Ovarian Cancer

Symptoms of ovarian cancer include abdominal bloating or a feeling of pressure, abdominal or pelvic pain, frequent urination, and feeling full quickly when eating.

The term ovarian cancer includes several different types of cancer (an uncontrolled division of abnormal cells that can form tumors) that all arise from cells of the ovary. Most commonly, tumors arise from the epithelium, or lining cells, of the ovary. These include epithelial ovarian (from the cells on the surface of the ovary), fallopian tube, and primary peritoneal (the lining inside the abdomen that coats many abdominal structures) cancers. These are all considered to be one disease process. There is also an entity called ovarian low malignant potential tumor; these tumors have some of the microscopic features of cancer but tend not to spread like typical cancers.

There are also fewer common forms of ovarian cancer within the ovary, including germ cell tumors and sex cord-stromal tumors. All of these diseases as well as their treatment will be discussed.

Epithelial ovarian cancer (EOC)

Epithelial ovarian cancer (EOC) or ovarian carcinoma accounts for a majority (85%-90%) of all ovarian cancers. It is generally thought of as one of three types of cancer that include ovarian, fallopian tube, and primary peritoneal (lining tissues of the pelvis and abdomen) cancer. All three tumor types behave and are treated the same way. The four most common tumor cell types of epithelial ovarian cancer are serous, mucinous, clear cell, and endometrioid. These cancers arise due to DNA changes in cells that lead to the development of cancer. The serous cell type is the most common variety. It is now thought that many of these cancers actually come from the lining in the fallopian tube, and fewer of them from the cells on the surface of the ovary, or the peritoneum. However, it is often hard to identify the sources of these cancers when they are found at advanced stages, which is very common.

These tumors are additionally classified into one of two types:

Type I tumors tend to grow more slowly than type II tumors. Low grade (grade 1) serous carcinoma, clear cell carcinoma, mucinous carcinoma and endometrioid carcinoma are examples of type I tumors.

Type II tumors grow faster and tend to spread sooner. High grade (grade 3) serous carcinoma is an example of a type II tumor.

Borderline ovarian tumors

So-called borderline tumors may develop into large masses that may cause symptoms, but they only rarely metastasize, that is, spread to other areas. Often, removal of the tumor, even at more advanced stages, can be a cure. The two most common types are atypical proliferative serous carcinoma and atypical proliferative mucinous carcinoma.

Germ cell tumors 

Germ cell tumors arise from the reproductive cells of the ovary. These tumors are uncommon and are seen most commonly in teens or young women. This type of tumor includes different categories: dysgerminomas, yolk sac tumors, embryonal carcinomas, polyembryomas, non-gestational choriocarcinomas, immature teratomas, and mixed germ cell tumors.

Stromal ovarian cancers

Another category of ovarian tumor is the sex cord-stromal tumors. These arise from supporting tissues within the ovary itself. As with germ cell tumors, these are uncommon. These cancers come from various types of cells within the ovary. They are much less common than the epithelial tumors. Stromal ovarian cancers (hormone-producing tumors) include granulosa-stromal tumors and Sertoli-Leydig cell tumors.

Risk factors are related to two major categories: menstrual cycles (ovulation) and family history.

• The more a woman ovulates (cycles) over her lifetime, the higher her risk of ovarian cancer. Thus starting her period (menarche) at a younger age, ending her periods (menopause) at a late age, and never getting pregnant (nulliparity) are all risk factors.
• Up to 25% of ovarian cancers are related to family cancer syndromes. Because of this, current guidelines suggest that all women with ovarian cancer should undergo testing for BRCA1 and BRCA2 gene changes (mutations).
• All patients with ovarian cancer will ideally discuss this topic with their doctor.
• These gene mutations can affect males as well as females. If a patient is positive for one of these, then her siblings and her children can be tested as well.
• Testing involves a simple blood test. The results of this test can greatly affect how family members are monitored for various cancers, including breast cancer, and family members of both sexes are encouraged to be tested.

BRCA1 and BRCA2 are genes that have been identified with hereditary cancer risk.

• BRCA1 and BRCA2 increase a woman's risk of breast cancer, for example. When compared with the general population risk (1.3% of women will develop ovarian cancer), women with BRCA1 and BRCA2 genetic mutations have a 35%-70% (BRCA1) or 10%-30% (BRCA2) chance of developing ovarian cancer in their lifetime.
• Lynch syndrome (typically colon and uterine cancer), Li-Fraumeni syndrome, and Cowden's syndrome are other conditions associated with an increased risk of ovarian cancer but are less common.

The less common varieties of ovarian cancer (borderline, germ cell, and stromal tumors) have few definable risk factors.

• The germ cell tumors are often seen at younger ages and are treated very differently both surgically and chemotherapeutically.

