POINT: Is There Still a Role for Intraperitoneal Platinum Therapy in Ovarian Cancer?

Oncology (Williston Park). 32(2):75-7, 79.

Keiichi Fujiwara, MD, PhD

Yes-IP Platinum Most Definitely Still Has a Place in the Treatment of Ovarian Cancer

Introduction

As is well known, ovarian cancer tends to spread inside the peritoneal cavity in the early phase of disease development. Intraperitoneal (IP) chemotherapy is a reasonable treatment approach for ovarian cancer because it can directly expose the surface tissues to which the cancer has disseminated to an extremely high concentration of the chemotherapy drug. It is known that the ratio of drug level (area under the curve [AUC]) to plasma in the peritoneal cavity is 12 times higher when cisplatin is infused intraperitoneally than when it is given intravenously[1] and 10 to 18 times higher when carboplatin is infused intraperitoneally.[1] Miyagi et al compared the pharmacokinetic differences between the intravenous (IV) and IP modes of infusion of carboplatin.[2] The 24-hour AUC for carboplatin in the serum was exactly the same regardless of whether the carboplatin was administered intravenously or intraperitoneally. However, the 24-hour AUC for carboplatin in the peritoneal cavity was approximately 17 times higher when the agent was administered by the IP route.[2]

Given the pharmacologic advantage of IP chemotherapy, multiple randomized phase III trials have been conducted to elucidate the role of platinum-based IP chemotherapy in ovarian cancer.

Results of Pre-2006 Randomized Phase III Clinical Trials

The first randomized phase III trial, Gynecologic Oncology Group (GOG) 104, compared the efficacy and safety of IP vs IV cisplatin chemotherapy in combination with IV cyclophosphamide, and showed an overall survival (OS) benefit for patients who were treated with IP chemotherapy.[3] Toxicity profiles, except for the profile for abdominal pain, also favored the IP chemotherapy arm.

The second randomized trial, GOG 114, compared IP vs IV cisplatin chemotherapy in combination with IV paclitaxel.[4] In this trial, progression-free survival (PFS) and OS favored the IP arm. However, both hematologic and nonhematologic toxicities were significantly worse in the IP arm, probably because 2 cycles of IV AUC=7 carboplatin were administered for the purpose of “chemotherapeutic debulking” before IP chemotherapy was administered.

The third randomized phase III trial, GOG 172, also compared IP vs IV cisplatin in combination with paclitaxel.[5] However, in this study, IP paclitaxel was administered on day 8 in the IP arm, while IV paclitaxel was given on day 1 in the IV arm. Although OS was significantly prolonged in the IP arm, toxicity was significantly worse for these patients.

The National Cancer Institute (NCI) conducted a meta-analysis of IP chemotherapy randomized trials-which included the results of GOG 172-and concluded that cisplatin-based IP chemotherapy is recommended for patients with optimally debulked stage III ovarian cancer.[6]

Issues and Challenges of 2006

Despite the recommendation by the NCI, IP chemotherapy has not become a standard therapy for advanced ovarian cancer. This is mainly because the results of the pre-2006 trials were not based on a comparison with IV carboplatin–based chemotherapy, which is the standard chemotherapy regimen for advanced ovarian cancer, and which is significantly less toxic than cisplatin-based chemotherapy. Thus, another randomized phase III trial was needed.

Post-2006 Randomized Phase III Clinical Trials of IP Chemotherapy

Three major randomized clinical trials have been initiated worldwide since 2006. One is the Intraperitoneal Therapy for Ovarian Cancer with Carboplatin (iPocc) trial, conducted by the Gynecologic Oncology Trial and Investigation Consortium (GOTIC)/Gynecologic Cancer Intergroup (GCIG). This trial is comparing the efficacy and safety of IP vs IV carboplatin chemotherapy in combination with weekly IV administration of dose-dense paclitaxel.[7] The iPocc trial was opened in 2010 and completed accrual in 2016; the final analysis will be made available in 2019.

The second of these trials is the GOG 252 trial. The design of this study was exactly the same as that of the iPocc trial except that bevacizumab was added to the chemotherapy phase and maintenance phase of both the IP and IV arms. Also, GOG 252 had an IP cisplatin arm, in which the modified dosing of the top-performing arm of GOG 172 (IP cisplatin plus IV paclitaxel and IP paclitaxel on day 8) was used. Bevacizumab was also utilized in the IP cisplatin arm. The results of GOG 252 were presented in 2016 at the Society of Gynecologic Oncology Annual Meeting.[8] In brief, both IP and IV carboplatin therapy were better tolerated-and to the same degree-compared with IP cisplatin. Neither the IP carboplatin nor the IP cisplatin arm demonstrated superior PFS or OS compared with the IV carboplatin–based standard arm.

The third trial is GCIG OV21/PETROC. This was originally intended to be a phase II/III trial, which tried to evaluate the efficacy of IP chemotherapy after neoadjuvant chemotherapy and interval debulking surgery for advanced ovarian cancer. The patients who achieved an optimal status after interval debulking surgery following neoadjuvant chemotherapy were randomly assigned to either an IV carboplatin–based regimen, an IP carboplatin–based regimen, or an IP cisplatin–based regimen. Paclitaxel was combined with all regimens on day 1 (given IV to all patients) and on day 8 (given via the same route of administration as the other agents in each respective arm). Bevacizumab was not used in this trial. GCIG OV21/PETROC was terminated after the phase II portion because of funding issues; therefore, the investigators presented the results of the phase II portion in 2016 at the American Society of Clinical Oncology (ASCO) Annual Meeting.[9] These results demonstrated that toxicity profiles were significantly better in the IP carboplatin arm. The 9-month progressive disease rate was also significantly better in the IP carboplatin arm.

