Search Continues for Optimal HIPEC Use in Ovarian Cancer

Ernest S. Han, MD, PhD, FACOG

Most high-volume centers are equipped to perform primary debulking in patients with advanced ovarian cancer, but for candidates who proceed with neoadjuvant chemotherapy instead, adding hyperthermic intraperitoneal chemotherapy (HIPEC) at the time of interval debulking may improve survival, explained Ernest S. Han, MD, PhD, FACOG.

“Heated intraperitoneal chemotherapy provides us with another option for patients who receive neoadjuvant chemotherapy and undergo interval debulking surgery,” said Han. “It seems to be safe based on the randomized trial data. However, we do need more clinical trials to further support this approach.”

The only randomized trial that has shown a benefit with HIPEC came out of The Netherlands. In the phase III trial, women with newly diagnosed stage III epithelial ovarian cancer who received HIPEC (n = 122) during surgery were 34% less likely to experience recurrence or death versus those who received surgery alone (n = 123). Moreover, women who had HIPEC had a longer median relapse-free survival compared with those who underwent surgery alone, at 14.2 months and 10.7 months, respectively. Additionally, HIPEC added over 10 months to the median overall survival (OS) of patients compared with surgery (45.7 months vs 33.9 months).

Although a similarly designed trial from Korea failed to demonstrate the same benefit (NCT03448354), Han explained that the procedure should still be discussed with patients who may be appropriate candidates. Due to the extensiveness of the procedure, ensuring that a multidisciplinary team is in place to manage any resulting toxicities or complications is critical, he added.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Ovarian Cancer, Han, assistant clinical professor, Division of Gynecologic Oncology, Department of Surgery, City of Hope, discussed the role of HIPEC in advanced ovarian cancer at the time of interval debulking, as well as anticipated research examining its use at time of primary debulking.

OncLive: Are there data to support the use of HIPEC in ovarian cancer?

Han: This is a very interesting topic in and of itself because it’s such a different approach towards chemotherapy administration for patients with ovarian cancer. We have a lot of great data for intraperitoneal chemotherapy (IP)—based chemotherapies for patients with ovarian cancer. For example, 3 large clinical trials indicated that there is benefit [with IP chemotherapy] compared with standard intravenous (IV) chemotherapy. Every time we've compared the two we've seen those benefits.

However, we didn’t see that same level of excitement in the last clinical trial that looked at IP chemotherapy. We found that the IP-based arms were essentially the same as IV chemotherapy. There are different reasons why that might be. Having said that, 3 of the 4 large trials have shown the strength of chemotherapy administered directly into the abdomen.

[These data have] now tied into this newer type of procedure, which uses heated chemotherapy inside the abdomen. It's not a new concept, but it is something that we have started to study more in ovarian cancer. There have been many mainly retrospective studies around the world that have looked at [HIPEC]. They have looked at their own data in terms of benefits, and it has not been exactly clear if there is a benefit [with this approach].

A randomized trial that was recently published in the New England Journal of Medicine does show a benefit with heated IP chemotherapy. This study tested its use in patients who were not candidates to undergo surgery first, so they received neoadjuvant chemotherapy. After several cycles, patients were either randomized to receive either heated chemotherapy with cisplatin or routine interval debulking surgery. That was then followed by a continuation of IV chemotherapy. Investigators showed that progression-free survival (PFS) was significantly better at over 4 months compared with the standard IV arm. Investigators also looked at OS as a secondary endpoint and showed a significant benefit there as well.

One might be wondering whether this approach was toxic because the heated chemotherapy was given in the face of a large debulking surgery. Based on this report, we didn't see any significant differences with the heated chemotherapy versus the standard surgery arm. The toxicities were comparable. This study does help indicate that it is a safe procedure, potentially with benefits.

A second study was done in Korea with HIPEC as well. Investigators didn’t see quite the same benefit as the Dutch study had shown in patients who had stage III/IV ovarian cancer. We don't have the actual published manuscript at this time; we're still waiting for that. The only published randomized data we have in this setting is the Dutch study. We are awaiting the data from the Korean group to see if there are any differences or concerns in that trial.

There is also a move to look at this approach in the frontline setting at the time of initial debulking surgery; there’s a planned randomized trial that will evaluate this. We’ve seen a benefit with HIPEC at interval debulking, but does it confer a benefit at the time of initial debulking surgery? That's an interesting question that we'll probably have to wait many years for before we get that data. It'll provide us with yet another option amongst many different options that are emerging for patients with ovarian cancer.

