Proforma for Registration of the Subject for Dissertation

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES,

BENGALORE, KARNATAKA

PROFORMA FOR REGISTRATION OF THE SUBJECT FOR DISSERTATION

6.0 BRIEF RESUME OF THE INDENTIFIED WORK

Introduction

Uterine fibroids are tumors or lumps made of muscle cells and other tissue that grow within the walls of the uterus. Fibroids may grow as a single tumor or in clusters. A single fibroid can be less than one inch in size or can grow to eight inches across or more. A bunch or cluster of fibroids can all vary in size. Uterine fibroids are the most common, non-cancerous tumors in women of childbearing age. Uterine fibroids (leiomyomas) are common noncancerous (benign) tumors of the uterus. They grow from the muscular wall of the uterus and are made up of muscle and fibrous tissue. As fibroids are almost always benign, with a negligible percentage showing the presence of a sarcoma (malignancy), fibroids only require treatment for the alleviation of symptoms due to the fibroid.1

Over the past two decades, advances in surgical techniques have led to the development of innovative and less invasive options for the local management of tumors. The principal driving force behind this is to reduce the perioperative morbidity and mortality rates associated with invasive procedures. Minimally invasive keyhole and laparoscopic surgeries have replaced open surgeries and are the order of the day. 2

Percutaneous procedures such as radiofrequency ablation and cryoablation are newer alternative approaches to tumour management, though they still require the insertion of probes and are not truly non-invasive by definition. By definition, “MR-guided high-intensity focused ultrasound (MRI-HIFU)” is a truly non-invasive procedure without skin penetration and is used for the precise and targeted therapeutic management of tumours. MRI guided HIFU or Magnetic Resonance Imaging- guided High Intensity Focused Ultrasound is an innovative mode for genuinely non-invasive treatment of fibroids. Under MRI guidance, sound waves are passed into the body and focused into the fibroid to heat and coagulate the tissues.2

The MRI acquires high resolution 3-D images of the fibroid and surrounding structures. These images are used for accurate planning and mapping of the treatment. During treatment, the HIFU transducer focuses the ultrasound beam into the fibroid as per the planned areas (cells) and heats the tissue up to 65 degree Celsius, coagulating it. This is called sonication. Sonalleve MRI guided HIFU ensures patient safety by having a number of safety mechanisms built into the system. All of these ensure that apart from the tissue being targeted, no other organ or tissue is affected by the treatment. During treatment, the MRI plays an important role by monitoring temperatures within the treatment areas as well as in the surrounding tissues. The recorded temperatures are then superimposed in the form of colour coded maps on the 3-D images that are being used for the treatment monitoring. Real-time feedback loop ensures that adequate heating takes place, treating every bit of tissue that has been targeted and volumetric ablation (a Philips proprietary technology) helps treat larger volumes efficiently and quickly. Thermal mapping contributes to safety by ensuring that the treatment remains within the recommended temperature levels, and that the surrounding tissues are not affected at all. In addition, Motion detection with automatic adjustment/suspension of sonication also ensures that the procedure is safe. An emergency stop button that is controlled by the patient allows the patient to pause the treatment whenever she needs to, and the treatment can be resumed once she is comfortable.1

In the pre-menopausal age group, traditional management techniques range from medical therapy to hysterectomy. The gap between these two techniques is immense, and this can be extremely discouraging for the patient. At present, fibroids are the most common indication for hysterectomy in India. Laproscopic or hysteroscopic myomectomies are restricted to small tumours in certain locations. Uterine artery embolisation is a less invasive technique, in which a percutaneous puncture of a vessel in the groin is performed and the artery supplying the fibroid is blocked. However, this technique may be complicated by severe post-procedural pain and a post-embolisation syndrome. MRI-HIFU is the new kid on the block — it has been used for the treatment of uterine fibroids in the United States since 2004.1

A relatively new treatment that uses magnetic resonance image (MRI) guided focused ultrasound to target and super-heat the blood flowing within specifically targeted uterine fibroids. This, in turn, causes the blood to clot and prevents further blood flow to the individual tumor. Without a blood flow, the fibroid dies. While the tumors are not removed and don't totally disappear with this treatment, they do go through a cellular change that can be effective in treating the symptoms of uterine fibroids in women with a small number of tumors. 1

Women in the pre-menopausal age group, interested in conserving the uterus are ideal candidates for MRI-HIFU of uterine fibroids. Real-time, MRI guidance allows the radiologist to target the fibroid with a high-intensity focused ultrasound (HIFU) energy beam. This process is called sonication. The therapeutic HIFU beam is delivered to the target, at which point the sound energy in the beam is converted to heat energy. This technique of ablation relies on heat-induced tissue necrosis (coagulative), which is achieved when the target is heated to a temperature at or beyond 57 C. importantly, this technique leaves the normal uterine muscle intact.2