According to the National Cancer Institute (NCI), there are over 19,000 cases of ovarian cancer and over 13,000 deaths from the condition each year. The vast majority of the cases are EOC and are found at stage 3 or later, meaning cancer has spread beyond the pelvis or to the lymph nodes. This is mostly due to the lack of definite symptoms and signs at the early stages of cancer growth. Around 1.2% of women will be diagnosed with cancer of the ovary at some point in life, thus, it is relatively rare. The median age of diagnosis is 63. However, approximately 25% of cases are diagnosed between ages 35 and 54. Caucasian women have the highest rate of diagnosis. The incidence rates for ovarian cancer have been declining slightly over the past years in the U.S., by about 3.2% per year. Death rates have also fallen an average of 2.8% per year.

Like many other cancers, when ovarian cancer is found at an early stage (for example, localized to the ovary or fallopian tube) the average survival rate of five years is very good (about 93%); most women at stage 1 will still be alive at five years. However, the five-year average survival rate for all women diagnosed with ovarian cancer is only 50.8%. This is because it is often found at an advanced stage in which the disease has already spread within the abdomen.

Survival is also dependent on the type of care the patient receives. Women suspected of having ovarian cancer should be referred to a gynecologic oncologist. These are physicians with special training in gynecologic (ovarian, uterine, cervical, vulvar, and vaginal) cancers. If a woman does not involve a doctor with this specialized training in her care, then studies show that her survival is significantly worse, often by many years. For this reason, every woman with this disease ideally will obtain a referral to a gynecologic oncologist before she starts any treatment or has any surgery.

Screening tests are used to test a healthy population in an attempt to diagnose a disease at an early stage. Unfortunately, there are no good screening tests for ovarian cancer, despite extensive ongoing research. Imaging (pelvic or abdominal ultrasound, X-rays, and CT scans), and blood tests should not be used as a screen, as they are inaccurate and lead many women to surgery who do not need it (they are false positive tests).

Diagnosis of ovarian cancer is often suspected based on symptoms and physical exam, and these are followed by imaging. The cancer symptoms and signs, when present, are very vague. Ovarian cancer symptoms and signs can include

• fatigue,
• getting full quickly (early satiety),
• abdominal swelling and bloating,
• clothes suddenly not fitting,
• leg swelling,
• changes in bowel habits,
• changes in bladder habits,
• abdominal pain, and
• shortness of breath.

As mentioned above, these symptoms can be very subtle and vague, as well as very common. This only makes diagnosing the disease that much more difficult. Some studies suggest that the average patient with ovarian cancer sees up to three different doctors prior to obtaining a definitive diagnosis. Often, it is the persistence of the patient that leads to a diagnosis. OLMPT and some benign tumors can present with similar symptoms. In addition, they are often seen with very large masses in the ovary. Often these masses are large enough to cause bloating, abdominal distension, constipation, and changes in bladder habits.

In the more uncommon ovarian types (stromal and germ cell tumors), symptoms are similar.

• Sometimes, granulosa cell tumors (granulosa-theca cell tumors) can occur with severe pain and blood in the belly from a ruptured tumor. These can often be confused with a ruptured ectopic pregnancy, as they tend to be found in women of reproductive age.

Often vague symptoms eventually lead to a clinical diagnosis or one based on suspicion generated by exams (for example, a pelvic exam that detects a mass or lump that is abnormal), laboratory tests, and imaging. However, an accurate diagnosis requires some of the mass or tumor to be removed, either by biopsy (less often), or preferably, surgery to verify the diagnosis. Often a high clinical suspicion can trigger a referral to a gynecologic oncologist.

• Various types of imaging studies can be used to preliminarily diagnose this disease and lead to tissue sampling. Pelvic or abdominal ultrasound and CT scans are the most commonly done studies. These often can give images that show masses in the abdomen and pelvis, fluid in the abdominal cavity (ascites), obstructions of the bowels or kidneys, or disease in the chest or liver. Many times, this is all that is necessary to trigger a referral to a specialist, as the suspicion of ovarian cancer can be quite high. PET scans can be used but often are not necessary if a CT scan is able to be performed.
• Blood work can be helpful as well. The CA-125 is a blood test that is often, but not always, elevated with ovarian cancer. If a postmenopausal woman has a mass and an elevated CA-125, she has an extremely high risk of having cancer. However, in younger women, CA-125 is extraordinarily inaccurate. It is elevated by a large number of disease processes, including but not limited to, diverticulitis, pregnancy, irritable bowel syndrome, appendicitis, liver disease, stomach disease, and more. No one should get this test done unless they actually have a mass, or their doctor has some reason to get it. It should not be drawn just to see the level since it is not a reliable screening test for ovarian cancer.
• HE4 is another blood test that is used in the U.S. to monitor patients with ovarian cancer to see if their cancer has recurred. Like CA-125, the HE4 test does not always detect cancer.
• OVA-1 is an example of a blood test that can be used to help doctors determine the likelihood that an identified mass will be cancerous. 

