WHAT IS OVARIAN CANCER?

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1 WHAT IS OVARIAN CANCER? The ovaries are small female reproductive organs that reside in the pelvis. There are two ovaries, one on each side of the uterus, or womb. The ovaries produce the female hormones, estrogen, and progesterone. Estrogen and progesterone control the development of female body characteristics (i.e., breasts, body shape and body hair) and regulate the menstrual cycle and pregnancy. The ovaries also store all of the egg cells. The ovaries release egg cells once a month during ovulation. The fallopian tubes deliver the egg cells from the ovaries to the uterus. Some ovarian tumors are benign (not cancerous). Malignant (cancerous) ovarian tumors can originate from cells found in an ovary. There are three types of ovarian tumors, named for the tissue in which they are found: Epithelial cell - cells that cover the surface of the ovary. Germ cell - cells that form the eggs in the ovary. Stromal cell - cells that form the ovary and produce female hormones. The majority of ovarian cancers develop from cells in the lining of the ovary. Most of these tumors are benign (noncancerous). However, epithelial ovarian cancer accounts for 85 to 90 percent of ovarian cancer cases. These are referred to collectively as epithelial ovarian cancers. In this overview, the term ovarian cancer refers to epithelial ovarian cancer. This section does not discuss benign ovarian tumors or ovarian germ cell tumors. Common Epithelial Tumors: Common epithelial cancers that start in the surface epithelium account for the majority of ovarian cancers and include the following types: Serous: This is the most common type of ovarian cancer and accounts for about 40 percent of common epithelial cancers. It occurs most often in women between the ages of 40 and 60. Endometrioid: This type of ovarian cancer accounts for about 20 percent of common epithelial cancers and is associated with endometriosis (growth of endometrial tissue outside the uterus) in 5 percent and endometrial carcinoma (cancer of the womb) in 20 percent of cases. It occurs most often in women between the ages of 50 and 70. Mucinous: Mucinous cancers account for one percent of common epithelial ovarian cancer and most often affect women between 30 to 50 years of age. Clear Cell Carcinoma: Clear cell carcinomas account for six percent of common epithelial tumors and most often affect women between age 40 and 80. Undifferentiated Cancers: The remaining 15 percent of common epithelial cancers are referred to as undifferentiated tumors because their exact cell of origin cannot be determined under a microscope. Borderline Ovarian Tumors: These ovarian tumors of low malignant potential are a subgroup of common epithelial tumors that occur in 10 to 15 percent of cases. These tumors are between cancerous and non-cancerous in nature. They originate on the surface of the ovary, but do not invade deeper tissues of the ovary. They have a better prognosis (prediction about the possible outcome of a disease) and cure rate than invasive ovarian tumors. WHAT CAUSES OVARIAN CANCER? Ovarian cancer is a common malignancy in women in the United States, with about 25,000 new cases diagnosed each year. Ovarian cancer accounts for nearly three percent of all cancers among women and ranks second among gynecologic cancers. Ovarian cancer has the highest mortality rate of all gynecologic cancers. It is the fifth leading cause of cancer death among U.S. women. The cause of ovarian cancer is unknown, but there are certain risk factors that increase a woman's chance of developing ovarian cancer.!1

2 The chance of an individual developing cancer depends on both genetic and non-genetic factors. A genetic factor is an inherited, unchangeable trait, while a non-genetic factor is a variable in a person s environment, which can often be changed. Non-genetic factors may include diet, exercise, or exposure to other substances present in our surroundings. These non-genetic factors are often referred to as environmental factors. Some non-genetic factors play a role in promoting the process of healthy cells turning cancerous (i.e. the correlation between smoking and lung cancer). Other cancers have no known environmental correlation but are known to have a genetic predisposition. A genetic predisposition means that a person may be at higher risk for a certain cancer if a family member has that type of cancer. A risk factor is anything that may increase a person's chance of developing a disease. It may be an activity, such as smoking, diet, family history, or many other things. Different diseases, including cancers, have different risk factors. When individuals are at high risk for a type of cancer, this means that they have certain characteristics or exposures, called risk factors that make them more likely to develop that type of cancer than those who do not have these risk factors. Although these factors can increase a person's risk, they do not necessarily cause the disease. Some people with one or more risk factors never develop cancer, while others develop cancer and have no known risk factors. Knowing your risk factors to any disease can help to guide you into the appropriate actions, including changing behaviors and being clinically monitored for the disease. The following have been suggested as risk factors for ovarian cancer: Early menarche - starting monthly periods early - before the age of 12 Late menopause (after the age of 52) Age - over the age of 50 Hormone replacement therapy Some studies have suggested that women who use hormone replacement therapy after menopause may have a slightly increased risk of ovarian cancer. Infertility (inability to become pregnant) Having a first child after the age of 30 Personal history of breast or colon cancer Family history First-degree relatives (such as mother, daughter, sister) of a woman who has had ovarian cancer are at a risk for developing the disease. The risk increases if two or more first-degree relatives have had ovarian cancer. A family history of breast or colon cancer is also associated with an increased risk of developing ovarian cancer. Fertility drugs In one clinical study, researchers examined risk factors such as a family history of ovarian cancer, a later age at menopause, not using oral contraceptives, not getting pregnant, a low intake of vegetables and a high intake of fat. The researchers concluded that these risk factors accounted for 51 percent of the ovarian cancer cases. Heredity and Genetic Factors Research has determined that 5 to 10 percent of all women with ovarian cancer have a genetic predisposition to the disease. This means that women with a family history (mother or sister) of ovarian cancer are at an increased risk of developing the disease, but the majority of ovarian cancers are not inherited.!2

