Surgeon Discusses Frontline Standard in Newly Diagnosed Ovarian Cancer

Neil Horowitz, MD

There are 2 potential treatment strategies for patients with newly diagnosed advanced ovarian cancer, explained Neil Horowitz, MD: primary cytoreductive surgery or neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS). Choosing between the 2, he added, can be a challenge.

If a surgeon decides to proceed with primary debulking, they should be confident that they can achieve no gross residual disease. However, if a patient presents with stage IV disease, liver involvement, bulky disease in the chest, or unresectable disease, they could be candidates for neoadjuvant NACT-IDS.

The ongoing TRUST trial (NCT02828618) was designed to compare these 2 approaches in an attempt to better define the surgical standard for patients, added Horowitz. The trial will randomize patients to undergo cytoreduction followed by 6 cycles of standard chemotherapy or 3 cycles of standard neoadjuvant chemotherapy followed by interval debulking surgery and another 3 cycles of standard chemotherapy. Primary results from the trial are expected in April 2023.

“In order to enroll patients on the trial you have to do a certain volume of surgery,” said Horowitz. “You have to show proficiency in the surgeries that are required to get down to no gross residual disease. You have to submit a video of your surgery. There are panels that judge whether it’s an appropriate, high-level surgery or one that can't participate.”

By standardizing the surgeons and their surgical ability, he added, the question of whether there is equivalency between primary debulking surgery and neoadjuvant chemotherapy may finally be answered.

OncLive: What is the role of cytoreductive surgery for these patients?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Ovarian Cancer, Horowitz, director of Clinical Research in Gynecologic Oncology, associate professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Dana-Farber Cancer Institute, discussed surgical options for patients with newly diagnosed ovarian cancer.Horowitz: The basis of my presentation [at the State of the Science Summit^TM] was the role of cytoreductive surgery in the upfront management of ovarian cancer. We looked at historical data with regard to surgery. Additionally, work from Joseph Meigs, MD, showed that the amount of residual disease is a predictor of long-term outcomes for women with ovarian cancer. Following those data, we tried to define what optimal cytoreduction is and how that definition has changed over time—how it evolved from less than 2 cm to what we believe should be no gross residual disease.

If a patient presents with advanced disease, how does that impact their surgical options?

We also compared the outcomes from primary cytoreductive surgery with neoadjuvant chemotherapy and interval cytoreduction. In addition, we discussed ways to predict which women may be best suited for upfront surgery versus neoadjuvant chemotherapy.Trying to decide which women should undergo primary cytoreductive surgery is a challenge. There is no standard predictive model, whether radiographic or in terms of CA125 values. There are certain disease locations that can be determined by imaging as “no-fly zones.”

Could cytoreduction lower the risk of acquired drug resistance?

Is no gross residual disease the definition of an optimal cytoreduction?

Could anything be done to improve the mortality rates or serious adverse events that may result from primary debulking?

Outside of those areas, it comes down to a surgeon’s preference and their willingness to push the envelope. It’s really reflective of their training and the support they have in their institution, specifically, the ancillary support to help get patients through whatever may happen. How to approach the disease surgically is individualized for the patient and the surgeon.The idea is that with less disease at the start of chemotherapy there are less cells that may become resistant to the chemotherapy; it's a matter of volume of disease and the time of exposure to the chemotherapy. Hopefully, with surgery we are removing cells that may have inherent disease resistance, and, at the same time, removing cells that would ultimately develop drug resistance over prolonged or repetitive exposure to the drug. These are 2 possible ways that cytoreduction may help.I don't know that it's the formal definition, but it’s our primary goal; that’s because of the substantial survival benefit patients get when we’re able to achieve no gross residual disease. That doesn't mean that less than 1 cm of residual disease is bad; it just isn't as good as no gross residual disease. The survival difference between those women who have suboptimal cytoreduction and optimal cytoreduction is not insignificant, but it's not nearly as large as you would hope for. If women are undertaking the time, the risk, and the potential morbidity and mortality of an upfront surgery, you need to get them into a category that is going to give them the biggest benefit.Mortality is not incredibly high, but you have to make sure that you do the appropriate perioperative prophylaxis and have the help of an intensivist to help manage patients who end up in the intensive care unit. We also use our other surgical oncology colleagues to assist in performing complicated surgeries that we do and don’t do on a regular basis.

What are the patient characteristics that help you decide whether primary debulking or neoadjuvant chemotherapy followed by interval debulking surgery is appropriate?

One of the biggest things would be to ensure that women who have primary cytoreductive surgery undergo it in a facility with experts [that are used to performing] complicated ovarian cancer surgery. Additionally, making sure that the hospitals are set up with consultative services and support that allow surgeons to get a patient to no gross residual disease. Essentially, you want to make sure that surgeries are done in high-volume places with high-volume surgeons.It comes down to the surgeon’s preference and how they tend to approach patients with presumed advanced stage ovarian cancer. There are certain women who are universally considered candidates for neoadjuvant chemotherapy, such as those who have clear stage IV disease, liver involvement, bulky disease in the chest, or disease by imaging that is deemed unresectable. Those women would be candidates for neoadjuvant chemotherapy.

In everybody else, it comes down to what the surgeon thinks they're able to do. There are surgeons who are starting to adapt to diagnostic laparoscopies to see if they can predict or understand who they would be able to cytoreduce down to no gross residual disease. There is a push at some institutions to start incorporating that modality to help assist in trying to decide between primary debulking and neoadjuvant chemotherapy.

There is an ongoing trial called the TRUST trial that is comparing neoadjuvant chemotherapy with primary debulking surgery; it’s trying to formalize surgery.