Thanh H. Dellinger, MD
Department of Surgery
Division of Gynecologic Oncology
City of Hope Comprehensive
City of Hope Beckman
Ovarian cancer is often found in advanced stages and is the leading cause of death from gynecologic malignancies. Therapies have focused primarily on intravenous (IV)–based chemotherapies and targeted agents. However, a strong rationale exists for targeting the abdominal and pelvic cavity because ovarian cancer typically involves the peritoneal lining and surfaces of organs in this area of the body. Recent clinical trials have supported the application of regional chemotherapies directly into the abdominal cavity.
Peritoneal surface malignancies of gynecologic origin, including ovarian, fallopian tube, primary peritoneal, and uterine cancers, are the deadliest of gynecologic cancers. This is largely attributable to a paucity of effective screening tools for these cancers and the absence of early symptoms. Therefore, most patients with these malignancies present at an advanced disease stage when tumors have spread to the pelvis, the omentum, and the upper abdomen.
In the United States, the current standard of care is primary maximal-effort cytoreductive surgery and chemotherapy. The goal is to achieve no gross residual disease at surgery completion and to follow up with a platinum and taxane-based chemotherapy regimen for 6 to 8 cycles. Patients whose disease is thought to be not optimally resectable are considered for preoperative neoadjuvant chemotherapy, which is followed by maximal-effort cytoreductive surgery if there is a documented response to treatment.1
Several chemotherapy regimens for treatment of primary ovarian cancer exist, including IV only, intraperitoneal (IP), and IV combinations.
Rationale for Cytoreduction With Regional Therapies
Gynecologic cancers are generally confined to the peritoneal cavity, both at initial diagnosis and at recurrence. Sloughed cancer cells travel with the circulating peritoneal fluid and disperse widely within the peritoneal cavity, often affecting freestanding organs. This activity suggests that the IP administration of chemotherapy should result in a pharmacologic advantage in exposure to and penetration of primary and recurrent tumors.
The peritoneal cavity provides a potential space for chemotherapy instillation, thus allowing the drug to come into direct contact with deposits of malignant cells. Direct contact with tumor deposits, particularly those <0.5 to 1 cm in maximum diameter, has been reported to result in better penetration of individual tumors. In addition, the potential for systemic toxicity may be reduced with IP chemotherapy because high ratios of IP-to-serum concentrations of drug should be achievable.
In addition, the infusion of chemotherapy into the peritoneal cavity also provides distinct pharmacokinetic advantages. Hyperthermic IP chemotherapy (HIPEC) strengthens the effect of IP chemotherapy through antitumor synergism, without systemic drug absorption. Hyperthermic perfusion of tumor sites is based on the principle that heat is directly cytotoxic to the tumor by disrupting the microtubule system, inducing primary protein damage and promoting vascular stasis in synergy with chemotherapy.2,3
Proposed mechanisms of synergy between heat and cisplatin include increased platinum DNA-adduct formation; enhanced transcellular transport, especially in optimally resected tumors; increased membrane permeability; and deeper tumor penetration. The combination of direct cytotoxicity to the peritoneal surface and synergy between heat and cisplatin, coupled with the advantage of dose-dense regional delivery of cytotoxic agents with relatively little systemic toxicity, makes HIPEC an attractive regional therapy in ovarian cancer.
Although HIPEC permits the local delivery of high drug concentrations to exposed peritoneal surface tumors, one important limiting factor is the narrow depth of tissue penetration by the delivered cytostatic agent.4
Depth of drug peritoneal penetration is limited to ≤3 mm from the parietal peritoneal surface.5,6
Hence, the efficacy of HIPEC is inversely proportional to the volume of residual disease, and therapeutic benefit is maximized when all grossly apparent disease is resected (complete cytoreduction). Optimal therapeutic synergy is achieved when HIPEC is administered immediately after maximal cytoreduction, thereby minimizing trapping of viable peritoneal tumor cells in fibrin and postoperative adhesions and maximizing the killing of tumor cells shed during resection.7
Adhesions are lysed during cytoreduction to facilitate uniform distribution of perfusate, maximize direct contact of drug with residual peritoneal tumor cells, and harness the advantage of thermo-chemotherapeutic antitumor synergism.8-11
Trials in Newly Diagnosed Ovarian Cancer
A recent phase III randomized prospective study reported a significant survival benefit for patients with ovarian cancer undergoing interval cytoreductive surgery (CRS) and HIPEC. Following neoadjuvant chemotherapy, 245 patients with newly diagnosed, advanced-stage ovarian cancer were randomized to interval CRS with or without HIPEC, with cisplatin (100 mg/m2
over 90 minutes).12
The primary endpoint of this study was recurrence-free survival (RFS), which was defined as the time from randomization to disease recurrence or progression or death from any cause, whichever occurred first. The median RFS was 10.7 months in the CRS group versus 14.2 months in the CRS-plus-HIPEC group. The median overall survival (OS) was longer in the CRS-plus-HIPEC group by nearly a year: 45.7 versus 33.9 months.
