HIPEC for Ovarian Cancer: An Exciting Locoregional Strategy

Roisin E. O'Cearbhaill, MD

Dennis S. Chi, MD

Oliver Zivanovic

Memorial Sloan Kettering Cancer Center

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.^2-4 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)

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 antineoplastic 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.

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 (3-4 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.

References

1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9-29.
2. Armstrong DK, Bundy B, Wenzel L, et al; GynecologicOncology Group. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34-43.
3. Alberts DS, Liu PY, Hannigan EV, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med. 1996;335:1950-1955.
4. Markman M, Bundy BN, Alberts DS, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol. 2001;19:1001-1007.
5. Verwaal VJ, van Ruth S, de Bree E, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versussystemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003;21:3737-3743.
6. Zivanovic O, Abramian A, Kullmann M, et al. HIPEC ROC I: a phase I study of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion followed by postoperative intravenous platinum-based chemotherapy in patients with platinum-sensitive recurrent epithelial ovarian cancer. Int J Cancer. 2015;136(3):699-708

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