The patient has a light snack, six hours prior to the procedure and fasts till the scheduled appointment time. A nurse cannulates her vein and inserts a catheter into the urinary bladder. The patient’s abdominal wall is in contact with the treatment interface embedded in the MRI table. During the sonication procedure, real-time MRI images are obtained and are processed online, allowing the radiologist to precisely target, optimise and modify beam dosage. The patient is awake and aware throughout the entire procedure. After a post-procedural clinical assessment, the urinary catheter and intravenous cannula are removed.1

Post-procedural symptoms may include lower abdominal pain, superficial tenderness or a low-grade fever, which may persist for a few days. These symptoms are often self-limiting and may be controlled using medications. An uncommon side effect includes sciatic neuralgia.1

In a comparative study between MRI-HIFU and hysterectomy, MRI-HIFU treatment of fibroids led to clinical improvement with fewer significant clinical complications and serious adverse events compared to hysterectomy at half-yearly follow-ups. All MRI-HIFU patients were treated on an outpatient basis, with significantly faster recovery, earlier resumption of work and a reduced economical impact.2

6.1 Need for study

One in every four Indian women develops uterine fibroids, which represents some 25 million women, and this is the single most common cause of infertility in this population. The benign, non-cancerous tumors grow inside, outside or within the lining of the uterus.3

The procedure is gaining wide acceptance because of the ease of use, exemplary safety and minimal disruption in the patients' daily routine. This is a day-care surgery, where the patient reports to the clinic for the procedure, undergoes the procedure and is able to walk out and go home after the procedure. The patient is able to go back to her regular routine within the next 24 hours, and the symptomatic relief obtained with this procedure is comparable to that following a Myomectomy in the long term.4

The results of one research study suggests that an even larger number of women may be affected by the condition than is known and that developing fibroids is, in large measure, dependent upon diet, obesity, and high blood pressure. Another finding of the researchers, who studied 2,142 women with infertility due to uterine fibroids, is that a woman's chances for developing fibroids increase if a first degree female relative also has the condition.5

Every 10 minutes, 12 hysterectomies are performed in the United States. According to a report published by Obstetrics and Gynaecology, 9 of them probably didn't meet the guidelines set out by the AmericanCollege of Obstetricians & Gynaecologists for hysterectomy.

~600,000 hysterectomies performed annually in the United States (~170,000 - ~300,000 due to uterine fibroids)

Over 5 billion dollars spent annually on hysterectomies (medical expense of procedures only)

Average time off from work to recover from a hysterectomy is 6 weeks (~144 million lost work hours)

~60% of all women undergoing hysterectomy have their ovaries removed (castration)

Over 5 billion dollars spent on hormone replacement therapy annually

37% of all women undergo hysterectomy by age 60

Myomectomy is performed less than 40,000 times a year in the U.S.

Over 25,000 uterine artery embolizations have been performed worldwide since 1996.

For every 10,000 hysterectomies performed, 11 women die. (Approximately 660 women die each year in the United States from complications of hysterectomy.)Possibly as many as 80% of all women have uterine fibroids. While the majority usually have no symptoms, 1 in 4 ends up with symptoms severe enough to require treatment.6

The non-invasive, outpatient uterine fibroids treatment is an alternative to hysterectomy, myomectomy and UAE. ExAblate treats uterine fibroids (myomas) using MR-guided focused ultrasound. More than 6500 women have already undergone this incision less procedure.

- It's non-invasive - so there's no cutting or general anaesthesia

- It's an outpatient procedure - so in most cases there's no hospital stay

- It's not experimental - so it's safe for use and reduces the risk of side effects

- There's a short recovery time - you'll return to livelihood quickly.6

Women suffering from uterine fibroids, a common gynaecological problem, need not go through painful surgery any more. The fibroids can be treated through a painless and bloodless procedure introduced in India for the first time in Mumbai's JaslokHospital. JaslokHospital Tuesday launched the procedure using GE Magnetic Resonance-guided Focused Ultrasound Surgery (MRgFUS) - which treats uterine fibroids by using high intensity ultrasound waves to non-invasively destroy benign tumours of the uterus. Uterine fibroids affect significantly large numbers of women - an estimated 50 percent - causing a variety of symptoms such as pelvic pain, incontinence and swelling of the abdomen. Presently, the most common treatment for fibroids is hysterectomy, a surgical procedure that involves a stay in hospital and up to six weeks of recovery time. The package is usually priced at up to Rs.1.5 lakh, while the new procedure is likely to cost half the amount.2

