[icon name=”user” class=”” unprefixed_class=””]  Illana A. Stanley, Ph.D.

Introduction to Ovarian Cancer

Ovarian cancer usually refers to ovarian epithelial carcinoma, by far the most common variety of ovarian malignancy. This malignancy is associated with the ovaries, the female reproductive organs where oocytes are stored and where release of oocytes occurs during ovulation¹. Recent census data indicates that as of 2014 there were 21,290 new cases of ovarian cancer diagnosed in the US and over 200,000 cases world wide with a resulting 14,180 deaths and ~150,000 deaths respectively², ³. Patients with ovarian cancer usually do not present with symptoms until later stages of disease, leading to advanced disease at diagnosis and poor prognosis.

OVARIAN CANCER DIAGNOSIS

Symptoms of ovarian cancer include increased bloating, pelvic or abdominal pain, difficulty eating and the sensation of getting full quickly. These symptoms must be persistent and progressive to be an indication of ovarian cancer rather than other more benign conditions⁴. If a patient presents with these symptoms, the Ob/Gyn will do a physical examination, likely followed by a transvaginalultrasound, a non-invasive procedure that can be used to visualize the ovaries and other features of the peritoneal cavity to look for abnormalities. A clinician may also measure levels of the ovarian cancer associated protein, cancer antigen-125 (CA-125) in the serum. Research has found that the protein CA-125 is present at much higher levels on the surface of ovarian cancer cells than normal cells and this protein has been used as a predictive indicator of ovarian cancer. Unfortunately testing for CA-125 levels in the serum can be prone to false positives⁴. If preliminary tests and symptoms are consistent with a diagnosis of ovarian cancer, surgery is required to confirm diagnosis, and stage the disease.

THE DIFFERENT TYPES OF OVARIAN CANCER

One of the first steps in diagnosis of a cancer is usually histologic staging. Like other solid tumors ovarian cancer can be staged in severity from stage I – IV. In addition ovarian cancers are often characterized by histologic appearance (how the cancerous cells appear under a microscope). There are several different histologic categories of ovarian cancer including serous (the most common), endometrioid, clear cell, mucinous and some less common mixed types. These histologic characterizations are important for prognosis and planning treatment.

Clinicians and researchers have discovered that many different cancers can be stratified into clinically relevant subtypes.Ovarian epithelial carcinoma is no exception. There are two main types of ovarian epithelial carcinoma, distinguished by their cell type of origin and disease progression.

Type I ovarian cancers account for ~30% of all ovarian epithelial neoplasms and include cancers with endometrioid and clear cell histologies⁵. Type I ovarian cancers are more likely to present at an earlier stage and endometriosis, a non-cancerousproliferative condition of the uterine lining, is thought to be a major contributor to this subtype of ovarian cancer⁶. Type I cancers generally grow slower, but there is evidence to suggest that these cancers can also be more resistant to chemotherapy, especially if they do present at an advanced stage⁵. Type II cancers are far more common, accounting for 60-70% of all ovarian cancers. Type II cancers are generally high-grade serous cancers which usually present at later stages and have a more rapid disease progression. The majority of Type II ovarian tumors likely originate from transformed cells at the end of fallopian tubes rather than ovarian epithelial cells⁶. For this reason cancers of the fallopian tube and peritoneal cancers are usually also classified as type II cancers⁵. Type I and Type II ovarian cancers are likely to originate through very different molecular events, as indicated by the distinct genetic mutations found in the different subtypes. For example, a well known tumor suppressor, TP53 is mutated in approximately 96% of Type II high grade serious ovarian carcinomas while Type I carcinomas harbor a more variable range of cancer causing mutations⁷.