3 There are several genetic syndromes associated with an increased risk for ovarian cancer that require clinical care by your physician or other health care professional. Listed here is a brief overview: Hereditary Breast Ovarian Cancer Syndrome (BRCA1 / BRCA2): The majority of hereditary ovarian cancers occur in women with a specific genetic abnormality. This is referred to as the BRCA1 or BRCA2 gene. The BRCA1 or breast cancer gene is located on chromosome 17. The BRCA2 or breast cancer gene is located on chromosome 13. Both BRCA1 and BRCA2 are tumor suppressor genes that usually have the job of controlling cell growth and cell death. Everyone has two BRCA1 (one on each chromosome #17) and two BRCA2 genes (one on each chromosome #13). When a person has one altered or mutated copy of either the BRCA1 or BRCA2 gene, their risk for various types of cancer increases. Women with the BRCA1 gene have an 85 percent risk of developing breast cancer, a 60 percent risk of developing ovarian cancer by age 70, and an increased risk of colon cancer. Individuals with the BRCA2 gene are also at an increased risk, although their risk is lower than those with the BRCA1 gene. The following features in a family characterize hereditary breast ovarian cancer (HBOC) syndrome: An early age of onset of breast cancer (often before age 50) Family history of both breast and ovarian cancer Increased chance of bilateral cancers (cancer that develop in both breasts, or both ovaries, independently) or an individual with both breast and ovarian cancer An autosomal dominant (produced when only one copy of the gene is present) pattern of inheritance (vertical transmission through either the mother or father s side of the family) An increased incidence of tumors of other specific organs, such as the prostate Other factors that increase the chance that a family has the hereditary breast ovarian cancer syndrome include: Family history of male breast cancer Ashkenazi Jewish ancestry Both copies of a tumor suppressor gene must be altered or mutated before a person will develop cancer. In HBOC, the first mutation is inherited from either the mother or father and is therefore present in all cells of the body. This is called a germline mutation. Whether a person who has a germline mutation will develop cancer and where the cancer(s) will develop depends upon where (which cell type) the second mutation occurs. For example, if the second mutation is in the ovary, then ovarian cancer may develop. If it is in the breast, breast cancer may develop. The process of tumor development actually requires mutations in multiple growth control genes. Loss of both copies of BRCA1 or BRCA2 is just the first step in the process. What causes these additional mutations to be acquired is unknown. Possible causes include chemical, physical, or biological environmental exposures, or chance errors in cell replication. Some individuals who have inherited a germline BRCA1 or BRCA2 mutation never develop cancer because they never get the second mutation necessary to knock out the function of the gene and start the process of tumor formation. This can make the cancer appear to skip generations in a family, when, in reality, the mutation is!3

4 present. Persons with a mutation, regardless of whether they develop cancer, have a 50/50 chance to pass the mutation on to the next generation. It is also important to remember that the BRCA1 and BRCA2 genes are not located on the sex chromosomes. Therefore, mutations can be inherited from the mother or the father s side of the family. Peutz-Jeghers Syndrome: Peutz-Jeghers syndrome (PJS) is a rare early-onset autosomal dominant (produced when only one copy of a gene is present) disorder. It is associated with specific physical characteristics in addition to increased cancer risks. The features associated with Peutz-Jeghers syndrome may include the following: Melanocytic macules (dark blue or brown moles) These moles may be located around and/or in the mouth (including the lips), and around the eyes, nostrils, and anus. Dark moles may also appear on the fingers. These lesions may fade by adulthood. Multiple polyps in the gastrointestinal tract Increased risk of benign (noncancerous) tumors of the ovaries and testes Increased risk of stomach, esophageal, breast, colon, pancreatic, and ovarian cancers Peutz-Jeghers syndrome is caused by mutations in a gene on chromosome 19 known as STK11. Mutations in STK11 are identified in about 70 percent of familial cases. Peutz-Jeghers syndrome is associated with up to a 93 percent chance of developing one of the associated cancers by age 64. The risks of breast and ovarian cancer fall within the ranges associated with mutations in the BRCA1 and BRCA2 genes. The STK11 gene is a tumor suppressor gene, which usually controls cell growth and cell death. Both copies of a tumor suppressor gene must be altered, or mutated, before a person will develop cancer. With Peutz-Jeghers syndrome, the first mutation is inherited from either the mother or the father and is therefore present in all cells of the body. This is called a germline mutation. Whether a person who has a germline mutation will develop cancer and where the cancer(s) will develop depends upon where (which cell type) the second mutation occurs. Ovarian Cancer and Hereditary Nonpolyposis Colon Cancer (HPNCC): The risk for ovarian cancer is increased with hereditary nonpolyposis colon cancer (HNPCC), an autosomal dominant (produced when only one copy of a gene is present) cancer genetic syndrome. A clinical diagnosis of HNPCC is made when all of the following characteristics are present in a family: Three or more relatives with colorectal cancer or other HNPCC-related cancer (cancer of the endometrium, ovary, small bowel, ureter, or renal pelvis) Cancer affecting at least two successive generations One person with cancer is a first-degree relative of the other two At least one case of cancer should be diagnosed under the age of 50 years A diagnosis of familial adenomatous polyposis (FAP) has been excluded The reported history of cancer has been verified by a pathology report However, some families with mutations in HNPCC-related genes may be tested without demonstrating all of the above characteristics.!4