Discussion of Results of Randomized Phase III Trials

All of the phase III studies, except for GOG 252, have shown better efficacy for IP chemotherapy compared with IV chemotherapy. The reason for the negative results of IP chemotherapy in the GOG 252 trial has not yet been elucidated. However, it is strongly suspected that the addition of bevacizumab may negatively affect the efficacy of IP chemotherapy. At the 2014 ASCO Annual Meeting, Gourley et al presented very interesting data from a genomic signature analysis that used data from the ICON7 study.[10] They demonstrated that the immune subtype of high-grade serous ovarian cancer has a better prognosis compared with other genomic subtypes; however, outcomes for patients in this group were adversely affected by the addition of bevacizumab. The GOG 252 study-when compared with the Japanese dose-dense chemotherapy study[11]-also suggests that the addition of bevacizumab may negatively affect the survival outcomes of patients treated with dose-dense paclitaxel chemotherapy.[12]

The data from Gourley et al and those from the comparison of GOG 252 with the Japanese dose-dense chemotherapy study suggest that the results of the iPocc trial, which genuinely compares the efficacy of IP vs IV carboplatin–based chemotherapy without bevacizumab, will be the touchstone for determining whether or not IP chemotherapy will continue to have a role as an important treatment option for ovarian cancer.

Biomarker Studies Associated With IP Chemotherapy in Ovarian Cancer

In the discussion of IP chemotherapy, it has become essential that the BRCA1/2 mutation status of the cancer tissue be considered. It was demonstrated that the survival outcomes of patients in the GOG 172 trial were best for those patients who had tumor BRCA1/2 mutations and who were treated with IP chemotherapy.[13] This study suggested that patients with BRCA mutations are extremely sensitive to platinums, and that ultra-high-dose platinum chemotherapy delivered via the IP route may be of benefit in this patient population.

Conclusions

Based on the evidence and discussion presented here, I conclude, again, that there is still a role for IP platinum therapy in ovarian cancer. We would emphasize that it is too early to discount its role until the data from the iPocc trial have matured. Also, it is important to identify the patient population who will reap the greatest benefit from IP chemotherapy.

Financial Disclosure: Dr. Fujiwara is a principal investigator for the iPocc trial, for which Bristol-Myers Squibb and Sandz provided the IP carboplatin (an investigational drug in Japan).

References:

1. Fujiwara K, Armstrong D, Morgan M, Markman M. Principles and practice of intraperitoneal chemotherapy for ovarian cancer. Int J Gynecol Cancer. 2007;17:1-20.

2. Miyagi Y, Fujiwara K, Kigawa J, et al. Intraperitoneal carboplatin infusion may be a pharmacologically more reasonable route than intravenous administration as a systemic chemotherapy. A comparative pharmacokinetic analysis of platinum using a new mathematical model after intraperitoneal vs. intravenous infusion of carboplatin-a Sankai Gynecology Study Group (SGSG) study. Gynecol Oncol. 2005;99:591-6.

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;335:1950-5.

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, Southwest Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol. 2001;19:1001-7.

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

6. National Cancer Institute clinical announcement. Intraperitoneal chemotherapy for ovarian cancer. 2006 Jan 5. https://ctep.cancer.gov/highlights/docs/clin_annc_010506.pdf. Accessed January 9, 2018.

7. Fujiwara K, Aotani E, Hamano T, et al. A randomized phase II/III trial of 3 weekly intraperitoneal versus intravenous carboplatin in combination with intravenous weekly dose-dense paclitaxel for newly diagnosed ovarian, fallopian tube and primary peritoneal cancer. Jpn J Clin Oncol. 2011;41:278-82.

8. Walker JL, Brady MF, DiSilvestro P, et al, editors. A phase III clinical trial of bevacizumab with IV versus IP chemotherapy in ovarian, fallopian tube, and primary peritoneal carcinoma. NCI-supplied agent: bevacizumab (NSC #704865, IND # 7921). A GOG/NRG trial (GOG 252). Presented at the Annual Meeting on Women’s Cancer; San Diego, CA; March 19–22, 2016. Abstract LBA6.

9. Mackay H, Gallagher CJ, Parulekar WR, et al. OV21/PETROC: a randomized Gynecologic Cancer Intergroup (GCIG) phase II study of intraperitoneal (IP) versus intravenous (IV) chemotherapy following neoadjuvant chemotherapy and optimal debulking surgery in epithelial ovarian cancer (EOC). J Clin Oncol. 2016;34(suppl):abstr LBA5503.

10. Gourley C, McCavigan A, Perren T, et al. Molecular subgroup of high-grade serous ovarian cancer (HGSOC) as a predictor of outcome following bevacizumab. J Clin Oncol. 2014;32(15 suppl):abstr 5502.

11. Katsumata N, Yasuda M, Isonishi S, et al. Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol. 2013;14:1020-6.

12. Chan JK, Brady MF, Penson RT, et al. Weekly vs. every-3-week paclitaxel and carboplatin for ovarian cancer. N Engl J Med. 2016;374:738-48.

13. Lesnock JL, Darcy KM, Tian C, et al. BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study. Br J Cancer. 2013;108:1231-7.