Epithelial ovarian cancer treatment most often consists of surgery and chemotherapy/targeted therapy. The order is best determined by a gynecologic oncologist.

Surgical treatment

Surgery is used for both staging and debulking. Staging is the determination of the extent to which cancer has spread in the body. Debulking is removing as much of the tumor as possible. This surgery usually results in the removal of both tubes and ovaries (known as salpingo-oophorectomy), the uterus (hysterectomy), removal of the omentum (omentectomy -- a large fat pad that hangs off of the colon), lymph node biopsies, and any other organ involved in the disease. This can mean a portion of the small bowel, large bowel, liver, the spleen, the gallbladder, a portion of the stomach, a portion of the diaphragm, and removal of a portion of the peritoneum (a thin lining in the abdomen that covers many of the organs and the inside of the abdominal wall). Done properly, this can be a very extensive surgery. The patients who live the longest have all of the visible nodules taken out at the time of surgery. To accomplish an "optimal debulking," at minimum, no individual nodule greater than 1 cm should be left behind. If this cannot be done, the patient is brought back to the operating room for a second surgery after a few rounds of chemotherapy (neoadjuvant chemotherapy and interval debulking surgery).

It should be noted that now many gynecologic oncologists believe that optimal debulking should mean that there is no visible disease left at the time of surgery. This has been a shift over the last few years. Historically, the goal was to leave no individual nodule greater than 2 cm behind. This has steadily progressed to the point where the term optimal debulking is now accepted by many to mean that there is no disease left to remove. As we have progressed to this point, surgery has become more involved, on a more routine basis. This has led to a concern about the undertreatment of elderly patients due to a fear that they cannot survive the surgical risks.

Chemotherapy

Any patient healthy enough to tolerate chemotherapy will often benefit greatly from its use. The drugs used in ovarian cancer tend to have fewer side effects, and thus are easier to tolerate than many other chemotherapy drugs. Currently, there are two ways to give chemotherapy for ovarian cancer. Traditionally, it is given into the vein intravenously (IV). When initially diagnosed, the usual first-line approach is to give a combination of a platinum drug (typically carboplatin) and a taxane drug, such as paclitaxel (Taxol) or docetaxel (Taxotere).

Another way of giving the chemotherapy is to place it directly into the abdomen (intraperitoneal or IP). In many studies, intraperitoneal administration has been shown to significantly increase survival. This is most often used after optimal surgical debulking. Currently, the drugs used are cisplatin and paclitaxel.

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other treatments to identify and attack (target) specific cancer cells without harming normal cells.

The drug bevacizumab is an example of targeted therapy that has been used in the treatment of advanced ovarian cancer. Bevacizumab (Avastin) is a monoclonal antibody that targets the development of blood vessels by a tumor.

Other targeted therapies for ovarian cancer include a group of drugs known as poly (ADP-ribose) polymerase inhibitors (PARP inhibitors). These drugs block an enzyme necessary for DNA repair and may cause cancer cells to die. Olaparib (Lynparza) and niraparib (Zejula) are examples of PARP inhibitors that may be used to treat advanced ovarian cancer. Angiogenesis inhibitors are a type of targeted therapy drug that works to prevent the growth of new blood vessels that tumors need to grow. Cediranib is an angiogenesis inhibitor being studied in the treatment of recurrent ovarian cancer.

Stromal and germ cell ovarian tumors are most often treated with a combination of chemotherapy drugs. There is much less research on these as they are more durable and much less common than epithelial tumors. Because of their rarity, it will be very difficult to find effective new treatments.

Immunotherapy

Immunotherapy is a treatment that uses the patient's immune system to fight cancer. It is now used in the management of several different types of cancer. With immunotherapy, substances made by the body or made synthetically are used to strengthen the body's natural defenses against cancer.

Hormone therapy

Hormone therapy uses drugs to block the effects of the hormone estrogen. Hormone therapy can be an option for some people with slower growing forms of ovarian cancer.

Experimental treatments

The Gynecologic Oncology Group is a national organization that sponsors clinical trials in gynecologic cancers. Patients can ask their physician if they are eligible for a clinical trial that may help them, as this is how new drugs are discovered. If a doctor or hospital does not participate in the GOG trials, a doctor can often contact a regional center that does.

Staging is the process of classifying a tumor according to the extent to which it has spread in the body at the time of diagnosis.