Criticisms of this study include the exclusion of patients with stage IV disease; these represent a large portion of patients with ovarian cancer undergoing neoadjuvant chemotherapy. Another concern expressed was that the median RFS achieved in this trial by the CRS-plus-HIPEC group did not reach the median progression-free survival (PFS), defined as the time until progression, death, or the date of last contact, whichever came first, of approximately 2 years for patients with advanced-stage ovarian cancer undergoing optimal CRS alone, as reported in other studies.13,14
However, compared with results of trials examining ovarian cancer cohorts undergoing neoadjuvant chemotherapy, these trial results approximate the OS.1
Several randomized controlled trials are ongoing in Europe and Asia that will shed further light on these concerns.15
Interestingly, one yet-unpublished Korean phase III trial that randomized 184 women with stage III or IV disease to CRS with or without HIPEC did not report a difference in 2-year PFS or 5-year OS between the 2 arms.16
Among retrospective data, the largest study included 92 patients with primary epithelial ovarian cancer (EOC) who underwent cisplatin with and without doxorubicin HIPEC. The median RFS, defined as the time from first HIPEC until recurrence or last follow-up, was 11.8 months, and the median OS was 35.4 months, with a 5-year OS of 17% for those with advanced EOC.17
Despite persistent concerns and criticisms regarding the use of HIPEC in ovarian cancer, current evidence suggests a role exists for CRS with HIPEC and that further studies are needed to identify subpopulations who best benefit from this treatment, as well as to continue the effort to optimize both the delivery and toxicities of HIPEC.
New Studies and Technologies in the Works
In conclusion, a large pool of evidence exists to support the use of HIPEC in ovarian cancer, and hyperthermic and other novel intraperitoneal chemotherapies should continue to be incorporated into novel clinical trial designs in ovarian cancer.
Although critics of HIPEC point toward the availability of alternative therapies in the up-front setting, such as maintenance therapy and the addition of bevacizumab (Avastin) to IP chemotherapy, more data are required to compare these treatment modalities and determine ideal patient subpopulations for HIPEC, optimal drug selection, and appropriate administration, for the purpose of improving PFS.
The variability of HIPEC administration remains a key issue because there is no standard chemotherapy agent, procedure duration, or temperature currently considered optimal or essential. Furthermore, the ideal tumor histology and disease indication for HIPEC are not well established.
Several phase III clinical trials in recurrent and primary ovarian cancer are under way in Europe and Asia (Table
), and their results are eagerly awaited. Additionally, other novel IP delivery methods are being explored, including pressurized IP aerosolized chemotherapy (PIPAC), an emerging, novel method to deliver pressurized, aerosol chemotherapy into the IP cavity of patients with ovarian cancer at the time of laparoscopic surgery. Preliminary data suggest that this novel IP delivery method is promising in ovarian cancer, allowing for reduced chemotherapy dosage, improved tissue absorption, and intra-abdominal dissemination.18
Lastly, investigators have not sufficiently explored the mechanism of how HIPEC exerts clinical benefit. Still unclear is whether heat by itself, the IP delivery, or the timing of chemotherapy administration is the key contributor to improved clinical outcomes. Studies exploring the effect of HIPEC on the immune microenvironment are lacking. Future HIPEC studies that include the molecular characterization of tumors will likely improve patient selection for this promising therapy.
Table. Select Clinical Trials Evaluating HIPEC in Ovarian Cancer
- Vergote I, Tropé CG, Amant F, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010;363(10): 943-953. doi: 10.1056/NEJMoa0908806.
