Current and Novel Treatment Strategies for Ovarian Cancer
This is a summary of a lecture presented on December 8, 2009.
Ovarian cancer is the ninth most common cancer among women in the United States, accounting for about 3% of all cancer diagnoses and for an estimated 21,550 new cases in 2009. It is also the fifth most common cause of cancer death, accounting for 5% of all deaths due to cancer in women. The five year survival rates have been improving, albeit slowly. Between 1996 and 2004 the five year survival rates for women diagnosed with localized disease averaged 94%. When the disease was found spread to the pelvis, the survival rates were about 70%. However, in the presence of advanced disease the survival rates declined to about 30%. Unfortunately, two-thirds of ovarian cancer patients are diagnosed with advanced disease.
There are many different kinds of ovarian cancers that originate from different cell types in the normal ovary. Epithelial cells outline the surface of the ovary, germ cells and sex cord stromal cells are located inside the ovary. These three cell types can develop into very different ovarian cancers and tend to be associated with different prognoses. In addition, the ovarian cancers from these cell types can generate subtypes of tumors. For example, epithelial cell tumors that tend to occur later in life can be classified as papillary serous adenocarcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma, mucinous adenocarcinoma and undifferentiated carcinoma. Germ cell tumors and sex cord stromal cell tumors have about 10 different subtypes and tend to occur at a younger age. The pathologist is responsible for looking at these cells under the microscope and classifying them into the appropriate categories based on what they look like.
Risk Factors for Ovarian Cancer
The most important risk factor is being a woman 50 years of age or older. The second most important risk relates to familial factors which include a family history of breast, ovarian or colon cancer. Two major genetic syndromes increase the risk of ovarian cancer significantly. These are BRCA gene mutations and Lynch syndrome, also called hereditary nonpolyposis colon cancer (HNPCC). Other potential but less important risk factors include early menarche (younger than age 12 years of age) and late menopause (older than 52 years of age). There is some concern that hormone replacement therapy or fertility drugs may play a role, but the data are not yet clear.
The lifetime risk of developing ovarian cancer in the general population is 1.5% by age 70. If there are two or more relatives with a history of ovarian cancer the risk increases to 5%. In women who have a BRCA1 gene mutation the risk increases to 45-55% depending on the specific mutation. In BRCA2 mutation carriers the risk is 15-25%. For individuals with Lynch Syndrome (HNPCC), there is a 10-12% chance of developing ovarian cancer. While having these genetic mutations increases the likelihood of developing ovarian cancer, only 10-12% of all ovarian cancers develop on this genetic background. This means that 88-90% of all ovarian cancers are “sporadic” without a known genetic link.
Any women who is concerned about being at increased risk for developing ovarian cancer, should consider genetic counseling and discuss the need for genetic testing and possible interventions. For example, if multiple family members have ovarian or breast cancer, it is appropriate to see a genetic counselor. In addition, if the age of onset of these cancers is younger than 50 years of age, there is bilateral breast cancer or both breast and ovarian cancer in the same patient, genetic counseling is warranted. There is also a higher rate of familial breast and ovarian cancer in women of Ashkenazi Jewish ancestry. Finally, if there is a history of male breast cancer a consultation with a genetic counselor is essential. UCLA has a genetic counseling service available that is involved in research to understand more about these individuals.
There are also factors that decrease the risk for ovarian cancer. Having multiple pregnancies and breastfeeding for longer periods of time decreases the risk of ovarian cancer. Use of oral contraceptive pills for as little as 2 years can reduce the risk of ovarian cancer even in those women who have genetic mutations.
The most effective method to prevent ovarian cancer is surgical removal of both ovaries and fallopian tubes. This is most often done by a laparoscopy. A surgeon makes a small incision at the umbilicus and inserts a camera into the abdomen to provide a visual field and light. Another instrument is inserted through another small incision to cut and remove the ovary and fallopian tubes. This procedure is performed under general anesthesia and usually does not require an overnight stay in the hospital
Ovarian Cancer Screening Methods
There are common misconceptions about ovarian cancer screening methods and their efficacy. The tools that are used to screen for ovarian cancer include the CA125 blood test, a pelvic exam and transvaginal ultrasound. There are certain abnormalities that can be discovered within ovarian cysts through the use of ultrasound. Some of the types of abnormalities that differentiate a cancer from a cyst are thick septations, papillary projections, a thick cyst wall or solid areas.
The CA125 is the most commonly used blood test for ovarian cancer. It is elevated in 80% of individuals who have ovarian cancer, but only about 50% of women with stage I ovarian cancer show an elevation. However, CA125 is not a specific blood test and it is also elevated in other cancers such as endometrial, colon, pancreas, stomach and breast cancer. Non-cancer conditions such as fibroids, hepatitis, pregnancy, abdominal infections, endometriosis, and heart failure can also lead to an elevated CA125. The CA125 is most useful to follow the progress of a woman who has already been diagnosed with ovarian cancer. It can be used to track how the individual is responding to treatment or whether the cancer is progressing.