5 The majority of HNPCC cases are caused by mutations in one of several mismatch-repair genes: MSH2, MSH6, and PMS1 on chromosome 2, MLH1 on chromosome 3, MSH3 on chromosome 5, and PMS2 on chromosome 7. MLH1 and MSH2 are the genes most commonly implicated. Mutations in any one of these genes presents an increased lifetime risk to develop colorectal cancer and, in females, an increased risk to develop ovarian (12 percent) and endometrial (up to 60 percent) cancer. The genes responsible for HNPCC are mismatch-repair genes. They correct "spelling errors" in DNA that happen during the cell division process. When these genes are altered, or mutated, mismatches in the DNA remain. Both copies of a mismatch-repair gene must be altered, or mutated, before a person will develop cancer. With HNPCC, the first mutation is inherited from either the mother or the father and is therefore present in all cells of the body. This is called a germline mutation. Whether a person who has a germline mutation will develop cancer and where the cancer(s) will develop depends upon where (which cell type) the second mutation occurs. Basal Cell Nevus Syndrome (Gorlin Syndrome): The risk for ovarian cancer is increased with basal cell nevus syndrome (also called Gorlin syndrome and nevoid basal cell carcinoma). It is a rare autosomal dominant (produced when only one copy of a gene is present) cancer genetic syndrome. Approximately 600 cases have been identified. Features associated with basal cell nevus syndrome may include the following: Development of more than two basal cell carcinomas (cancer of the outer layer of the skin) before the age of 30 Cysts in the jaw Characteristic facial appearance (60 percent of people) Calcification of the falx (a variation in the appearance of the skull that is visible on x-rays) Pits in the palms and soles of the feet Eye abnormalities Rib or vertebral abnormalities Increased risk of medulloblastoma (brain tumor) Increased risk of cardiac and ovarian fibromas (benign, or noncancerous, tumors) Basal cell nevus syndrome is caused by a tumor suppressor gene, called PTCH, located on chromosome 9. Mutations in this gene may increase the risk of ovarian cancer. Tumor suppressor genes usually control cell growth and cell death. Both copies of a tumor suppressor gene must be altered, or mutated, before a person will develop cancer. With basal cell nevus syndrome, the first mutation is inherited from either the mother or the father in 60 to 80 percent of cases. In 20 to 40 percent of cases, the first mutation is not inherited and arises de novo (for the first time) in the fertilized egg from which the person with symptoms was conceived. Whether de novo or inherited, this first mutation is present in all of the cells of the body and, as such, is called a germline mutation. Whether a person who has a germline mutation will develop cancer and where the cancer(s) will develop depends upon where (which cell type) the second mutation occurs. Environmental or Non-Genetic Factors Clinical research has suggested that increasing age, the use of hormone replacement therapy after menopause, the use of fertility drugs, exposure to talcum powder, and a high-fat diet may increase the risk of developing ovarian cancer.!5

6 Prevention Cancer is largely a preventable illness. Two-thirds of cancer deaths in the United States can be linked to tobacco use, poor diet, obesity, and lack of exercise. All of these factors can be modified. Nevertheless, an awareness of the opportunity to prevent cancer through changes in lifestyle is still under-appreciated. Some studies have indicated that women may reduce their risk of developing ovarian cancer by using oral contraceptives, giving birth to at least one child, breastfeeding and having a hysterectomy or tubal ligation. In addition, women may want to avoid fertility drugs, talcum powder, and a high-fat diet. Removal of the Ovaries: In women who have a strong family history of ovarian cancer or the presence of the BRCA1 or BRCA2 genes, removal of the ovaries may be effective prevention of ovarian cancer; however, this procedure has not been proven to prevent cancer in all cases. Researchers also lack sufficient documentation that this is the optimal approach for young women. Women with the BRCA1 or BRCA2 gene need to consider the potential for complications and side effects before committing to this procedure. Once the ovaries are removed, women no longer produce estrogen and may need long-term hormone replacement. In addition, there are other risks associated with early menopause. Oral Contraceptives: The use of oral contraceptives in women with the BRCA1 or BRCA2 gene may reduce the risk of ovarian cancer by 40-50% and is currently the most frequent treatment recommended in younger women with these genetic abnormalities. Diet: Diet is a fertile area for immediate individual and societal intervention to decrease the risk of developing certain cancers. Numerous studies have provided a wealth of often-contradictory information about the detrimental and protective factors of different foods. There is convincing evidence that excess body fat substantially increases the risk for many types of cancer. While much of the cancer-related nutrition information cautions against a high-fat diet, the real culprit is an excess of calories. Studies indicate that there is little, if any, relationship between body fat and fat composition of the diet. These studies show that excessive caloric intake from both fats and carbohydrates have the same result of excess body fat. The ideal way to avoid excess body fat is to limit caloric intake and/or balance caloric intake with ample exercise. It is still important to limit fat intake, as evidence still supports a relationship between cancer and polyunsaturated, saturated and animal fats. Specifically, studies show that high consumption of red meat and dairy products can increase the risk of certain cancers. One strategy for positive dietary change is to replace red meat with chicken, fish, nuts, and legumes. High fruit and vegetable consumption has been associated with a reduced risk for developing at least 10 different cancers. This may be a result of potentially protective factors such as carotenoids, folic acid, vitamin C, flavonoids, phytoestrogens, and isothiocyanates. These are often referred to as antioxidants. There is strong evidence that moderate to high alcohol consumption also increases the risk of certain cancers. One reason for this relationship may be that alcohol interferes with the availability of folic acid. Alcohol in combination with tobacco creates an even greater risk of certain types of cancer. Although excessive alcohol ingestion and all tobacco use are best avoided, they are not major causes of ovarian cancer. Exercise: Higher levels of physical activity may reduce the incidence of some cancers. According to researchers at Harvard, if the entire population increased their level of physical activity by 30 minutes of brisk walking per day (or the equivalent energy expenditure in other activities), we would observe a 15 percent reduction in the incidence of colon cancer. The association between exercise and ovarian cancer is not as well defined.!6