Surgery has been the standard of care in selected cases with solid tumors. However, a majority of patients are unable to undergo surgical resection because of the tumor sites, advanced stages, or poor general condition. High intensity focused ultrasound (HIFU) is a novel non-invasive technique that is capable of producing coagulative necrosis at a precise focal point within the body, without harming overlying and adjacent structures even within the path of the beam. Diagnostic ultrasound was the first imaging modality used for guiding HIFU ablation in the 1990s. Over the last decade, thousands of patients with uterine fibroids, liver cancer, breast cancer, pancreatic cancer, bone tumors, renal cancer have been treated with ultrasound imaging-guided HIFU (USgHIFU) worldwide. This USgHIFU system [Chongqing Haifu (HIFU) Tech Co., Ltd., Chongqing, China] was first equipped in Asia, now in Europe. Several research groups have demonstrated that HIFU is safe and effective in treating human solid tumors. In 2004, the magnetic resonance guided focused ultrasound surgery (MRgFUS) was approved by the United States Food and Drug Administration (FDA) for clinical treatments of uterine fibroids. We conclude that HIFU offers patients another choice when no other treatment available or when patients refused surgical operation. This technique may play a key role in future clinical practice.7

Surgery has been the standard of care in selected patients with solid tumors, offering the chance of complete cure by tumor removal. However, a majority of patients are unable to undergo surgical resection because of the tumor sites, advanced stage of tumors, or poor general condition. Clinicians have been trying to find out novel treatment techniques, such as radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), cryoablation, microwave coagulation, laser-induced interstitial thermotherapy, and HIFU, to treat those patients. Among these techniques, HIFU is the only non-invasive technique. HIFU ablation is also known as focused ultrasound ablation, focused ultrasound surgery (FUS). The possibility that focused ultrasound ablation might be developed as a result of controlling local heating phenomena was introduced by Lynn et al. in the 1940s, but the technique was not developed at that time because of inadequate targeting methods. In the 1980s, HIFU has received considerable attention. Chongqing group began HIFU project in China in 1988. After 10 years of basic research, Wang et al proposed a new conception of the ′biological focal field′ in 1997. In the last decade, several clinical HIFU projects have been conducted by various research groups and significant results indicated that HIFU ablation would be safe, effective, and feasible in clinical application.7

HIFU is a non-invasive technique and thus may be of particular value for patients at risk for surgical operation. In addition to the potential for curative treatment and the extension of life expectancy, HIFU has been demonstrated to reduce or eliminate tumor-related pain and thus improve quality of life for patients with advanced disease. Currently, both ultrasound imaging-guided HIFU (USgHIFU) and magnetic resonance imaging guided HIFU (MRgHIFU) devices have been developed in Chongqing, China. Insightech has also developed MRI-guided focused ultrasound surgery (MRgFUS). MRgHIFU or MRgFUS is mainly used to treat uterine fibroids. In contrast, USgHIFU is not only used to treat uterine fibroids, but also to treat liver cancer, pancreatic cancer, breast cancer, bone cancer and renal cancer. This article reviews the clinical use of MRgHIFU and USgHIFU.8

6.2 REVIEW OF LITERATURE

Randomized in vivo animal study was conducted to determine the feasibility of uterine tissue ablation in vivo using a transvaginal focused ultrasound applicator guided by ultrasound imaging at Academic research environment Uterine treatment location was determined using a computerized targeting system. Five sonications 10 seconds in duration and averaging 2,000 W/cm2 of focal ultrasound intensity were applied in each animal's uterus. Animals were euthanized either immediately or 2, 7, or 30 days post-treatment. Treatments resulted in coagulative necrosis. Histopathological analysis showed that over 7 days, inflammatory cells appeared and smooth muscle bundles regenerated. By day 30, treated tissues healed and scar tissue formed. None of the animals showed abnormal behavior or medical problems. Complications in three animals were damage to the vaginal wall and colon, possibly due to inadequate applicator cooling and an empty bladder during treatment. Transvaginal image-guided high-intensity focused ultrasound has potential for treating uterine fibroids. Further safety testing of this treatment will prepare it for human use.9

A High-intensity focused ultrasound was applied intraoperatively to uterine fibroid tumors in rats was conducted to determine the efficacy and safety of high-intensity focused ultrasound (HIFU) for the treatment of uterine fibroid tumors in an in situ animal model at Department of Bioengineering, and Applied Physics Laboratory, University of Washington, Seattle, Washington Thirty-five tumors in 27 Eker rats that had spontaneous in situ uterine fibroids were randomly assigned into two groups receiving HIFU (n = 29) or sham (n = 6) treatments. Animals were anesthetized, and tumors were exposed surgically. The HIFU was applied at 3.5 MHz in 10-second bursts to produce coagulative necrosis lesions (3 mm by 10 mm), spaced 5 mm apart. Sham treatments consisted of exposing the tumors, and handling them similarly to those in the HIFU treatment group, but HIFU was not applied. More than half of the tumors in the HIFU treatment group showed significant tumor volume reduction. The average tumor volume in the sham treatment group increased 40-fold. Gross and histological analysis showed coagulative necrosis of tumor cells in the HIFU treatment group. It concluded that the HIFU may provide an effective and safe method of treating uterine fibroid tumors.10