STAGES OF OVARIAN CANCER

As with other cancers a system of staging is used to denote the clinically significant progression of the disease and provide clinicians with a standard measure for making a prognosis and planning treatment. The most recent and widely adopted staging protocol for ovarian cancer as well as the related fallopian tube and peritoneal cancers was developed by the International Federation of Gynecology and Obstetrics (FIGO) and was most recently revised in 2013. Ovarian cancer staging is determined based on a combination of 3 factors which are summarized using “TNM” notation in the FIGO system. ‘T’ followed by a number represents the extent of the primary tumor. N (0 or 1) indicates the absence of presence of local lymph node metastasis. M (0 or 1) indicates the absence or presence of distant metastasis. The general stages of ovarian cancer are summarized as follows⁸:

STAGE I (T1, N0, M0)

The cancer is found in one or both ovaries but it hasn’t spread to other organs, lymph nodes or distant sites. Stage IA-B ovarian cancers are limited to one or both ovaries but without malignant cells being found on the outside of the ovary or in the abdominal fluid (ascites) or fluid used to wash the peritoneal cavity during surgery. Stage IC tumors are still limited to the ovaries but there is a higher chance of potential spread due to one or more of the following: surgical spill or tumor capsule rupture, cancer found on the surface of the ovaries, and malignant cells found in the fluid surrounding the ovaries or the wash fluid used during surgery.

STAGE II (T2, N0, M0)

The tumor involves one or both ovaries with extension to the pelvic part of the peritoneal cavity. This is a fairly rare and somewhat ill defined stage for ovarian cancer. Stage IIA cancers are found with tumor implants into neighboring organs like the fallopian tubes and uterus. Stage IIB tumors have spread to other parts of the pelvic region. There is still no lymph node involvement or distant metastasis.

STAGE III (T1/T2, N0/N1, M0)

Most Type II cancers (high grade serous carcinomas) present as stage III cancers. Stage III cancers have spread outside of the pelvic region but not outside of the peritoneal cavity. Stage III is also achieved if there is involvement of the nearby retroperitoneal lymph nodes (N1). Stages IIIA-IIIC depend largely on the size of metastases (microscopic, less than 2cm or larger than 2cm in diameter) found in the peritoneal cavity.

STAGE IV (ANY T, ANY N, M1)

Stage IV ovarian cancer is the most advanced stage for this disease. Ovarian cancers are classified as stage IV if metastasis is found outside of the peritoneal cavity, in organs such as the liver, lungs and spleen etc. Stage IV cancer is also achieved if there is any lymph node involvement other than the retroperitoneal lymph nodes.

CURRENT STANDARD OF CARE FOR OVARIAN CANCER

The first line of treatment for ovarian cancer is usually surgery. The goal of surgery is to first confirm the diagnosis of cancer, and stage and characterize the cancer, as discussed above. Most importantly, the goal of the initial surgery is cytoreduction, or the removal of as much of the primary tumor as possible. Optimal cytoreduction is achieved when there is no visible residual tumor left following surgery. Long-term patient outcomes are greatly improved when optimal cytoreduction can be achieved. Median overall survival for patients with no residual disease after cytoreduction is 70 months or greater^{9, 10}. There is also evidence that the removal of lymph nodes, a procedure known as a lymphadenectomy, can also improve patient outcomes, especially in the context of optimal cytoreduction of the primary tumor¹¹. Surgical specialization can improve a patient’s chances for optimal cytoreduction. For this reason, whenever possible it is recommended that a gynecologic oncologist be involved in the surgical care. In these cases approximately 60-70% of patients can expect to achieve optimal cytoreduction¹⁰.

Typically, after surgery, patients undergo a course of chemotherapy. The current standard treatment is a combination of two drugs belonging to the classesplatin and taxane. The most commonly used drugs in ovarian cancer treatment are carboplatin and paclitaxel. This drug combination was shown to be as effective and better tolerated than the previously usedcisplatin/paclitaxel combination^{12, 13}.