Ovarian cancer staging:

• Stage 1: Limited to one or both ovaries
• Stage 2: Limited to the pelvis
• Stage 3: Disease outside of the pelvis, but limited to the abdomen, or lymph node involvement, but not including the inside of the liver
• Stage 4: Disease spread to the liver or outside of the abdomen

Complete staging of ovarian cancer includes hysterectomy, removal of the ovaries, tubes, pelvic and aortic lymph node biopsies or dissection, biopsies of the omentum (a large fatty structure that provides support for abdominal organs), and peritoneal (lining tissue of the abdomen) biopsies.

Ovarian cancer staging is determined surgically unless it is stage 4 (metastasis outside of the abdomen, or metastasis to the liver -- not on the surface of the liver). If it is stage 4, or very advanced stage 3, then often this is proven with biopsy, and chemotherapy may start neoadjuvant (before surgery). If the disease does not obviously stage 4, then aggressive surgical staging and debulking (see next section) often is considered. This decision is based on the health of the patient, as well as the judgment of the surgeon as to the chance of achieving an optimal debulking (see treatment below).

Epithelial ovarian cancer is the deadliest of gynecologic cancers.

• Approximately 80% of patients will eventually die of the disease.
• However, survival in the short term is quite good, meaning many years. With the addition of IP chemotherapy, the survival of ovarian cancer has been significantly extended.
  • According to studies, if a patient undergoes optimal debulking followed by IP chemotherapy, then they have a greater than 50% chance to still be alive in six years. This is quite good compared to other advanced-stage cancers.
• Even in the recurrent setting, epithelial ovarian cancer is often very sensitive to chemotherapy. The disease can often go into complete remission (no detectable disease) many times. However, once it recurs, it is not curable and will continue to come back, although drugs may treat recurrent ovarian cancers and prolong survival.

Germ cell and stromal tumors have a much better prognosis. They are often cured because they are more often detected at early stages.

5-year relative survival rates for ovarian (or fallopian tube) cancer

These numbers are based on people diagnosed with cancers of the ovary (or fallopian tube) between 2011 and 2017. These survival rates differ based on the type of ovarian cancer (invasive epithelial, stromal, or germ cell tumor).

*SEER = Surveillance, Epidemiology, and End Results

There is no way to truly prevent ovarian cancer. One would think that removal of the fallopian tubes and ovaries would prevent the disease but this is not always the case (primary peritoneal cancer can arise in the pelvis even after the ovaries have been removed). However, there are ways to significantly reduce your risk.

• If a woman takes birth control pills for more than 10 years, then her risk of ovarian cancer drops significantly.
• Tubal ligation has long been known to decrease the risk of ovarian cancer.
• Recently, removal of the entire tube has been shown to further decrease the risk. This procedure, called a salpingectomy, can be considered by any woman considering a tubal ligation. Removal of the ovaries does decrease the risk of cancer, but at the cost of increasing death due to heart disease and other causes. Currently, this procedure is often saved for specific situations (genetic risk, family history) in patients under 60 to 65 years of age and is not used in the general population. Until recently, if a woman was close to menopause and was undergoing surgery, then the ovaries and tubes would be removed.
• The recent studies indicating that many of these cancers actually come from the fallopian tube, and the studies indicating that removal of even postmenopausal ovaries causes other problems have caused a significant shift in this philosophy. Certainly, the tubes should be removed at the time of hysterectomy for any woman. The need for the removal of the ovaries is much more uncertain.

Genetic abnormalities are an exception to this recommendation. If a patient is positive for a BRCA or Lynch syndrome genetic defect (mutation), then the patient should strongly consider removal of her tubes and ovaries to decrease the chance of her getting cancer. Women with these mutations are at a very high risk of ovarian cancer, and in this situation, the risk of heart disease is not as significant as the death of one of these cancers. This can be planned at the end of childbearing, or at age 35. Each patient is recommended to discuss this with her doctor, or a genetic counselor.

A diagnosis of cancer is often accompanied by the emotional side effects of anxiety, fear, and depression. Just as treatments are designed to help fight cancer growth and spread, self-care and support measures to help one handle the emotional aspect of the diagnosis can be extremely valuable.

Many hospitals and cancer treatment centers offer cancer support groups and counseling services to help manage the trying emotional side effects of cancer and its treatment. There are also a number of valuable online resources for both patients and families.

For example, the American Cancer Society offers tips on coping with cancer in everyday life; coping checklists for patients and caregivers; managing anger, fear, and depression; and a series of online "I can cope" classes through their website.

The National Ovarian Cancer Coalition (NOCC) also offers online resources on coping with ovarian cancer.

The National Cancer Institute offers a variety of patient education publications about coping with the effects of cancer and its treatment on everyday life, including materials for caregivers and family.