HIPEC and cytoreductive surgery do not improve outcomes over cytoreductive surgery alone in patients with platinum-sensitive recurrent ovarian cancer

Dec. 22, 2021

Given the success of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal cancers, there is great interest in adapting this treatment for patients with ovarian cancer. Data supporting the use of HIPEC in ovarian cancer are variable. A recently published multicenter, randomized phase 2 study failed to demonstrate benefit of HIPEC with carboplatin for platinum-sensitive recurrent ovarian cancer.

In this study, published in the Journal of Clinical Oncology (JCO) in 2021, patients were randomly assigned to either secondary cytoreductive surgery (CRS) with HIPEC followed by five cycles of carboplatinum-based chemotherapy or CRS followed by six cycles of carboplatinum-based chemotherapy. Patients who received HIPEC had no improvement in survival or time to recurrence.

"This is surprising — we anticipated this would be a positive study," says Carrie L. Langstraat, M.D., a gynecologic oncologist at Mayo Clinic's campus in Rochester, Minnesota, and JCO article author. "It's unfortunate, but it's good we know this."

Study design and findings

This study enrolled 98 participants who underwent complete CRS. Patients were randomized intraoperatively to HIPEC or no HIPEC. Forty-nine patients received HIPEC with carboplatin, 800 mg/m2 for 90 minutes, followed by five cycles of platinum-based IV chemotherapy. The other 49 patients received six cycles of platinum-based IV chemotherapy following CRS.

Although surgeons often choose cisplatin for HIPEC, this agent yields higher kidney toxicity and increased adverse effects, including hearing loss and neuropathy. Thus, this study's investigators selected carboplatin, with its lower side effect profile compared with that of cisplatin. In addition, Oliver Zivanovic, M.D., Ph.D., the lead study author, had previous research experience studying carboplatin in dose-finding phase 1 trials.

Investigators developed the study using a pick-the-winner design. They intended the winning arm to have 17 or more of 49 patients demonstrating no disease progression at 24 months post-surgery. Yet for the HIPEC and standard therapy arms, median progression-free survival proved to be 12.3 and 15.7 months, respectively. At 24 months, eight patients (16.3%) in the HIPEC arm experienced no disease progression or death, while 12 (24.5%) in the standard arm did not experience disease progression or death. Thus, the study had no winning arm.

As secondary objectives, researchers studied HIPEC pharmacokinetics and postoperative toxicity. Though HIPEC treatment wasn't superior, investigators found that study participants tolerated it well.

Prevalent treatment, yet lacking gold standard trial results

HIPEC has been a hot topic for patients with ovarian cancer, says Dr. Langstraat. Gynecologic oncologists extrapolated its use from other intraperitoneal cancers, such as colon and appendiceal cancers; surgeons have found it especially effective in the latter.

For intraperitoneal cancer specialists, therefore, HIPEC seemed logical to apply to other abdominal cavity cancers. Yet, different from many cancer treatments, it lacked clinical research support with results demonstrating efficacy.

"Previous to the study we published in JCO, there was no randomized, controlled trial with HIPEC in patients with platinum-sensitive recurrent ovarian cancer," says Dr. Langstraat. "HIPEC is being used for treatment of ovarian cancer without really defining which agent is best to use or if it's best to use HIPEC at all. Surgeons are treating many patients with recurrent ovarian cancer with HIPEC off-study. Our study's results show that we should take a step back and evaluate rather than extrapolate data from other cancers."

Other potential avenues for HIPEC, recurrent ovarian cancer treatment

Dr. Langstraat says HIPEC is not categorically out as a recurrent ovarian cancer treatment. HIPEC may be effective with higher carboplatin doses or with a different agent, such as cisplatin.

She also notes that HIPEC may have a larger role at initial ovarian cancer diagnosis versus at recurrence. In one randomized, controlled Dutch study published in The New England Journal of Medicine in 2018, HIPEC proved more effective than standard therapy in patients undergoing interval debulking surgery after neoadjuvant chemotherapy for stage 3 epithelial ovarian cancer.

U.S. surgeons continue to have interest in HIPEC and defining where to best use it, says Dr. Langstraat.

Defining the surgical role for recurrent ovarian cancer

Surgery's role in the treatment of recurrent ovarian cancer also has been controversial. Currently, there are no minimal effective treatment options for patients at this stage.

Dr. Langstraat says the role of surgery in recurrent ovarian cancer is uncertain, and most likely its benefit is limited to a well-selected subset of patients. Thus, in the absence of further study, she indicates that it's logical to use surgery in cases in which the cancer type is most receptive to treatment.

"If surgery works for recurrent ovarian cancer, it's for a narrow, defined group," she says. "Our time is best spent achieving complete cytoreduction in the group of patients with platinum-sensitive recurrence with low disease burden."

Thoughts for referring physicians

To receive the best possible cytoreduction for primary or recurrent ovarian cancer, Dr. Langstraat highly encourages physicians to send patients to a specialty center such as Mayo Clinic, where surgeons routinely perform this procedure. Patient outcomes are improved when treated by specialists in ovarian cancer who have a high rate of complete surgical resection, she says. For example, a Dutch retrospective study of 1,077 patients with ovarian cancer published in a 2009 issue of Gynecologic Oncology showed that "overall survival was best in patients treated in specialized hospitals and by high-volume gynecologists."

An academic medical center also is a beneficial place for patients diagnosed at any ovarian cancer stage, as these facilities offer clinical trials in which patients can access new agents unavailable off-study.

For patients undergoing primary surgery at Mayo Clinic in Minnesota, 68% experience complete resection and 90% have less than 1 cm of disease at completion of surgery, says Dr. Langstraat. Mayo Clinic will also take on ovarian cancer cases other centers may decline.

To refer a patient, referring care providers may fill out an online referral form or call (507) 538-8400.

For more information

Zivanovic O, et al. Secondary cytoreduction and carboplatin hyperthermic intraperitoneal chemotherapy for platinum-sensitive recurrent ovarian cancer: An MSK team ovary phase II study. Journal of Clinical Oncology. 2021;39:2594.

Van Driel WJ, et al. Hyperthermic intraperitoneal chemotherapy in ovarian cancer. The New England Journal of Medicine. 2018;378:230.

Vernooij FA, et al. Specialized and high-volume care leads to better outcomes of ovarian cancer treatment in the Netherlands. Gynecologic Oncology. 2009;112:455.

Refer a patient. Mayo Clinic Medical Professionals Provider Relations.