HIPEC for Ovarian Cancer: An Exciting Locoregional Strategy

Approximately 22,000 women will be diagnosed with epithelial ovarian cancer (EOC) in the United States in 2014, making it the nation’s second most common gynecologic malignancy.(1) The cancer, which often presents at an advanced stage, causes more deaths than any other type of gynecologic malignancy.

Current standard treatment for EOC is a combination of surgery and platinum-based chemotherapy. Although most patients initially respond to treatment, the majority of them eventually develop resistance to platinum therapy, and the cancer recurs. Long-term cure rates languish between 20 and 30 percent.

An important and unique characteristic of ovarian cancer is that it tends to recur within, and remain confined to, the abdominal (peritoneal) cavity for most of its natural history, rather than spreading to distant organs. Once a recurrence in the peritoneal cavity is diagnosed, the disease is no longer curable, and median progression-free survival is six to nine months.

Prevention of disease progression and improvement of treatment strategies are therefore of utmost importance.

Clinical Trials

Because the peritoneal cavity is the predominant site of disease, local intraperitoneal (IP) drug delivery has been evaluated in randomized clinical trials.(2)(3)(4) These trials compared standard intravenous (IV) chemotherapy to cisplatin-based IP therapy delivered through an IP access device after postoperative recovery (several weeks after surgery).

In a 2006 trial,(2) a statistically significant increase in the median progression-free and overall survival was recorded for the cisplatin/paclitaxel IP treatment compared to the IV group, with a survival benefit of 6 and 16 months respectively. However, a substantial percentage of patients were unable to complete the planned six cycles of cisplatin/paclitaxel IP chemotherapy, in most cases due to abdominal discomfort following postoperative adhesion barriers and IP catheter-related complications.(2)

Hyperthermic Intraoperative Intraperitoneal Chemotherapy (HIPEC)

Figure 1. After surgical cytoreduction, percutaneous inflow and outflow catheters and IP temperature probes are placed in the peritoneal cavity. Figure 1. After surgical cytoreduction, percutaneous inflow and outflow catheters and IP temperature probes are placed in the peritoneal cavity. The catheters are connected to the perfusion system, and normal saline is heated to 41-43°C and circulated through the abdomen. Upon reaching the desired intraperitoneal temperature, the chemotherapeutic agent (carboplatin) is added to the perfusate.

The hyperthermic chemoperfusion is performed for 90 minutes, during which the perfusion rate, perfusion volume, and inflow and outflow temperatures are monitored and adjusted if necessary. After completion of perfusion, the perfusate is drained and the abdomen is irrigated with normal saline.
HIPEC differs from traditional postoperative IP delivery primarily in terms of timing (it is administered as a one-time dose in the operating room at the time of cytoreductive surgery) and heating of the anti-neoplastic drug (Figure 1).

The local therapeutic strategy has been explored in the treatment of other solid tumors, including pseudomyxoma peritonei and appendiceal and colorectal cancers,(5) both of which have a similar propensity for peritoneal spread as EOC.

Proposed advantages of the intraoperative, single-dose approach include controlled intraoperative drug exposure without the barriers of postoperative adhesions. In addition, hyperthermia has been shown to increase tumor penetration of anticancer drugs and to synergistically enhance cyotoxicity of platinum agents.

Similar to postoperative IP treatment, the approach is most effective in patients with minimal residual disease after cytoreductive surgery. In contrast to established experience with postoperative normothermic IP treatment, prospective studies on HIPEC in EOC are scant.

In short, surgical cytoreduction with HIPEC is a rational but still experimental approach in the management of EOC.

Next Steps

Memorial Sloan Kettering researchers are currently exploring the combination of surgical tumor resection and HIPEC with platinum agents in patients with recurrent ovarian cancer.

An initial small pilot study showed HIPEC to be safe.(6) Pharmacokinetic data confirmed exceedingly high IP drug concentrations. In addition, analysis of tissue confirmed platinum-induced DNA adducts in tumor biopsies, demonstrating penetration and antineoplastic activity in target cells. After 20 months of median follow-up time, the median progression-free survival was 13.6 months. The results were encouraging to further determine the efficacy of HIPEC as a complementary treatment in patients with EOC.

MSK’s Gynecologic Disease Management Team subsequently initiated a randomized phase II study (Figure 2) — the first in-human randomized trial in the United States designed to compare the efficacy and safety of HIPEC with carboplatin at a dose of 800 mg/m2 administered as HIPEC after surgical resection in patients with recurrent ovarian cancer.

Figure 2. MSK randomized phase II study scheme. Figure 2. MSK randomized phase II study scheme. This is the first in-human randomized trial in the United States designed to compare the efficacy and safety of HIPEC with carboplatin at a dose of 800 mg/m2 administered as HIPEC after surgical resection in patients with recurrent ovarian cancer.

In the trial, patients with minimal residual disease of 5 mm or less will be randomized 1:1 to surgery with HIPEC (experimental arm, n=49) or surgery only (standard therapy arm, n=49). Both arms will receive standard postoperative IV chemotherapy after recovery (three to four weeks after surgery).

Our primary objective is to determine the proportion of patients who will have no evidence of disease progression at 24 months after surgical resection, with or without HIPEC. The trial will further explore the safety and efficacy of HIPEC, and the results may have an impact on how patients with advanced ovarian cancer are treated in the future.