1998 20. Tadir Y: Intrauterine light probe for photodynamic ablation therapy. Obstet Gynecol 93:299-303, 1999 21. Thijssen RFA: Radiofrequency-induced endometrial ablation: An update. Br J Obstet Gynaecol 104:608-613, 1997 22. Vessey MP, Villard-Mackintosh L, McPherson K, et al: The epidemiology of hysterectomy: Findings in a large cohort study. Br J Obstet Gynaecol 99:402-407, 1992

Address reprint requests to Jay M. Cooper, MD University of Arizona, School of Medicine Phoenix Baptist Hospital 6036 N 19th Avenue Suite 401 Phoenix, AZ 85015