7 WHAT ARE THE SIGNS AND SYMPTOMS OF OVARIAN CANCER? Ovarian cancer is often originally suspected in women when their physician finds an abnormal pelvic growth during an internal pelvic examination. Unfortunately, due to a lack of definitive symptoms, the majority of women with ovarian cancer are not diagnosed until their cancer has reached an advanced stage, when it is considered incurable. For this reason, ovarian cancer has been referred to as the silent killer. However, some recent studies have indicated that the majority of women with ovarian cancer actually do experience symptoms before their diagnosis. Since symptoms may be discreet and vary from person to person, they may not be associated with the symptoms of ovarian cancer. The following are the most common symptoms of ovarian cancer. However, each individual may experience symptoms differently. Symptoms may include: General discomfort in the lower abdomen, including any of the following: o o o o o o o o o Feeling swollen or bloated Increased abdominal size A loss of appetite or a feeling of fullness - even after a light meal Gas, indigestion, and nausea Abdominal pain Diarrhea or constipation Urinary frequency or incontinence by the growing tumor, which may press on nearby organs, such as the bowel or bladder Pelvic pain Pain with intercourse o Abnormal vaginal bleeding General symptoms may include: o o o o Weight loss Back pain Fatigue Difficulty breathing Build up of fluid around the lungs may cause shortness of breath. Ovarian cancer may spread to the lining of the abdominal cavity and lead to the build up of fluid inside the abdomen, called ascites. This fluid places pressure on the lungs. Because epithelial ovarian cancers begin deep in the pelvis, they often do not cause any symptoms until they are at an advanced stage. At the time of initial diagnosis, the majority of women already have advanced stage III or IV cancer. The symptoms of ovarian cancer may resemble other medical conditions or problems. Always consult your physician for a diagnosis. HOW IS OVARIAN CANCER DIAGNOSED? Information about the prevention of cancer and the science of screening appropriate individuals at high risk of developing cancer is gaining interest. Physicians and individuals alike recognize that the best "treatment" of cancer is preventing its occurrence in the first place or detecting it early when it may be most treatable. Diagnosis includes a medical history and physical examination, including a pelvic examination to feel the vagina, rectum, and lower abdomen for masses or growths.!7

8 Screening and Early Detection of Ovarian Cancer For many types of cancer, progress in the areas of cancer screening and treatment has offered promise for earlier detection and higher cure rates. The term screening refers to the regular use of certain examinations or tests in persons who do not have any symptoms of a cancer but are at high risk for that cancer. The risk factors are different for different types of cancer. An awareness of these risk factors is important. Refer to the section on What Causes Ovarian Cancer? to review specific risk factors. The predictive value of screening may be greater for women who are at a high risk of developing ovarian cancer, but whether screening will allow for early detection and improve survival among such women remains unknown. Annual Pelvic Examination: Currently, the most widely used way to detect ovarian cancer is to undergo a complete gynecologic examination at least once per year. Because ovarian cancers begin deep in the pelvis, they often do not cause any symptoms until they are at an advanced stage. In order to improve outcomes for women with ovarian cancer, the disease has to be diagnosed early, before it spreads. A Pap test may be requested as part of the pelvic examination. Several new methods of screening have been tried, but none have been uniformly successful. While these options have yet to become standard procedure, they may play a role in the early detection of ovarian cancer in selected patients in the future. These include: Transvaginal Ultrasound: Ultrasound is an imaging technique that uses sound waves to produce an image on a monitor of the abdominal organs, such as the uterus, liver, and kidneys. Two recent clinical studies have shown that transvaginal ultrasound may be an effective screening technique for detecting ovarian cancer. During a transvaginal ultrasound, a receiver is inserted into the vagina. The receiver transmits sound waves to create a picture of internal structures. Because cancerous tumors are a different density than normal tissue, the sound waves create a different pattern when they bounce off the cancer. Transvaginal ultrasound has been used to detect stage I and stage II ovarian cancer in many women, dramatically increasing chances for a cure. These early stage cancers probably would not have been detected by a normal pelvic examination. Women over 50 and women at a high risk for developing ovarian cancer may want to speak with their physicians about including this test in their annual examination. CA-125: Elevated levels of the protein CA-125 in the blood have been associated with ovarian cancer. However, elevated CA-125 levels do not necessarily suggest ovarian cancer because CA-125 levels can be elevated in a number of other cancers, benign conditions and during the first trimester of pregnancy. The normal level of CA-125 is less than 35 units per milliliter in the blood. In general, the higher the level of CA-125 found, the greater the chance of having ovarian cancer, especially for women past menopause. Once a diagnosis of ovarian cancer has been established, the level of CA-125 in the blood is a useful indicator of cancer growth during or after treatment. Predictive Genetic Testing: The identification of cancer susceptibility genes has led to predictive genetic testing. The breast cancer susceptibility genes, BRCA1 and BRCA2, have also been associated with an increased risk of ovarian cancer. Since most ovarian cancers are not the result of known inherited mutations, not all women would benefit from genetic testing. However, women who appear to be at a high risk may benefit from undergoing a test to determine if they do carry the BRCA1 or BRCA2 gene. An accurate genetic test can reveal a genetic mutation, but cannot guarantee that cancer will or will not develop. At!8