- Teicher BA, Kowal CD, Kennedy KA, Sartorelli AC. Enhancement by hyperthermia of the in vitro cytotoxicity of mitomycin C toward hypoxic tumor cells. Cancer Res. 1981;41(3):1096-1069.
- El-Kareh AW, Secomb TW. A theoretical model for intraperitoneal delivery of cisplatin and the effect of hyperthermia on drug penetration distance. Neoplasia. 2004;6(2):117-127. doi: 10.1593/neo.03205.
- van Ruth S, Verwaal VJ, Hart AA, van Slooten GW, Zoetmulder FA. Heat penetration in locally applied hyperthermia in the abdomen during intra-operative hyperthermic intraperitoneal chemotherapy. Anticancer Res. 2003;23(2B):1501-1508.
- Kerr DJ, Kaye SB. Aspects of cytotoxic drug penetration, with particular reference to anthracyclines. Cancer Chemother Pharmacol. 1987;19(1):1-5.
- Los G, Mutsaers PH, van der Vijgh WJ, Baldew GS, de Graaf PW, McVie JG. Direct diffusion of cis-diamminedichloroplatinum(II) in intraperitoneal rat tumors after intraperitoneal chemotherapy: a comparison with systemic chemotherapy. Cancer Res. 1989;49(12):3380-3384.
- Zoetmulder F. Cancer cell seeding during abdominal surgery: experimental studies. In: Sugarbaker PH, ed. Peritoneal Carcinomatosis: Principles of Management. Boston, MA: Kluwer Academic Press; 1996.
- Katz MH, Barone RM. The rationale of perioperative intraperitoneal chemotherapy in the treatment of peritoneal surface malignancies. Surg Oncol Clin N Am. 2003;12(3):673-688.
- Yan TD, Black D, Savady R, Sugarbaker PH. Systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal carcinoma. J Clin Oncol. 2006;24(24):4011-4019. doi: 10.1200/JCO.2006.07.1142.
- Hahn GM, Braun J, Har-Kedar I. Thermochemotherapy: synergism between hyperthermia (42-43 degrees) and adriamycin (of bleomycin) in mammalian cell inactivation. Proc Natl Acad Sci U S A. 1975;72(3):937-940. doi: 10.1073/pnas.72.3.937.
- Barlogie B, Corry PM, Drewinko B. In vitro thermochemotherapy of human colon cancer cells with cis-dichlorodiammineplatinum(II) and mitomycin C. Cancer Res. 1980;40(4):1165-1168.
- van Driel WJ, Koole SN, Sikorska K, et al. Hyperthermic intraperitoneal chemotherapy in ovarian cancer. N Engl J Med. 2018;378(3):230-240. doi: 10.1056/NEJMoa1708618.
- Armstrong DK, Bundy B, Wenzel L, et al; Gynecologic Oncology Group. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354(1):34-43. doi: 10.1056/NEJMoa052985.
- Landrum LM, Java J, Mathews CA, et al. Prognostic factors for stage III epithelial ovarian cancer treated with intraperitoneal chemotherapy: a Gynecologic Oncology Group study. Gynecol Oncol. 2013;130(1):12-18. doi: 10.1016/j.ygyno.2013.04.001.
- Naumann RW, Coleman RL, Brown J, Moore KN. Phase III trials in ovarian cancer: the evolving landscape of front line therapy. Gynecol Oncol. 2019;153(2):436-444. doi: 10.1016/j.ygyno.2019.02.008.
- Lim MC, Chang SJ, Jong Yoo H, et al. Randomized trial of hyperthermic intraperitoneal chemotherapy (HIPEC) in women with primary advanced peritoneal, ovarian, and tubal cancer. J Clin Oncol. 2017;37(suppl 15; abstr 5520).
- Bakrin N, Bereder JM, Decullier E, et al. Peritoneal carcinomatosis treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced ovarian carcinoma: a French multicentre retrospective cohort study of 566 patients. Eur J Surg Oncol. 2013;39(12):1435-1443. doi: 10.1016/j.ejso.2013.09.030.
- Tempfer CB, Winnekendonk G, Solass W, et al. Pressurized intraperitoneal aerosol chemotherapy in women with recurrent ovarian cancer: a phase 2 study. Gynecol Oncol. 2015;137(2):223-228. doi: 10.1016/j.ygyno.2015.02.009.