When administering chemotherapy to ovarian cancer patients, the method of delivery and the frequency of dosing can make a difference for overall survival. Cancer drugs can be delivered by various means including: oral intake (via the mouth), intravenous delivery (injected into the circulation via a peripheral vein) and intraperitoneal delivery (delivery directly into the abdominal or peritoneal cavity). The US National Cancer Institute currently recommends that chemotherapy for ovarian epithelial carcinoma be administered by a combination of intraperitoneal (IP) deliveryand intravenous (IV) delivery rather than by the intravenous route alone¹⁴. This is based on trials showing that IP delivery of chemotherapy significantly increased overall survival compared to IV delivery of the same drugs (65.6 months versus 49.7months). It should be noted that in the trial IP delivery of chemotherapy was not as well tolerated, and some patients in the IP group could not complete the full course of treatment¹⁵. Frequency of drug administration can also influence patient outcomes. A trial conducted by the Japanese Gynecologic Oncology Group (JGOG) showed that weekly administration of paclitaxel versus paclitaxel administered every 3 weeks led to improved progression free and overall survival¹⁶.

Some clinicians may recommend neoadjuvant chemotherapy, chemotherapy which precedes the initial debulking surgery. The goal of such treatment is to reduce the morbidity and mortality associated with surgery and increase the likelihood of optimal cytoreduction. However, there is some debate in the field on the effectiveness of this approach. Current research has been inconclusive on whether neoadjuvant chemotherapy improves overall survival in patients, although there is some evidence to suggest that neoadjuvant therapy can reduce surgery associated complications¹⁷.

Treatment options for recurrent disease are more complicated. It is generally agreed that a second cytoreductive surgery in a patient with disease recurrence is only advisable in patients for which the disease relapsed more than 6 months after completion of chemotherapy. When planning a course of action for recurrent ovarian cancer, it is important to first determine if the cancer is still sensitive to the standard chemotherapy drugs. This will help inform the clinical team on the appropriate treatment options that have the highest probability of improving patient outcomes while minimizing morbidity associated with ineffective treatment⁵.

RISK FACTORS FOR OVARIAN CANCER

Ovarian cancer shares many risk factors with other cancers. This includes increased risk with advanced age, a common trait for many cancers. Most effected women will develop ovarian cancer after menopause, and over half of all ovarian cancers are diagnosed in women who are 63 years of age or older¹. Obesity is also a risk factor for ovarian cancer. Obesity is associated with several detrimental physiological changes that can increase the overall cancer risk. In addition, obesity is especially relevant to common female cancers because obesity increases the circulating estrogens which can have specific impacts on estrogen sensitive tissues like the mammary glands and the female reproductive organs, including the ovaries and fallopian tubes¹⁸. In agreement with this hypothesis, there is evidence that long-term (>10yrs) use of estrogen hormone therapy for menopause can also increase a women’s risk of developing ovarian cancer¹⁹. There is some uncertainty regarding if the increase in risk is equivalent for estrogen only hormone therapy compared to estrogens taken together with progesterone.

A family history of ovarian cancer, or in certain cases other cancers like breast and colorectal cancer, places an individual at increased risk for developing ovarian cancer. In most cases the underlying inherited genetic factors that predispose a person to ovarian cancer are unknown, but in rare cases genetic familial cancer syndromes have revealed specific genetic lesions that greatly increase the risk of ovarian and other cancers. Some of the most well characterized mutations associated with breast and ovarian cancer are inherited mutations in the BRCA1 and BRCA2 genes, which predispose women to developing cancers of the breast, fallopian tube and peritoneal cavity. BRCA1 and BRCA2 are important for repairing DNA damage and, as such, act as tumor suppressors, helping to prevent the accumulation of genetic errors that could drive tumor generation²⁰.

WAYS TO REDUCE OVARIAN CANCER RISK

In addition to the factors which can increase the risk of developing ovarian cancer, there are luckily also some behaviors associated with a reduced risk of this cancer. Becoming pregnant at an earlier age (before 26) and carrying the pregnancy to term is associated with a lower risk for ovarian cancer. This risk is further reduced by the total number of full term pregnancies a woman has. Conversely individuals who do not have children before 35 years of age are at increased risk for ovarian cancer. Somewhat paradoxically, there is strong evidence that oral contraceptive use can also reduce the risk of ovarian cancer. The protective effects of oral contraceptives increase with the duration of use and persist for many years after stopping use¹. It is hypothesized that the reason for the protective effects of pregnancy and oral contraceptives is due to a reduction in the total number of ovulation cycles experienced by women while pregnant or through hormonal intervention. The process of ovulation exposes the ovaries to continuous cycles of damage which is hypothesized to increase ovarian cancer risk over time⁶. The protective effects of oral contraceptives are even greater for ovarian cancers that are associated with endometriosis²¹.