9 this point, genetic tests are used to identify individuals who are at an increased risk of developing cancer, so that these individuals may have the option of taking preventive measures, such as increased surveillance. Your physician may order other diagnostic tests, including: Computed tomography (CT or CAT scan) - a noninvasive procedure that takes crosssectional images of the brain or other internal organs; to detect any abnormalities that may not show up on an ordinary x-ray. The CT scan may indicate enlarged lymph nodes - a possible sign of a spreading cancer or of an infection. Lower gastrointestinal (GI) series - x-rays of the colon and rectum using a contrast dye called barium. Intravenous pyelogram (IVP) - x-ray of the kidneys and ureters, taken after the injection of a dye. Biopsy - a procedure in which tissue samples are removed from the body for examination under a microscope; to determine if cancer or other abnormal cells are present. The diagnosis of cancer is confirmed only by a biopsy. Accurate surgical evaluation of ovarian cancer is necessary for nearly all patients. This can only be accomplished during a laparotomy (a procedure in which an incision is made in the abdomen to expose the abdominal contents for diagnosis or surgery) to determine the stage of the cancer and to remove as much cancer as possible. Following surgical removal and staging of ovarian cancer, a final stage will be given. A Roman numeral from I to IV describes the stage and a letter from "A" to "C" describes a sub-stage. Stage I: Cancer is found only in one or both of the ovaries. Cancer cells may also be found in abdominal fluid, or ascites (fluid in the abdomen). The cancer has not spread to other pelvic or abdominal organs, lymph nodes, or sites outside of the abdomen. Stage II: Cancer is found in the ovaries and has spread to the uterus (womb), the fallopian tubes, or other parts within the pelvis. Cancer cells may also be found in abdominal fluid, or ascites. The cancer has not spread to the upper abdomen, lymph nodes, or sites outside the abdomen. Stage III: Cancer is found in the ovaries and has spread to other body locations within the abdomen, such as the surface of the liver, intestine (bowel) or lymph nodes. (Lymph nodes are part of the immune system. They produce and store infection-fighting cells). The cancer has not spread to sites outside the abdomen or inside the liver. Stage IV: Cancer is found in the ovaries and has spread outside the abdomen or inside of the liver. Recurrent or Refractory: Recurrent disease means that the cancer has returned (recurred) after it has been treated. Refractory disease means the cancer is no longer responding to treatment. HOW IS OVARIAN CANCER TREATED? Specific treatment for ovarian cancer will be determined by your physician based on: Your age, overall health, and medical history Extent of the disease Your tolerance for specific medications, procedures, or therapies Expectations for the course of the disease Your opinion or preference!9

10 The successful treatment of ovarian cancer requires the involvement and coordination of several different treatment approaches, including surgery, chemotherapy and, in rare cases, radiation therapy. Nearly all women with ovarian cancer will undergo surgery and chemotherapy. Despite surgical removal of the cancer, many patients with ovarian cancer will already have microscopic cancer cells, called micrometastases. These spread away from the ovary to other locations in the abdomen and distant parts of the body. These micrometastases often cannot be detected by currently available tests. Surgery is a local therapy and cannot treat micrometastatic cancer. Therefore, additional systemic treatment using chemotherapy is required to treat micrometastatic cancer. Information obtained during surgery and from other tests determines whether additional treatment with chemotherapy is necessary. Because most patients with ovarian cancer have advanced disease at diagnosis, the majority of patients will receive chemotherapy as part of the overall treatment plan. Ovarian cancers may spread to other organs in the pelvis, local or regional lymph nodes, the surface of the abdominal contents, or through the blood to other locations in the body, such as the lungs, liver, and less frequently, to other organs. In order to effectively plan treatment, it is important to first determine the extent of the spread or the stage of the cancer. Surgery for ovarian cancer may include: o o Salpingo-oophorectomy - surgery to remove the fallopian tubes and ovaries Hysterectomy - surgical removal of the uterus o Pelvic lymph node dissection - removal of some lymph nodes from the pelvis Chemotherapy - the use of anticancer drugs to treat cancerous cells. In most cases, chemotherapy works by interfering with the cancer cell s ability to grow or reproduce. Different groups of drugs work in different ways to fight cancer cells. The oncologist will recommend a treatment plan for each individual. Radiation therapy - the use of high-energy radiation to kill cancer cells and to shrink tumors. Radiation therapy, like surgery, is a local treatment used to eliminate or eradicate cancer that can be encompassed within a radiation field. Radiation therapy is not typically useful in eradicating cancer cells that have already spread to other parts of the body. Currently, the use of radiation therapy has largely been replaced by chemotherapy. However, since chemotherapy does not cure all patients, clinical trials are ongoing to evaluate how best to integrate radiation therapy into the overall treatment of patients with advanced ovarian cancer. There are two ways to deliver radiation therapy, including the following: o o External radiation (external beam therapy) - a treatment that precisely sends high levels of radiation directly to the cancer cells. The radiation therapist controls the machine. Since radiation is used to kill cancer cells and to shrink tumors, special shields may be used to protect the tissue surrounding the treatment area. Radiation treatments are painless and usually last a few minutes. Internal radiation (brachytherapy, implant radiation) - radiation is given inside the body as close to the cancer as possible. In some cases, a treatment called intraperitoneal radiation therapy is used. A radioactive liquid is given through a catheter into the abdomen. All new treatment information concerning ovarian cancer is categorized and discussed by the stage. In order to learn more about the most recent information available concerning the treatment of ovarian cancer; click on the stage for which you are interested. More detailed information on surgical interventions or radiation therapy for ovarian cancer are in the following links: LINK: SURGERY FOR OVARIAN CANCER!10

