Clinical Trials of Hyperthermic Intraperitoneal Chemotherapy in Advanced Ovarian Cancer: Unanswered Questions

September 15, 2015

Based on the currently available scientific evidence, HIPEC should not be considered a standard therapeutic option after optimal cytoreduction in advanced ovarian cancer, nor should it be offered outside of a clinical trial.

Treatment of advanced ovarian cancer remains a challenge, since the majority of patients will develop recurrences, often most evident on peritoneal surfaces. The current conventional intraperitoneal (IP) chemotherapy, defined mostly in three published phase III trials of the Gynecologic Oncology Group (GOG), plus the largest and yet to be analyzed GOG 252 trial, was designed to maximize platinum dose intensity in the presence of microscopic or small-volume residual disease on peritoneal surfaces after surgery, and prior to the emergence of substantial platinum resistance.[1-3] Although results from increased dose intensity achievable by intravenous (IV) platinum-based therapy appeared to reach a plateau in efficacy (but not in major toxic effects-best documented in extensive carboplatin studies),[4-6] the substantially greater IP dose intensity delivered to cells on peritoneal nodules could lead to more efficient eradication in areas of early and life-threatening treatment failures, without greater dose-limiting toxicities. The clinical evidence supporting the efficacy of this conventional IP cisplatin-based chemotherapy is well established, and a recent update of the last two published studies by the GOG provide irrefutable evidence of an improvement in overall survival (with an adjusted hazard ratio of 0.76) compared with IV cisplatin + paclitaxel.[7] However, despite improved survival with IP therapy (which led to the 2006 clinical announcement by the National Cancer Institute in support of IP chemotherapy as standard of care for patients with advanced optimally cytoreduced disease),[8] it has not been widely adopted into routine clinical practice. Reasons for this include variations in the three IP regimens that were declared superior, the inadequacy of the IV cisplatin + paclitaxel control in GOG 114 and GOG 172, the added 2 cycles of high-dose IV carboplatin in GOG 114, and concerns over poor patient tolerability, particularly in GOG 172, including neurotoxicity and catheter-related complications with IP therapy (not surprisingly, when IP paclitaxel was added on day 8 following administration of IP cisplatin, 100 mg/m2, on day 2 of each cycle). Current directions for administration of this conventional GOG IP therapy include testing a decreased dose of cisplatin to 75 mg/m2, omission of IP paclitaxel, substitution of IP carboplatin for cisplatin, and use of bevacizumab to improve retention of chemotherapy within nodules in the peritoneal cavity.[9] Encouraging pilot studies, such as those that added IP bortezomib to IP carboplatin as a means of overcoming platinum resistance (NCT01074411), warrant future consideration. Another potential role for IP cisplatin also worthy of consideration is as consolidation chemotherapy after neoadjuvant chemotherapy with interval debulking surgery in bulky advanced presentations.[10,11] The validity of these approaches needs to be tested in the phase III setting, coupled with translational studies assessing platinum resistance.[12]

Drs. Oseledchyk and Zivanovic provide an overview of the role of hyperthermic IP chemotherapy (HIPEC) in advanced ovarian cancer and cite clinical trials that range from feasibility studies to randomized phase II and III trials-most of them in the recurrent setting, with patients likely exhibiting some degree of platinum resistance relative to the sensitivity to platinum agents observed at presentation (even if designated platinum-sensitive).[13] HIPEC, as initially developed by Dr. Paul Sugarbaker, was meant to control the local growth of mucinous adenocarcinomas of the peritoneal cavity that are notoriously refractory to chemotherapy, and often subjected to repeated palliative surgeries.[14] Sugarbaker’s impressive survival results in this area are suggestive of better control of the disease after surgery plus HIPEC than after surgery alone. Now HIPEC is increasingly being used for a number of malignancies that present with peritoneal carcinomatosis, including gastric, colorectal, appendiceal, and pancreatic cancers, and pseudomyxoma peritonei, which are notoriously insensitive to chemotherapy upon recurrence.[15]

