When compared with intravenous (IV) chemotherapy, the use of intraperitoneal (IP) carboplatin with dose-dense weekly paclitaxel improved progression-free survival in patients with ovarian, fallopian tube, or primary peritoneal carcinoma, according to data presented at the 2022 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer.¹

Keiichi Fujiwara, MD, PhD

Results of the phase II/III iPocc trial showed a 17% reduction in the risk for disease progression or death in patients receiving IP vs IV chemotherapy in the intent-to-treat population (hazard ratio [HR] = 0.83; P = .041). Median progression-free survival was 23.5 months with IP chemotherapy compared with 20.7 months with IV chemotherapy. Additional findings, however, showed no difference in overall survival between study arms. Authors of the study suggested that a survival advantage with IP chemotherapy may have been mitigated by the development of newer treatment modalities, particularly PARP (poly [ADP-ribose] polymerase) inhibition.

“IP chemotherapy without bevacizumab improved progression-free survival over the IV regimen regardless of the residual tumor size after initial surgery,” said lead study author Keiichi Fujiwara, MD, PhD, Professor of Gynecologic Oncology at Saitama Medical University International Medical Center, Hidaka-Shi, Japan. “Future trials are necessary to elucidate the true role of IP carboplatin-based chemotherapy in the PARP inhibitor era.”

Future trials are necessary to elucidate the true role of IP carboplatin-based chemotherapy in the PARP inhibitor era.

— Keiichi Fujiwara, MD, PhD

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Background

According to Dr. Fujiwara, prior randomized trials have demonstrated the survival benefit of IP cisplatin-based chemotherapy vs IV chemotherapy for optimally debulked advanced ovarian cancer. However, first-line IP chemotherapy has not been widely accepted as a standard treatment due to the complexity of study designs and toxicity issues.² Moreover, IP carboplatin has never been studied in a phase III trial prior to the initiation of iPocc.

“The GOG-252 and OV21/PETROC trials showed that carboplatin is better than cisplatin for IP therapy in terms of toxicities, but the phase III GOG-252 trial failed to show superiority over IV carboplatin treatment,” said Dr. Fujiwara, who noted that patient selection is also an open question.^3,4 “Our pharmacokinetic study suggested that IP carboplatin therapy should be effective for patients with large-sized residual disease, as most platinum is absorbed via peritoneal capillaries and will reach the inner core of large tumors via systemic circulation.”⁵

Study Methods

In the iPocc trial, Dr. Fujiwara and colleagues sought to determine the efficacy of IP carboplatin compared with IV carboplatin in combination with IV paclitaxel in 655 patients with stage II to IV ovarian, fallopian tube, and primary peritoneal cancer.

Patients with both minimal and larger residual disease after initial surgery were included in the study, but those with borderline malignancies and prior chemotherapy or prior radiation therapy for the current disease were excluded. Patients with severe complications, pleural effusion requiring continuous drainage, active infectious disease, or symptomatic brain metastasis were also excluded from the trial.

Patients were randomly assigned to receive paclitaxel at 80 mg/m² IV on days 1, 8, and 15 with either IV or IP carboplatin at an area under the curve of 6 every 21 days for six to eight cycles. No bevacizumab or maintenance therapy was administered. The primary endpoint was progression-free survival; secondary endpoints included overall survival, toxicity, and quality of life.

Progression-Free Survival Improved, but Overall Survival Unchanged

As Dr. Fujiwara reported, patient characteristics were well balanced between the IV and IP arms. Unlike the previous IP randomization trials, however, 55% of enrolled patients had residual disease larger than 2 cm after initial surgery, said Dr. Fujiwara.

Progression-free survival for the modified intent-to-treat population was significantly better in the IP arm (hazard ratio [HR] = 0.83; P =.041), and the difference in progression-free survival in the intent-to-treat population was even more robust (HR = 0.78; P = .009). The progression-free survival benefit with IP chemotherapy was observed across prespecified subgroups, including those with residual disease that was larger than 2 cm.

“Of note, the Kaplan-Meier curves did not come together even after 10 years,” Dr. Fujiwara added. “This implies there are approximately 7% more patients who are surviving without disease progression in the IP arm compared with the IV arm.”

Overall survival and response rates did not significantly differ between the two study arms. Adverse events were also similar between the two groups, according to Dr. Fujiwara, except for catheter-related infections, which were more common in the IP arm (all-grade, 0.7% vs 10.1%; grade ≥ 3, 0.3% vs 8.4%).

iPocc vs GOG-252

Dr. Fujiwara also noted comparisons between the iPocc trial and the GOG-252 trial, which failed to demonstrate any difference in progression-free and overall survival with IV chemotherapy plus bevacizumab vs IP chemotherapy plus bevacizumab in advanced ovarian cancer with no macroscopic disease.

“The major differences between the iPocc and GOG-252 trials was the use of bevacizumab in GOG-252,” said Dr. Fujiwara. “Bevacizumab may be preserved for the later line when carboplatin is used for the first line in IP therapy.”

“The inclusion of larger residual tumors in the iPocc trial may be another reason for the differences in outcomes, but I think that’s unlikely,” he added. With respect to overall survival, Dr. Fujiwara noted that the increased role of PARP inhibition may have had an impact.

“Future research, such as the ongoing TRiPocc study, is needed to identify biomarkers for patient selection,” he said. “We also need to elucidate the role of IP carboplatin-based chemotherapy in patients with BRCA mutations.”

“Finally, based on the long-term progression-free survival advantage, IP chemotherapy might be a strong weapon for low-to-middle income countries, where maintenance bevacizumab or PARP inhibitors are not available or affordable,” Dr. Fujiwara concluded. 

DISCLOSURE: Dr. Fujiwara reported financial relationships with AstraZeneca, Daiichi Sankyo, Eisai, Genmab, Kyowa Kirin, MSD, Takeda, Zeria, and Seagen.

REFERENCES

1. Fujiwara K, Nagao S, Yamamoto K, et al: A randomized phase 3 trial of intraperitoneal versus intravenous carboplatin with dose-dense weekly paclitaxel in patients with ovarian, fallopian tube, or primary peritoneal carcinoma (a GOTIC-001/JGOG-3019/GCIG, iPocc trial). 2022 SGO Annual Meeting on Women’s Cancer. Abstract 241. Presented March 19, 2022.

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

3. Walker JL, Brady MF, Wenzel L, et al: Randomized trial of intravenous versus intraperitoneal chemotherapy plus bevacizumab in advanced ovarian carcinoma: An NRG Oncology/Gynecologic Oncology Group Study. J Clin Oncol 37:1380-1390, 2019.

4. Provencher DM, Gallagher CJ, Parulekar WR, et al: OV21/PETROC: A randomized Gynecologic Cancer Intergroup phase II study of intraperitoneal versus intravenous chemotherapy following neoadjuvant chemotherapy and optimal debulking surgery in epithelial ovarian cancer. Ann Oncol 29:431-438, 2018.

5. 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 99:591-596, 2005.