There have been multiple clinical trials in different countries with large numbers of patients investigating the efficacy of CA125 blood test, a pelvic exam and transvaginal ultrasound as screening for ovarian cancer. These studies generally do not support a generalized screening approach. One ongoing study in the United Kingdom just published preliminary result after 4 years of screening of 200,000 women. Using screening with CA125 serum marker followed by gynecologic ultrasound in the case of abnormal CA125 levels, the investigators found 34 ovarian cancers in 97 surgeries.
The US Preventative Services Task Force, the American Cancer Society, the American College of Obstetricians and Gynecologists, and the National Comprehensive Cancer Network do not recommend routine screening. The National Comprehensive Cancer Network (NCCN) recommends screening of high-risk women (i.e., those women with either a family history of ovarian or breast cancer OR a documented BRCA mutation) with transvaginal ultrasonography and CA125 measurements every 6 months starting at the age of 35 years or 5 to 10 years before the earliest age at diagnosis of ovarian cancer in relatives. NCCN also recommends strong consideration of risk-reducing prophylactic salpingo-oophorectomy (removal of the ovaries and fallopian tubes) at the completion of childbearing in women with a BRCA mutation.
Symptoms of Ovarian Cancer
Most women who have ovarian cancer do have symptoms including abdominal pain and distention, weight changes, early satiety, increased urinary frequency and urgency, changes in bowel habits (constipation, diarrhea), fatigue and shortness of breath. The problem is that the symptoms are often not recognized since they more often caused by conditions other than ovarian cancer.
It is important that women who may have ovarian cancer get referred to a gynecologic oncologist. The American College of Obstetricians and Gynecologists recommends that premenopausal women with a CA 125 level of 200 U/mL or higher, evidence of ascites, abdominal or distant metastases or a family history of breast or ovarian cancer should be referred to expert care. Women who are post-menopausal (over age 50) should be referred if the CA125 is above 35 U/mL, have ascites, nodular or fixed pelvic mass, evidence of abdominal or distant metastasis, and a family history of breast or ovarian cancer.
Newly Diagnosed Ovarian Cancer
The diagnosis of ovarian cancer is suspected based on physical, ultrasound and CT scan findings. In general, patients should undergo surgery for ovarian cancer as the initial treatment. This includes a full abdominal exploration, tumor debulking, hysterectomy, removal of both ovaries and fallopian tubes, omentectomy, pelvic and para-aortic lymphadenectomy. Ovarian cancer tends to spread throughout the pelvic and abdominal areas. The first surgery is the most important one and should be done by a gynecologic oncologist experienced in treating ovarian cancer. The goal of this surgery is the complete removal of all tumor disease. There is a strong relationship between the percentage of the tumor removed during the first surgery and the length of survival.
In over 95% of the cases, chemotherapy needs to follow surgery. The most common chemotherapeutic agents fall into two primary categories, platinum (carboplatin and cisplatin) and taxane agents (taxol and taxotere). The most common approach includes six treatments of combined chemotherapy. In this first line of chemotherapy, the most common regimens include intravenous platinum and taxane, intraperitoneal and intravenous platinum and taxane, intravenous platinum alone, or intravenous alone or combined with intraperitoneal platinum and taxane plus an experimental agent in clinical trials. For some patients who cannot tolerate two drugs, the platinum agent might be given alone.
Intraperitoneal chemotherapy is infused directly into the abdomen and pelvis via a tubing system. This treatment approach has more side effects and is more difficult to tolerate compared to intravenous chemotherapy, but it has been shown to have benefits with regards to increased time to progression of disease and improvement of survival. In one large trial by the Gynecologic Oncology Group, the time to progression was 23.8 months in patients who received intraperitoneal therapy compared to 18.3 months in those who received only intravenous therapy. In addition, survival was enhanced from 49.7 months in those patients who received only intravenous therapy to 65.6 months in those who received intraperitoneal treatments. While not all patients could tolerate 6 cycles of intraperitoneal therapy, there were greater benefits even when only 2 cycles of intraperitoneal chemotherapy were completed .
Clinical studies have also looked at whether using three chemotherapeutic agents for first line chemotherapy would be beneficial, but the data does not support this treatment approach. Recently, promising results have been obtained using taxol infusions every week instead of every three weeks in combination with carboplatin every three weeks. A recent study showed an improvement in progression free survival from 17.2 months to 28 months. It also showed an improvement in survival at three years from 65.1% to 72.1% compared to patients who receive both drugs every three weeks.