Presumably, perioperative perfusion of IP therapy at temperatures around 42°C immediately following maximal cytoreductive surgery enhances the antitumor effects of drugs, including cisplatin, by augmenting cytotoxicity secondary to loss of DNA repair activities.[16] The hypotheses offered to explain the better outcomes are (1) that the procedure capitalizes on the preferred timing of regional therapy immediately after tumor debulking and prior to formation of postoperative adhesions that hinder drug distribution and efficacy, (2) that there is a synergistic antitumor effect of chemotherapy combined with hyperthermia, (3) that hyperthermia reverses platinum resistance, and (4) that hyperthermia enhances the penetration of drugs into tumors.[17-21]

How valid are these hypotheses for ovarian cancer treatment-especially when the recurrence is still sensitive to platinums and other drugs? The experience with HIPEC in ovarian cancer has been primarily limited to heterogeneous retrospective and case-control series, which do not demonstrate an advantage in overall survival over a vast number of clinical trials by the GOG and others. Ongoing studies and those already published show study variations in patient selection (eg, primary or secondary surgery, first or subsequent recurrences, indeterminate histologic subtypes, etc), differences in chemotherapy drugs and doses, and variability in the temperature and length of hyperthermia. Although HIPEC appears to be relatively well tolerated in appropriately selected patient populations, it is not uncommon for severe postoperative morbidity rates to reach 25%.[22] With regard to drug-related complications, we bring attention to cisplatin-related renal toxicity: although this drug is attractive in any late setting of recurrent ovarian cancer, toxicities have been described in several studies with cisplatin use after HIPEC (Table). This raises the key question for subsequent studies: Is the addition of hyperthermia worth the risk of renal toxicity in the absence of greater insight into platinum resistance and its reversal by hyperthermia? Finally, there are currently no published data from well-designed prospective randomized trials or studies that directly compare HIPEC with conventional postoperative IP therapy, which has a proven survival benefit in a specific upfront setting.

In summary, based on the currently available scientific evidence, HIPEC should not be considered a standard therapeutic option after optimal cytoreduction in advanced ovarian cancer, nor should it be offered outside of a clinical trial. Moreover, still not settled is the question of the optimal drug regimen to use for HIPEC, and the contribution of cisplatin to efficacy and toxicity. The review by Drs. Oseledchyk and Zivanovic points to the rationale for studying HIPEC, and several current prospective randomized trials are evaluating HIPEC in both primary and recurrent disease. In addition, the authors mention novel investigations to improve drug delivery or penetration into the peritoneum, including nanoparticle delivery of IP chemotherapy, which warrant further study. Our commentary is designed to remind the reader of the results from GOG studies of IP therapy (without HIPEC) and of the particular need to understand platinum resistance. We also hope to raise awareness of the renal toxicities of IP cisplatin when administered in the setting of HIPEC.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. 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;335:1950-5.

2. 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;19:1001-7.

3. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34-43.

4. Gore M, Mainwaring P, A’Hern R, et al. Randomized trial of dose-intensity with single-agent carboplatin in patients with epithelial ovarian cancer. J Clin Oncol. 1998;16:2426-34.

5. Calvert AH, Newell DR, Gore ME. Future directions with carboplatin: Can therapeutic monitoring, high-dose administration, and hematologic support with growth factors expand the spectrum compared with cisplatin? Semin Oncol. 1992;19(1 suppl 2):155-63.

6. Jodrell DI, Egorin MJ, Canetta RM, et al. Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer. J Clin Oncol. 1992;10:520-8.

7. Tewari D, Java JJ, Salani R, et al. Long-term survival advantage and prognostic factors associated with intraperitoneal chemotherapy treatment in advanced ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2015;33:1460-6.

8. National Cancer Institute. NCI issues clinical announcement for intraperitoneal chemotherapy for ovarian cancer. 2006. http://ctep.cancer.gov/highlights/docs/clin_annc_010506.pdf. Accessed August 13, 2015.

9. Kwa M, Jandial D. Modulation of intraperitoneal (IP) chemotherapy in ovarian cancer. Transl Cancer Res. 2014;4:60-9.

10. 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;363:943-53.