Certain surgical interventions can also significantly reduce the risk of ovarian cancer. For example, tubal ligation and hysterectomy have been shown to reduce ovarian cancer risk. In this case the risk reduction is greatest for endometrioid and clear-cell carcinomas^{22, 23}. Salpingectomy, the surgical removal of the fallopian tubes, can also reduce the risk of developing ovarian cancer. This makes sense given the origin of the most common type II form of ovarian cancer at the distal end of the fallopian tubes. The Society of Gynecologic Oncology recommends that, for women carrying a BRCA1 or BRCA2 germline mutation, salpingectomy in addition to oophorectomy (the removal of the ovaries) should be considered after child-bearing to reduce the high risk of developing ovarian cancer in these patients⁶.

CURRENT PROGRESS ON IMPROVING OVARIAN CANCER OUTCOMES

Due to the high likelihood of ovarian cancer patients presenting with advanced disease at diagnosis and, as a result, having a poor prognosis, there has been substantial effort in the research community to improve screening strategies to facilitate earlier detection of disease. Stage I ovarian cancer can have as high as a 90-95% probability of cure therefore, improvements in ovarian cancer screening and earlier diagnosis have the potential to make a large clinical impact on this challenging disease⁴. Unfortunately, thus far, efforts to define a screening protocol that can reduce overall mortality have not been very successful. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is the most recent large scale US based trial for investigating improvements in cancer screening. This randomized control trial followed 68,616 women from 1993 to 2007 and compared the outcomes for women screened for ovarian cancer using an annual CA-125 serum measurement combined with transvaginal ultrasound. This trial failed to find any benefit to overall mortality for the screening group compared to the control group²⁴.There is a large ongoing study in the United Kingdom that seeks to improve upon the usage of CA-125 for ovarian cancer screening by using a more sophisticated prediction algorithm for identifying at risk women. This trial is expected to reach completion sometime in 2015²⁵.

With regards to ovarian cancer treatment, there is currently active research into developing new, more targeted classes of drugs, that can work together with chemotherapy to improve patient outcomes.

Like most chemotherapy drugs, the standard treatments for ovarian cancer, carboplatin and paclitaxel, work by interfering with DNA replication and cell division respectively, two processes fundamental to rapidly proliferating cells in a tumor^26,27. However, many normal cells can also be adversely affected by these agents. For this reason traditional chemotherapy drugs are extremely toxic and are oftenalso carcinogenic. Cancer treatment, including ovarian cancer treatment, desperately needs new, more targeted therapies that take better advantage of the difference between cancer cells and normal cells to stop cancer growth while avoiding associated toxicity to the patient.

One example of a targeted therapy that has made its way from the laboratory bench to the bedside is anti-angiogenic therapy. Tumors, like other tissues still require a blood supply to deliver oxygen and nutrients and remove waste. Unlike healthy tissue the vasculature of most solid tumors, including ovarian cancer are disorganized and leaky, leading to areas of low oxygen or hypoxia and also perhaps leading to reduced delivery of circulating drugs to all parts of the tumor²⁸. Several drugs have been developed which are able to target and inhibit new blood vessel growth in cancer. In ovarian cancer these anti-angiogenic therapies have generally been tested in combination with standard chemotherapy drugs and as maintenance therapy after the standard round of chemotherapy. Studies so far suggest that a combination of anti-angiogenic drugs and chemotherapy can increase progression free survival and in the case of patients with very advanced stage cancers also may have the ability to increase overall survival^29,30.

Clinicians and researchers hope that continued efforts to improve early detection and develop new targeted therapies, as well as a better understanding of the early stages of ovarian cancer development will provide the new tools needed to confront the current challenges of ovarian cancer treatment.

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