Other clinical trials have studied whether continuing some form of therapy after the initial chemotherapy treatment will prevent the recurrence of ovarian cancer (consolidation therapy). One approach has been the monthly administration of Taxol for one year which can increase the interval to recurrence. However, no consolidation therapy has shown a benefit for overall survival at this time.
Treatment of Recurrent Ovarian Cancer
The degree of recurrence risk increases with a higher stage of disease. Only about 5% of patients who have Stage 1A and 1B (grades 1 and 2) will relapse after primary treatment. Patients with early stage disease (Stage 1) who have grade 3 disease have a 20% relapse rate. Stage II has a 30% relapse rate and Stage III patients, who receive optimal debulking surgery, have a 50-60% chance of relapse. If the patient had suboptimal initial surgery with residual tumor disease greater than 1 cm, the risk of relapse increases significantly to about 70-80%. For patients with stage IV disease there is an approximately 80-90% chance of recurrence.
One of the most important factors in the treatment of recurrent disease is the length of time from completion of the initial treatment to the diagnosis of recurrence. Patients who recur in less than 12 months are considered to have platinum resistant disease. Patients whose recurrence is diagnosed more than 12 months later, in general have platinum sensitive disease. In addition to these factors, it is important to evaluate the extent of the disease and whether another surgery is a reasonable option. A second surgery may make sense if it has been 12 or more months to recurrence, if this is an isolated recurrence, the disease can be completely removed, and the patient has the ability to tolerate the surgery. How well the patient tolerates treatment is another factor to consider including side effects from previous chemotherapy such as neuropathy and complications of surgery. Finally, the goals of treatment should be discussed between the patient and the physician, including the chance of cure versus prolongation of survival, symptom management and improved quality of life. Clinical trials may be an option, but the timing of when these are considered depends on a variety of factors including access to the study medication.
There are many chemotherapy options for recurrent ovarian cancer. The most frequently used drugs include carboplatin, cisplatin, topotecan, paclitaxel, docetaxel, liposomal doxorubicin, oral etoposide, gemcitabine, tamoxifen, cyclophosphamide, and hexamethylmelamine. Other drugs in use include oxaliplatin, pemetrex, vinorelbine, 5-FU/leucovorin, irinotecan, ifosfamide, capecitabine, or letrozole. In general, patients with platinum-sensitive disease show a better response to other chemotherapeutic agents compared to patients with platinum-resistant disease.
Novel Treatment Options
Research has been progressing rapidly in ovarian cancer and has resulted in a much better understanding about the factors that influence growth and progression. Molecular biology techniques have revealed extensive genetic profiles of ovarian cancers. There is a growing understanding of the molecular pathways and how these circuits are interconnected to promote cell growth or cell death.
The main new therapeutic strategies include antibodies against cell surface receptors, small molecules that can invade the cell and directly act upon cancer related proteins, and research in vaccines to stimulate the immune responses. One of the most promising developments has been research on targeting tumor vessels. Tumors need an adequate blood supply to feed them. Through the secretion of one particular protein called vascular endothelial growth factor (VEGF), small tumors send out messages to make more blood vessels. This process is called angiogenesis. New drugs target this process and work as angiogenic inhibitors. Bevacizumab (Avastin) is a humanized antibody that binds to VEGF and prevents VEGF from stimulating angiogenesis. Bevacizumab has anti-tumor effects in about 20-30% of all patients with ovarian cancer and has an average length of response of about 5 months. We do not know yet whether Bevacizumab will improve the time to progression of disease in the newly diagnosed patients when given with carboplatin and paclitaxel, but large clinical trials are in progress.
Another very promising approach is the development of treatments that inhibit the repair of DNA. PARP proteins are important in the repair of DNA damage as for example caused by chemotherapy. Recent research has shown that PARP inhibitors prevent the damaged cancer cells from repairing themselves, thus leading them to cell death. This strategy is effective primarily in patients who have BRCA mutations, but seem to also have effects in the absence of these mutations.
Various clinical trials are ongoing in the United States and worldwide. There are different molecular therapies under investigation for ovarian cancer with the promise of more. Treatments and approaches are changing in ovarian cancer, so it is important to stay updated.
For further information about ovarian cancer consider the following web sites:
- US National Institutes of Health
- American Cancer Society
- Gynecologic Oncology Group
- Society of Gynecologic Oncologists
- National Comprehensive Cancer Network
In the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology at UCLA, ovarian cancer treatment requires a team approach that includes gynecologic oncologists, medical oncologists, radiation oncologists, genetic counselors, psychologists and oncology social workers and other members of the integrative oncology team. At the foundation, however, is a team of researchers like those at UCLA’s Jonsson Comprehensive Cancer Center who are dedicated to finding better treatments.
For reprint authorization, contact SimmsMannCenter@mednet.ucla.edu.