11. Andreopoulou E, Chen T, Liebes L, et al. Phase 1/pharmacology study of intraperitoneal topotecan alone and with cisplatin: potential for consolidation in ovarian cancer. Cancer Chemother Pharmacol. 2011;68:457-63.

12. Oza AM, Weberpals JI, Provencher DM, et al. An international, biomarker-directed, randomized phase II trial of AZD1775 plus paclitaxel and carboplatin (P/C) for the treatment of women with platinum-sensitive, TP53-mutant ovarian cancer. J Clin Oncol. 2015;33(suppl):abstr 5506.

13. Oseledchyk A, Zivanovic O. Intraoperative hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer. Oncology (Williston Park). 2015;29:695-701, 706.

14. Sugarbaker PH. Laboratory and clinical basis for hyperthermia as a component of intracavitary chemotherapy. Int J Hyperthermia. 2007;23:431-42.

15. Loggie BW, Thomas P. Gastrointestinal cancers with peritoneal carcinomatosis: surgery and hyperthermic intraperitoneal chemotherapy. Oncology (Williston Park). 2015;29:515-21.

16. van de Vaart PJ, van der Vange N, Zoetmulder FA, et al. Intraperitoneal cisplatin with regional hyperthermia in advanced ovarian cancer: pharmacokinetics and cisplatin-DNA adduct formation in patients and ovarian cancer cell lines. Eur J Cancer. 1998;34:148-54.

17. Los G, van Vugt MJ, Pinedo HM. Response of peritoneal solid tumours after intraperitoneal chemohyperthermia treatment with cisplatin or carboplatin. Br J Cancer. 1994;69:235-41.

18. Helm CW, Bristow RE, Kusamura S, et al. Hyperthermic intraperitoneal chemotherapy with and without cytoreductive surgery for epithelial ovarian cancer. J Surg Oncol. 2008;98:283-90.

19. Christophi C, Winkworth A, Muralihdaran V, Evans P. The treatment of malignancy by hyperthermia. Surg Oncol. 1998;7:83-90.

20. Maymon R, Bar-Shira Maymon B, Holzinger M, et al. Augmentative effects of intracellular chemotherapy penetration combined with hyperthermia in human ovarian cancer cell lines. Gynecol Oncol. 1994;55:265-70.

21. Classe JM, Glehen O, Decullier E, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for first relapse of ovarian cancer. Anticancer Res. 2015;35:4997-5005.

22. Chiva LM, Gonzalez-Martin A. A critical appraisal of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of advanced and recurrent ovarian cancer. Gynecol Oncol. 2015;136:130-5.

23. Zanon C, Clara R, Chiappino I, et al. Cytoreductive surgery and intraperitoneal chemohyperthermia for recurrent peritoneal carcinomatosis from ovarian cancer. World J Surg. 2004;28:1040-5.

24. Di Giorgio A, Naticchioni E, Biacchi D, et al. Cytoreductive surgery (peritoneal procedures) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of diffuse peritoneal carcinomatosis from ovarian cancer. Cancer. 2008;113:315-25.

25. Cotte E, Colomban O, Guitton J, et al. Population pharmacokinetics and pharmacodynamics of cisplatinum during hyperthermic intraperitoneal chemotherapy using a closed abdominal procedure. J Clin Pharmacol. 2011;51:9-18.

26. Warschkow W, Tarantino I, Lange J, et al. Does hyperthermic intraoperative chemotherapy lead to improved outcomes in patients with ovarian cancer? A single center cohort study in 111 consecutive patients. Patient Saf Surg. 2012;6:12.

27. 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;136:699-708.

28. Deraco M, Virzi S, Iusco DR, et al. Secondary cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for recurrent epithelial ovarian cancer: a multi-institutional study. BJOG. 2012;119:800-9.

29. Hakeam HA, Breakiet M, Azzam A, et al. The incidence of cisplatin nephrotoxicity post hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery. Ren Fail. 2014;36:1486-91.