Ovarian cancer is the second most common gynecological cancer, affecting more than 22,000 women a year in the U.S., yet it remains the most common cause of gynecological cancer death. The vast majority of these cancers begin in the epithelial cells that make up the outer covering of the ovary. When discussing aggressive ovarian cancer, we're talking about the histological subtype of high-grade serous epithelial cancer.
Unfortunately, this aggressive form of the disease is not a small sub-group. It accounts for most diagnoses. Other types of less-common epithelial ovarian cancer include mucinous and clear cell, sex cord-stromal tumors, and germ cell malignancies.
What makes these tumors aggressive is their histology, possible resistance to chemotherapy, late stage at diagnosis, and inevitable recurrence. These tumors are most frequently diagnosed at stage III or IV and even after an initial promising response they almost always recur and develop resistance to chemotherapy.
The most important decision to be made after diagnosis is determining whether an R0 resection can be achieved, removing all visible tumor at the time of surgery.
If optimal (R0) resection can be achieved, it is known that these patients have an increased overall survival and are candidates for intraperitoneal (IP) chemotherapy, which delivers high-doses directly to the abdomen.
A First Choice Treatment Option
Our best approach to ovarian cancer involves upfront debulking surgery followed by six cycles of both IV and IP chemotherapy given simultaneously and utilizing similar platinum- and taxane-based drugs.
IP chemotherapy is an option if optimal cytoreduction was achieved at the time of upfront debulking surgery. GOG 172 demonstrated a 17-month improved overall survival compared to IV chemotherapy alone (N Engl J Med 2006;354(1):34-43). The addition of IP chemotherapy, however, is known to have increased side effects and greater toxicities.
In patients where the disease burden is determined to be too great to achieve R0 resection (either based on imaging or diagnostic laparoscopy), the treatment then involves 3-4 cycles of neoadjuvant chemotherapy, followed by interval debulking surgery, followed by 3-4 cycles of adjuvant chemotherapy. It is currently being studied whether there would be any survival benefit of these patients undergoing IP chemotherapy after interval debulking; the results have not yet been published (NCT00993655).
Fighting Ovarian Cancer Recurrence
When the cancer returns, patients are offered surgery and chemotherapy again, this time delivering hyperthermic intraperitoneal chemotherapy (HIPEC). With this approach, heated chemotherapy is delivered directly into the abdomen at the time of interval cytoreductive surgery.
The surgical incision is closed and the patient is rolled from side to side, allowing the drugs to bathe the peritoneal cavity in the drugs for approximately 1.5 hours. The abdomen is then flushed out and the incision closed. The CHIPOR protocol evaluating the survival benefit in patients with recurrent ovarian cancer is still enrolling, and no results have been published yet.
However, HIPEC may offer improved survival when used as an upfront treatment for those who cannot have IP. A recent article published in the New England Journal of Medicine reported findings that demonstrated an almost 12-month improvement in overall survival with the addition of HIPEC at the time of interval tumor debulking (2018;378:230-240).
How do you lower the mortality rate of an aggressive cancer? Two frustrating roadblocks to better outcomes include the ovarian cancer's poor response to chemotherapy and its near inevitable recurrence. To address these issues, Roswell Park has clinical trials that are studying how the latest immunotherapy strategies may play a role in fighting ovarian cancer.
One promising approach aims to improve response to upfront therapy with checkpoint inhibitors. This drug class, known as PD-L1 antibodies, works to in effect take the brakes off the immune system response. A clinical trial currently open at Roswell Park (NCT03038100) will assess the benefit of adding the checkpoint inhibitor, atezolizumab, to standard chemotherapy (carboplatin, paclitaxel, and bevacizumab) in the setting of neoadjuvant chemotherapy, or after a suboptimal cytoreductive surgery.
Atezolizumab is an antibody that affects the immune system by blocking the PD-L1 pathway, which is involved in the decrease of the body's natural immune response to fight cancer. By blocking the PD-L1 pathway, atezolizumab may help the immune system stop or reverse the growth of tumors.
Ovarian cancer recurs in most cases, even among patients with a very good initial response, leading to lifelong, ongoing treatment, and no evidence supports any maintenance chemotherapy to prevent ovarian cancer recurrence. Roswell Park has developed a vaccine that aims to prevent recurrence in women who have had a complete response to first-line therapy.
Currently in clinical trials, the vaccine is for women whose ovarian tumors test positive for the antigen NY-ESO-1. This immunotherapy is similar to prevention vaccines because it causes the immune system to react against cancer cells like a vaccine would to a virus or bacteria. The vaccine would stimulate the immune system to produce immune cells and antibodies that will help locate NY-ESO-1 and/or LAGE-1 protein on cancer cells. The immune system would hopefully eliminate any cancer cells.
Finally, perhaps our best strategy would follow how we've made strides against other difficult cancers—detect the cancer at an earlier stage. Unlike with cervical cancer, where the Pap and HPV screening tests can detect the cancer at very early, or even precancerous stages, no such screening exists for detecting ovarian cancer in the general population.
Current methods involving serum CA-125 testing and vaginal ultrasound have failed to demonstrate improvement in early detection, even in the high-risk population, and screening for the general population is still lacking. To improve survival today, the best option is to prevent disease in patients that are at high risk to develop ovarian cancer—women with BRCA1, BRCA2 gene mutations, etc.—and the development of a vaccine to prevent recurrence in patients who are diagnosed with ovarian cancer.
STACEY AKERS, MD, FACOG, is Gynecologic Oncologist and Assistant Professor of Oncology at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y.