11 LINK: RADIATION THERAPY FOR OVARIAN CANCER LINK: STAGE I OVARIAN CANCER LINK: STAGE II OVARIAN CANCER LINK: STAGE III OVARIAN CANCER LINK: STAGE IV OVARIAN CANCER LINK: RECURRENT OVARIAN CANCER LINK: SURGERY FOR OVARIAN CANCER Historically, patients with ovarian cancer were initially treated with initial debulking, maximal surgical removal of their cancer followed by chemotherapy. Over the past several years there has been increasing interest in administering chemotherapy before surgery. This is referred to as neoadjuvant therapy. Surgery to remove cancer with chemotherapy administered before and after surgery is referred to as interval debulking. By administering chemotherapy first, micrometastatic cancer cells may be more easily destroyed and chemotherapy may reduce the amount of cancer. This allows more complete removal of the cancer. Currently, the majority of patients are still offered initial debulking surgery followed by chemotherapy. However, neoadjuvant chemotherapy and interval debulking are increasingly being used and you may want to inquire as to the potential risks and benefits of interval debulking. Laparotomy (Initial Debulking) For patients diagnosed with ovarian cancer during surgery, the first phase of treatment is surgical laparotomy or exploration of the abdomen. During a laparotomy, the surgeon makes an incision down the middle of the abdomen and attempts to remove as much of the cancer within the abdomen and pelvis as possible. The goal of laparotomy is to accurately diagnose and stage the cancer and gain prognostic information that can determine whether additional therapy is necessary. Patients with stage I disease may have the entire cancer removed and may not need to receive additional treatment. Patients with stage II-IV disease undergo surgical "debulking" or removal of the cancer. Typical debulking during the laparotomy includes: A total hysterectomy (removal of the uterus) Bilateral salpingo-oophorectomy (removal of the ovaries and fallopian tubes) Omentectomy (removal of a flap of fatty tissue covering the bowel in the abdomen) And "debulking" to remove any visible cancer within the abdomen If the cancer appears to be limited to the ovaries or the pelvis, the surgeon will also cut small pieces of tissue (biopsy) from the upper abdomen, collect abdominal fluid samples and remove lymph nodes so that they can be examined under a microscope to determine whether they contain cancer. These extensive and time-consuming surgeries are best performed by a gynecologic oncologist, who is a surgeon specialized in the treatment of female pelvic cancers. For patients with metastatic ovarian cancer (cancer detected outside the abdomen), surgery may be beneficial for relief of symptoms and to improve duration of survival. Surgery to remove cancer in the abdomen may help relieve pain, prevent obstruction or blockage of the bowel, and improve a patient's nutritional status. The typical surgery for ovarian cancer prevents women from future childbearing because the reproductive organs (ovaries and uterus) are removed. Occasionally, ovarian cancer will occur in a younger woman who wishes to maintain fertility.! 11

