Diagnosis and Treatment of Epithelial Ovarian Cancer

Ovarian cancer represents about 25% of all female genital tract malignancies. However, there are more deaths from ovarian cancer each year in the United States than from endometrial cancer and cervical cancer combined. The lifetime risk of developing spontaneous ovarian cancer is about 1.7%. Epithelial ovarian cancer was expected cause 15,520 deaths in 2008. Mean age at diagnosis is 60. There has been a significant improvement in the five year survival rate for patients with ovarian cancer. This is likely a combination of better tumor debulking surgeries and better chemotherapeutic options.

Most patients with epithelial ovarian cancer do not have signs or symptoms until disease spreads to the upper abdomen. 70% of patients present with advanced disease. Symptoms for early stage ovarian cancer can include nonspecific pelvic discomfort, urinary frequency and constipation which are caused by an enlarging pelvic mass. With advanced disease, patients experience abdominal pain, bloating, anorexia, nausea and constipation.

The best tumor marker for ovarian cancer is CA 125. Minor elevations in CA 125 can also be seen in endometriosis, benign tumors, fibroids and in pregnant and postpartum women. In addition, moderate elevation of CA 125 can be seen in other adnocarcinoma such as breast and endometrial cancer. The sensitivity of CA 125 is 70% to 80% and the specificity is 98.6% to 99.4%. However, in the average risk population with low prevalence of ovarian cancer, the false positive can be unacceptably high.

The National Cancer Institute recommends screening for ovarian cancer in women with known genetic syndromes associated with this disease and for women with strong family history. Routine screening of women without family history of ovarian cancer is not recommended. The known genetic syndromes include hereditary breast and ovarian cancer syndrome associated with BRCA 1, BRCA 2 and Hereditary Nonpolyposis Colorectal Cancer Syndrome (HNPCC). The absolute risk of ovarian cancer in the presence of either BRCA 1 or BRCA 2 mutation ranges from 16% to 60%. For patients with HNPCC syndrome, the lifetime risk of ovarian cancer is 9% to 12%.

Epithelial ovarian cancer accounts for about 90% of ovarian cancers. Common histologies include serous, mucinous, endometroid, transitiona and clear cell types. Germ cell tumors include dysgerminoma, endodermal sinus tumor, malignant teratoma embryonal carcinoma or primary choriocarcinoma. Stromal tumors include granulose tumor or Sertoli-Leydig tumor.

Upon initial presentation, surgery is used for confirmation and staging of ovarian cancer. Stage I disease is confined to one or both ovaries. Stage II involves one or both ovaries with extension to the pelvic viscera. Stage III is associated with implants on the abdominopelvic wall or the serosal surface of the liver or involves small bowel or omentum. Stage IV disease involves distant metastasis. The 5 year survival for stage IA disease and grade 1 or 2 histology is greater than 90%. For high risk stage I disease and stage II disease, 5 year survival is 80%. For patients with stage III disease after optimal debulking, 5 year survival is 20% to 30%. This reduces to be less than 10% for stage III patients with suboptimal debulking and stage IV disease.

Stage I ovarian cancer with favorable prognostic features can be treated with surgery alone. For women with high risk, early stage cancer (Stage I grade 3 or stage II disease), adjuvant chemotherapy with platinum based agents show an 11% improvement in progression free survival and 8% improvement in overall survival. For stage III and IV disease, the current standard of care include maximal attempt at surgical cytoreduction followed by chemotherapy with platinum based agents.

Optimal debulking is an important part in the treatment of ovarian cancer. Retrospective data have shown that survival is better for women who receive chemotherapy in the presence of low volume disease. In the setting where optimal surgical cytoreduction cannot be achieved, an alternative approach is for the patient to receive chemotherapy up front. For patients who have a partial response to neoadjuvant chemotherapy, it may be appropriate to attempt surgical removal of macroscopic disease at that time.

As for the standard of care in chemotherapy for advanced ovarian cancer, studies have shown that paclitaxel/cisplatin combination is superior to cyclophosphamide/cisplatin combination. Later studies showed that carboplatin/paclitaxel is at least as effective as cisplatin/paclitaxel.

Intraperitoneal chemotherapy is an appealing approach for treating a disease that is largely confined in the peritoneal space. GOG 172 which was a phase III clinical trials demonstrated that this regional approach resulted in superior progression free survival and overall survival when compared with the intravenous approach alone. The disadvantage of this approach includes local toxicity, and requirement for intraperitoneal catheter placement.

Because of the high recurrence rate in patients with advanced ovarian cancer, the issue of whether consolidation chemotherapy may improve time to progression and overall survival was examined in a phase III trial comparing 3 and 12 cycles of taxol. Progression free survival favored the 12 cycle arm. However, overall survival was not different between the two arms. Therefore, the oncologist needs to discuss with the patient and allow them to decide whether the improved progression free survival justifies toxicities including peripheral neuropathy and alopecia.

For many patients with advanced ovarian cancer who have an initial treatment response, disease relapses at a later time. The treatment of patients with recurrent disease or resistant disease needs to be individualized. For people with long treatment free interval, similar drugs many be reused. There are also a number of single agent drugs with activity in ovarian cancer. These include altretamine, bevacizumab, docetaxel, etoposide, gemcitabine, liposomal doxorubicin, paclitaxel, tamoxifen, topotecan and vinorelbine.

Radiation can also play a role in the palliation of some patients with recurrent ovarian cancer. Symptoms such as pain from growing pelvic mass or bone metastasis can be palliated. Very rarely cerebral metastasis can develop which can also be treated with radiation.

The best treatment of ovarian cancer needs a team approach between the primary care physician, gynecological oncology surgeon, medical oncologists and radiation oncologists. As more chemotherapeutic agents become available and as we further understand the biology of epithelial ovarian cancer, we hope to further improve the overall survival and quality of life of our patients.

Gigi Q. Chen, MD, practices at Diablo Valley Oncology and Hematology at the California Cancer Research and Treatment Center at Pleasant Hill, California. Her facility specializes in comprehensive, cutting-edge treatment of all forms of cancer through clinical trials, chemotherapy, biological treatments, diagnostic imaging, and radiation.