Is this being incorporated into the design of the TRUST trial?

It's a good question. In the TRUST trial, I don't know if HIPEC is being administered. I don't know if it's an exclusion criterion. In TRUST, they're really looking at primary debulking surgery versus interval debulking surgery. I don't know if patients will be allowed on trial if they received HIPEC. The trial is aiming to answer a purely surgical question regarding the best timing of surgery. The OVHIPEC-2 trial is looking at HIPEC in the frontline setting; that will aim to answer whether there is a benefit to its use in the frontline setting.

Do you the data warrant the use of this approach in practice?

It has to be looked at with caution. It's a study you have to at least talk about with your patients. It's also important that you have the institutional support and the hospital support to perform these types of treatments, as they can be toxic. In our own institutions, we’ve seen patients who have had some renal toxicity and other toxicities from the operation. We are still trying to help optimize the conditions so that patients can get back to health as soon as possible, as it is such another major insult to them. Not only have they undergone a major debulking surgery, but now they're undergoing the heated IP chemotherapy; it's like a “double whammy.” It takes a multidisciplinary team approach, and it takes institutional and nursing support to get patients through the recovery process.

In terms of the logistics, could you expand on who and what is required?

You need the surgical expertise. Oftentimes, in our institution, we will work with our surgical oncologists. There are gynecologic oncologists who are also able to perform these types of procedures. In our institution, we're fortunate to also have the expertise of surgical oncologists. Oftentimes, we will perform procedures together and combine our efforts in order to maximize debulking surgery followed by heated chemotherapy. The other major important part of this is the support afterwards, because patients can get very sick. There can be significant bowel dysfunction and a prolonged recovery process, so we need major supportive care from nursing, occupational physical therapy, and nutrition staff.

Are there certain selection criteria that help you decide who is eligible to receive HIPEC?

We always look at age as a major factor; it's similar to when we're deciding on who gets a major debulking surgery. It is certainly with higher risk compared with baseline debulking surgery. We do counsel patients very carefully about expectations. Patients will typically be in the hospital a little longer compared with a standard debulking surgery. At our institution, we do this under the hospices of our own clinical trial.

Does the enhanced recovery after surgery (ERAS) protocol apply in this setting?

It's a very important aspect, but very little is known about using ERAS in this particular situation compared with debulking surgery alone. Certainly, a lot of the literature for gynecologic oncology is now emerging for standard debulking. It'll be interesting to see if there are any significant differences that we need to also now incorporate for patients with the added hyperthermic IP chemotherapy. There is definitely room for some research and a better understanding of how to optimize a patient's recovery afterwards. Similar aspects of what we use in debulking surgery also apply to some degree in this setting, but I don't think it all completely applies. It's something that needs to be studied further.

What is your advice for clinicians who are considering using HIPEC?

Whether a patient diagnosed with ovarian cancer should undergo surgery first versus chemotherapy first is a very hot area of discussion right now. We now have several large clinical trials that support the safety, and maybe even the equivalency, of using neoadjuvant chemotherapy versus upfront debulking surgery. We still need better ways to determine who is the best candidate to undergo surgery as opposed to chemotherapy. Across the board, there are patient factors that help us decide. Patients who are very malnourished, have too much extensive disease on imaging, or have other medical factors, might drive a clinician toward neoadjuvant chemotherapy; that's a given. However, if a patient could undergo surgery first, we’re at a very tough point now in figuring out how to best decipher which patients will benefit from debulking.

There are laparoscopic trials and the development of a scoring system; that is certainly one way to go about it. Yet, it is another surgery that we impose on the patient. If there are other noninvasive ways [we could study] that would certainly be beneficial for patients so that they don’t have to undergo anesthesia and the knife. For now, the diagnostic laparoscopy is a starting point.

Ultimately, it rests on the surgeon, in terms of their level of comfort as well as the kind of support the hospital has. Depending on the patient and the institution, not having access to a

certain type of surgeon or surgeons who can accomplish debulking surgery may drive patient care. I do like to emphasize [that patients go] to high-volume centers, or a tertiary care center, where the resources and staff are available to help them undergo debulking surgeries to the point of complete resection.

van Driel WJ, Koole SN, Sikorska K, et al. Hyperthermic intraperitoneal chemotherapy in ovarian cancer. N Engl J Med. 2018;378:230-240. doi: 10.1056/NEJMoa1708618.