12 If the cancer involves only one ovary and the surgery shows no cancer beyond a single ovary; a unilateral salpingo-oophorectomy (removal of one ovary and fallopian tube) can be performed. This allows the patient to bear children and still provides adequate treatment for the cancer. After childbearing is complete, the remaining ovary and the uterus are often removed in an effort to prevent a recurrence. Despite surgical removal of the cancer, the majority of patients with stage II-IV ovarian cancer will experience a recurrence. This is because patients have micrometastases, which are undetectable microscopic cancer cells that have spread from the original site of cancer to distant locations in the body. In other cases, patients have visible spread of cancer cells outside the ovary into the abdomen, pelvis, or lymph nodes that cannot be completely removed by surgery. When the cancer is removed with surgery so that no remaining cancer is larger than 1 cm (about three-quarters of an inch), the cancer referred to as "optimally debulked." When cancer larger than 1 cm remains after the surgery, the cancer is referred to as "suboptimally debulked." Patients with optimally debulked cancer are more likely to live longer and less likely to experience cancer recurrence following chemotherapy than patients who are suboptimally debulked. Patients who undergo laparotomy for ovarian cancer may experience lower abdominal pain after the operation. Complications related to surgery may include bleeding, infection, slow recovery of bowel function, temporary difficulty with emptying the bladder or other less common conditions. Your surgeon should explain the risk of side effects associated with treatment. Second-Look Laparotomy After completion of chemotherapy, patients undergo a physical examination, a CA-125 blood test, and radiologic studies to evaluate the effectiveness of treatment. When all of these tests are negative for cancer, a patient is said to be in a complete clinical remission. Many patients in complete remission still have microscopic cancer that was not detected with the available tests. Some doctors recommend additional surgical evaluation after completion of chemotherapy to further evaluate the response to treatment. This operation is called a "secondlook laparotomy." A second-look laparotomy is the most accurate method of detecting persistent cancer cells when CA-125 levels are normal. Second-look laparotomy will detect evidence of cancer in at least half of patients thought to be in clinical remission. Even when the second-look laparotomy does not detect any cancer cells, cancer still recurs in approximately 30 to 50 percent of patients. Routine second-look laparotomy is no longer recommended as standard treatment. Many doctors recommend that it only be used as part of a clinical trial. This is because a second-look laparotomy only has value to a patient if the information gained during the laparotomy can change a patient's outcome or subsequent treatment options. This is important for patients to understand because undergoing a second or unnecessary surgery is associated with additional risks and emotional discomfort. These risks include bowel obstruction, adhesions (scar tissue that bind pelvic organs together) and pain. Secondary Debulking When second-look laparotomy detects residual cancer, the additional surgical removal of the cancer is referred to as secondary debulking. While some clinical studies suggest that patients who undergo "additional debulking" at second-look laparotomy may live longer, other doctors do not agree. Strategies to Improve Treatment The following are all surgical treatment strategies currently being evaluated in clinical studies. Given the poor outcomes of treatment for ovarian cancer, the greatest benefit to patients wishing to pursue aggressive or potentially curative treatments may be participation in clinical studies. Neoadjuvant Chemotherapy and Interval Debulking: The combination of surgical debulking and chemotherapy treatment is the standard of care for treatment of stage II-IV ovarian cancer. There is some controversy, however, regarding the timing of surgical debulking.!12

13 Neoadjuvant refers to the administration of anti-cancer chemotherapy before surgery. When surgery is performed after chemotherapy treatment, it is referred to as interval debulking. Some doctors believe that neoadjuvant chemotherapy and interval debulking can reduce the size of the cancer, thereby allowing easier surgical removal, and more effective results from the subsequent chemotherapy. Clinical Trial In 1995, doctors from Europe reported in the New England Journal of Medicine the results of the first significant comparative trial directly evaluating interval surgical debulking as part of an overall treatment plan for women with advanced ovarian cancer. In this clinical study, women with stage IIB to IV ovarian cancer were suboptimally surgically debulked at diagnosis. Patients were initially treated with three cycles of cyclophosphamide (Cytoxan) and cisplatin (Platinol) chemotherapy and then reevaluated. Patients who had no evidence of progressive cancer either received additional debulking surgery or no additional surgery. All patients were then treated with three more cycles of cyclophosphamide and cisplatin chemotherapy. Trial Results Clinical Trial Women who underwent interval debulking surgery survived longer and experienced a longer time to cancer recurrence than women not treated with interval debulking surgery. On average, women treated with interval debulking survived 26 months, compared to 20 months and were alive without evidence of cancer recurrence for 18 months, compared to 13 months for women not treated with interval debulking. Two years from treatment, 56 percent of women treated with interval debulking survived, compared to only 46 percent not treated with debulking surgery. Approximately 15 percent of patients experienced complications from the interval debulking surgery, although these complications were minor in nature. Researchers from Germany recently conducted a clinical trial evaluating neoadjuvant chemotherapy in 63 patients with stage III ovarian cancer and ascites. Patients were divided into two groups: one group (control group) received standard therapy consisting of debulking surgery followed by chemotherapy, while the other group (treatment group) received three cycles of neoadjuvant chemotherapy followed by the standard treatment regimen. Trial Results The rate of complete cancer removal was 32 percent in the group of patients who received neoadjuvant chemotherapy, compared to only 13 percent in the group of patients who only received standard therapy. Importantly, this transferred into improved survival, with patients who received neoadjuvant therapy surviving on average 42 months after treatment, compared to only 23 months for patients who received standard treatment. There was no difference between the two groups in time spent in surgery, blood transfusion requirements, side effects, or mortality during surgery. The results of this clinical trial suggest that neoadjuvant chemotherapy may significantly improve survival in patients with stage III ovarian cancer. More research is currently underway to confirm these results in larger clinical trials. These clinical trials demonstrate that women treated with chemotherapy before surgery are more likely to live longer and experience a longer time until cancer recurrence. Additional confirmatory studies are ongoing to evaluate the role of neoadjuvant therapy and interval debulking surgery. LINK: RADIATION THERAPY FOR OVARIAN CANCER!13

