Debate Continues Between Primary Debulking and Neoadjuvant Chemo in Advanced Ovarian Cancer

Stephen J. Lee, MD

For patients with newly diagnosed advanced ovarian cancer, there are still mixed opinions on whether primary debulking surgery is the preferred intervention, over neoadjuvant chemotherapy followed by interval debulking.

However, there are data sets to support both approaches; as such, deciding which to pursue should be based on patient factors and institutional support, said Stephen J. Lee, MD.

Among the 4 randomized phase III trials that have been published, the EORTC 55961 and CHORUS trials showed similar rates of overall survival (OS), irrespective of whether patients received primary debulking or neoadjuvant chemotherapy. Similarly, the SCORPION and JCOG 0602 trials showed similar rates of survival between arms, but at a much higher magnitude—confounding clinicians.

“There are studies to support both sides, and each side has their studies to quote,” said Lee, a gynecologic oncology surgeon at City of Hope. “It comes down to the discussion with the patient, your overall comfort level and the support you have at your institution to take care of the patient after extensive surgery.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Ovarian Cancer, Lee, who is also an assistant clinical professor, Division of Gynecologic Oncology, Department of Surgery at City of Hope, discussed the trials that have added to existing controversies regarding the optimal management of patients with newly diagnosed advanced ovarian cancer and highlighted best practices for deciding between the approaches.

OncLive: What data support the use of primary debulking and neoadjuvant chemotherapy?

Lee: The debate still exists regarding which [approach] is the optimal route to proceed with, whether it's a debulking procedure versus neoadjuvant chemotherapy followed by interval debulking surgery. There have been multiple trials conducted in the United States and in Europe, as well as several single-institution studies that support primary debulking surgery in which you get the extent of disease out. This is known as optimal debulking surgery, residual disease less than 1 cm or no gross residual disease. That’s the goal of surgery, as patients who have more of their tumor removed have better outcomes. This type of surgery is quite extensive and can lead to a higher risk of complications as well as morbidity.

Thus, other avenues are being researched [with the goal of figuring out] how we can attain no gross residual disease while minimizing morbidity; that's where neoadjuvant chemotherapy comes in. There are 4 trials that [have investigated] neoadjuvant chemotherapy. The first 2 are the EORTC [55961] trial and the CHORUS trial. In the [EORTC trial], the OS [with primary debulking] was on the order of 29 to 30 months. That’s in stark contrast to what we would expect to be about 40 to 50 months based upon our primary debulking surgery literature. It's of concern that there is that discrepancy. Of course, cross-trial comparisons always have their caveats, but it's something of note.

At the 2018 ASCO Annual Meeting, 2 other trials were discussed in abstract form. One was the SCORPION trial from Italy, and the other was a JCOG [0602] trial from Japan. Here, investigators didn't see a significant difference in OS between the primary debulking surgery arm compared with the neoadjuvant chemotherapy arm. The OS data were more in line with what we've seen in other studies with upfront primary debulking surgery, around the order of 40 to 50 months.

Now we have 4 trials, 2 that show outcomes that are not comparable with what we would expect, and another 2 trials that still haven't been published fully that show survivals that are more in line with what we'd expect. Now, there is also a study called the TRUST study. That's a multinational trial investigating radical upfront surgery for patients with [newly diagnosed] ovarian cancer. It’s still accruing. We won't have data for another several years, but that's supposed to be our tie breaker.

Are there any other trials to anticipate besides TRUST?

We talked about the 4 randomized trials, with 2 on one side, and 2 on the other. Most people pick and choose what fits their bias. The TRUST trial is really looking at centers that have been specially selected that have extensive experience performing these surgeries. The trial is accruing from those centers specifically, so we'll have to see what those results show.

Have any advances been made in surgical techniques that have reduced the morbidity of primary debulking?

There are multiple single-institution studies, particularly from Memorial Sloan Kettering Cancer Center and Mayo Clinic, that have published extensively on the surgical paradigm and how it has changed over the years. Starting with performing low anterior resection, then moving onto to extensive upper abdominal surgery—to get to the point of optimal debulking or no gross residual disease—has improved outcomes. There is a higher risk of complications and morbidity with these extensive surgeries, so we do have to choose our patients appropriately. Now, the focus has been on how to minimize complications, and that involves the enhanced recovery after surgery (ERAS) protocol, in addition to what we can do preoperatively, intraoperatively, as well as postoperatively. There's a lot of research in that realm.

What factors do you consider when choosing between primary debulking surgery and neoadjuvant chemotherapy?

When patients who are diagnosed with a suspected advanced ovarian cancer come into my office, I take many factors into account. Just because you can remove something or surgically resect something, does not necessarily mean that you should do it. You take into account patient factors, such as their age, comorbidities, performance status, and overall desires and wishes. You also look at their radiographic imaging, which is not perfect, but it's kind of the best we have without performing an invasive procedure to detect the extent of disease. After combining those features together, we make a decision as to who would be appropriate for a primary debulking surgery attempt.

Is there a certain comfort level with surgery as opposed to neoadjuvant chemotherapy?

Primary debulking surgery really involves a team approach, even with gynecologic oncologists who have been trained extensively in radical upper abdominal surgery. Oftentimes, you do need to have the assistance of your surgical oncology colleagues or hepatobiliary surgical colleagues. Those [specialists] aren't available in every single institution. That may limit how extensive of a surgery you can perform and who you take to the operating room.

Is there an approach that you personally prefer?

The Society of Gynecologic Oncology and ASCO released a statement in 2016. In their guidelines for advanced ovarian cancer management, [they state that] the first person [a patient should see] is a gynecologic oncologist. Moreover, that is the person who should make the decision as to whether you proceed with a primary debulking surgery or neoadjuvant chemotherapy. My preference is to take patients who can tolerate surgery, and who I believe I can achieve an optimal debulking or a complete gross resection, [and have them undergo] primary debulking surgery followed by adjuvant chemotherapy.

Most people will talk about several factors, including patient factors. Specifically, their age, comorbidities, and performance status. I don’t really look at CA-125, as it doesn't always correlate to extent of disease. I'm lucky to work at City of Hope where we do have extensive surgical expertise and colleagues who we are able to work with collaboratively. That makes the difficult cases or the more extensive surgeries more doable.

With radiographic imaging, I’m looking for extent of disease with a CT scan of the chest, abdomen, and pelvis. CT scan is not perfect. I tell patients, “It's like Google maps. I can see your front door and your backyard, but I can't really see what's inside the house.” Even though CT scan is quite good, it doesn't show you all the disease that is there. However, that’s the extent of what I generally use to determine whether patients go to surgery or chemotherapy first.

What is your advice to gynecologic oncologists working in the space?

In terms of treating patients with advanced ovarian cancer, ideally, gynecologic oncologists should be the first [healthcare professionals that] patients see. We are the people who make the decision as to whether patients have surgery or chemotherapy first. Each surgeon is going to have a certain comfort level with certain types of procedures and the extent of surgery that can be done by themselves or in conjunction with others at the institution they work at. All of that has to be considered to determine whether patients go to surgery or receive neoadjuvant chemotherapy first. It's still not entirely clear whether one approach is better than the other.