14 Delivery of Radiation Therapy for Ovarian Cancer Modern radiation therapy for ovarian cancer is given via machines called linear accelerators that produce high-energy external radiation beams that penetrate the tissues and deliver the radiation dose deep into the areas where the cancer resides. These modern machines and other state-ofthe-art techniques have enabled radiation oncologists to significantly reduce side effects, while improving the ability to deliver a curative radiation dose to cancer-containing areas and minimizing the radiation dose to normal tissue. For example, with modern radiation therapy, skin burns almost never occur, unless the skin is being deliberately targeted or because of unusual patient anatomy. For widespread ovarian cancer, the entire abdomen is often treated with radiation, with boosts to areas of large cancer growths in the pelvis. Simulation After an initial consultation with a radiation oncologist, the next session is usually a planning session, which is called a "simulation. This is a treatment planning session, during which the radiation treatment fields are determined. Of all of the visits to the radiation oncology facility, the simulation session may actually take the most time. During simulation, patients lie on a table somewhat similar to that used for a CT scan. The table can be raised, lowered, and rotated around a central axis. The "simulator" machine is a machine whose dimensions and movements closely match that of an actual linear accelerator. Rather than delivering radiation treatment, the simulator lets the radiation oncologist and technologists see the area to be treated. The simulation is usually guided by fluoroscopy, so that a patient's internal anatomy can be observed (mainly the skeleton, but if contrast material is given, the kidneys, bowels, bladder or esophagus can be visualized as well). The room is periodically darkened while the treatment fields are being set, and temporary marks may be made on the patient's skin with magic markers. One or more radiation technologists and often a dosimetrist, who performs calculations necessary in the treatment planning, aid the radiation oncologist. The simulation may last anywhere from 15 minutes to an hour or more, depending on the complexity of what is being planned. Once the aspects of the treatment fields are satisfactorily set, x-rays representing the treatment fields are taken. In most centers, the patient is given multiple "tattoos" to mark the treatment fields and replace the marks previously made with magic markers. These tattoos are not elaborate and consist of no more than pinpricks followed by ink, appearing like a small freckle. Tattoos enable the radiation technologists to set up the treatment fields each day with precision, while allowing the patient to wash and bathe without worrying about obscuring the treatment fields. Radiation treatment is usually given in another room separate from the simulation room. The treatment plans and treatment fields resulting from the simulation session are transferred over to the treatment room, which contains a linear accelerator focused on a patient table similar to the one in the simulation room. The treatment plan is verified and treatment is started only after the radiation oncologist and technologists have rechecked the treatment field and calculations, and are thoroughly satisfied with the setup. Treatment Schedules A typical course of radiation therapy for ovarian cancer would entail daily radiation treatments, Monday through Friday, for three to five weeks. This may vary depending on individual circumstances. The actual treatment with radiation generally lasts no more than a few minutes, during which time the patient is unlikely to feel any discomfort. Anesthesia is not needed for radiation treatments and patients generally have few restrictions on activities during radiation therapy. Many patients continue to work during the weeks of treatment. Patients are encouraged to carefully gauge how they feel and not to overexert themselves. Side Effects and Complications The majority of patients are able to complete radiation therapy for ovarian cancer without significant difficulty. Side effects and potential complications of radiation therapy are limited to the!14

15 areas that are receiving treatment with radiation. The chance of a patient experiencing side effects is highly variable. A dose that causes some discomfort in one patient may cause no side effects in other patients. In patients who undergo one or more surgical operations, bowel obstruction may occur. If side effects occur, the patient should inform the technologists and radiation oncologist, because treatment for these side effects is usually available and effective. Radiation therapy to the abdominal/pelvic area may cause diarrhea, abdominal cramping or increased frequency of bowel movements or urination. These symptoms are usually temporary and resolve once the radiation is completed. Occasionally, abdominal cramping may be accompanied by nausea. Some patients have changes in sleep or rest patterns during the time they are receiving radiation therapy and some patients will describe a sense of tiredness and fatigue. Blood counts can be affected by radiation therapy. In particular, the white blood cell and platelet counts may be decreased. This is dependent on how much bone marrow is in the treatment field and whether the patient has previously received or is currently receiving chemotherapy. These changes in cell counts are usually insignificant and resolve once the radiation is completed. Many radiation therapy institutions make it a policy to check the blood counts at least once during the radiation treatments. Late complications are infrequent following radiation treatment of ovarian cancer. Potential complications do include bowel obstruction, ulcers, or cancers caused by the radiation. Previous extensive abdominal or pelvic surgery, radiation therapy, and/or concurrent chemotherapy also affect the probabilities of these late complications. Adjuvant Radiation Therapy It is important to understand that many patients with ovarian cancer already have small amounts of cancer that have spread into the lymph nodes and cannot be detected with any of the currently available tests. Undetectable areas of cancer are referred to as micrometastases. The presence of micrometastases causes cancer recurrence following treatment with surgery alone. An effective treatment is needed to cleanse the body of micrometastases in order to improve a patient's duration of survival and the potential for cure. The delivery of cancer treatment following local treatment with surgery is referred to as "adjuvant" therapy and may include chemotherapy, radiation therapy, and/or biologic therapy. Adjuvant radiation therapy administered after surgery was frequently used before effective chemotherapy was developed. Adjuvant radiation has largely been replaced by adjuvant chemotherapy. However, the combination of chemotherapy and radiation therapy following surgical removal of the cancer may help prevent cancer recurrences. Clinical Trial Austrian researchers treated 64 women with advanced ovarian cancer who underwent surgery and chemotherapy treatment with carboplatin (Paraplatin), epirubicin (Ellence), and prednimustine. After this initial treatment, 32 women who had no remaining detectable cancer were assigned to receive either no further treatment or radiation therapy. The radiation therapy regimen consisted of the delivery of high-energy rays to the whole abdominal area, with additional treatment to the pelvis and para-aortic areas, over a period of 4 weeks. Trial Results After two years, 31 percent of the women who had received radiation therapy and 44 percent of those who had not received radiation therapy had experienced a recurrence. After five years, 51 percent of those who had received radiation therapy and 74 percent of those who did not experienced a recurrence. The 2-year survival rates were 87 percent in women who received radiation therapy and 61 percent in those who had not.!15