Intraperitoneal Carboplatin Plus Paclitaxel Improves PFS in Ovarian Cancer, Yet OS Results Remain Unchanged Vs IV Chemo

The use of intraperitoneal (IP) carboplatin with paclitaxel improved progression-free survival (PFS) compared with intravenous (IV) chemotherapy for patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer, but overall survival (OS) benefit was not derived, according to results from the phase 2/3 intraPeritoneal therapy for ovarian cancer with carboplatin (iPocc) trial (NCT01506856) that were presented at The Society of Gynecologic Oncology (SGO) 2022 Annual Meeting on Women’s Cancer.¹

Findings showed that, in the intent-to-treat (ITT) population, the median PFS was 23.5 months with IP chemotherapy (n = 328) compared with 20.7 months with IV chemotherapy (n = 327), leading to a 17% reduction in the risk of disease progression or death (HR, 0.83; 95% CI, 0.69-0.99; P = .041).

In the modified ITT population, the median PFS was 22.9 months and 20.0 months in the IP (n = 299) and IV (n = 303) chemotherapy arms, respectively (HR, 0.78; 95% CI, 0.65-0.94; P = .009).

However, additional findings showed that the median OS was 64.9 months with IP chemotherapy vs 67.0 months with IV chemotherapy in the ITT population (HR, 0.95; 95% CI, 0.77-1.17; P = .041). In the modified ITT group, the median OS was 64.9 months and 64.0 months, respectively (HR, 0.91; 95% CI, 0.73-1.13; P = .403).

“IP chemotherapy without bevacizumab [Avastin] improved PFS over the IV regimen in patients with ovarian cancer, fallopian tube, and peritoneal carcinoma, regardless of the residual tumor size after initial surgery,” lead study author Keiichi Fujiwara, MD, PhD, chairman of the Department of Gynecologic Oncology, Division of Gynecologic Oncology, at Saitama Medical University International Medical Center in Hidaka-Shi, Japan, said in a presentation during the meeting. “The role of IP carboplatin-based chemotherapy in the PARP inhibitor era should be elucidated.”

Although IP chemotherapy has demonstrated a survival benefit vs IV treatment in patients with optimally debulked advanced ovarian cancer, Fujiwara noted that frontline IP chemotherapy has not been widely accepted as the standard of care,^2-4 mainly due to complexity of study designs and toxicities. Additionally, it had not been previously compared with IV carboplatin/paclitaxel.

Prior to the iPocc trial, IP carboplatin had not been explored in a phase 3 study. In a pharmacokinetics study, data suggested that IP chemotherapy would be effective in patients with large-size residual disease, due to platinum-based therapy being absorbed via peritoneal capillaries that will reach the inner core of large tumors through systemic circulation.⁵

In the open-label iPocc trial, investigators 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 epithelial ovarian, fallopian tube, or primary peritoneal cancer, including those with bulky tumors.

Patients could have either minimal or large size residual ovarian cancer after initial surgery. However, patients could not have borderline malignancies, received prior chemotherapy or radiation, have active concurrent malignancies or a history of malignancies within the prior 5 years, have severe complications, pleural effusion requiring continuous drainage, active infectious disease, or symptomatic brain metastasis.

Patients were randomized to receive paclitaxel at 80 mg/m2 IV on days 1, 8, and 15 with either IV or IP carboplatin at area under the curve 6 every 21 days for 6 to 8 cycles. No bevacizumab or maintenance therapy was administered.

The primary end point was PFS, and secondary end points included OS, toxicity, and quality of life.

Patient characteristics were similar between the 2 arms. The median age was 59 years (range, 30-84), most patients had an ECOG performance status of 0 (75.1%), and 91.6% of patients were of Asian-Japanese race. The primary site of disease was in the fallopian tube (5.1%), ovary (75.7%), peritoneum (14.7%), and other (4.6%). A total 68.4% of patients had FIGO stage III disease, and 55% of patients had residual disease that was greater than 2 cm. Serous histology made up 64.1% of patients, compared with clear cell (11.3%), endometrioid (9.3%), mucinous (2.3%), and other (13.0%). The median follow-up time was 55.8 months.

Fujiwara noted that the PFS benefit with IP chemotherapy was observed across prespecified subgroups, including those with residual disease that was larger than 2 cm.

The objective response rate with IP chemotherapy was 70.2% (95% CI, 62.7%-76.9%) and 72.6% (95% CI, 65.2%-79.2%) with IV chemotherapy (odds ratio [OR], 0.89; 95% CI, 0.55-1.42; P = .0633).

Regarding safety, adverse events (AEs) were similar between the 2 arms; the rate of grade 3 or higher AEs in the IV arm vs the IP arm at 96.0% and 93.2%, respectively (OR, 0.58; 95% CI, 0.28-1.21).

However, there was a lower rate of catheter-related toxicities in the IV arm vs the IP arm with regard to catheter-related infections (all-grade, 0.7% vs 10.1%; grade ≥3, 0.3% vs 8.4%), abdominal infection (all-grade, 1.7% vs 2.4%; grade ≥3 1.7% vs 2.0%), and vaginal anastomotic leak (all-grade, 0.3% vs 5.7%; grade ≥3, 0.0% vs 1.0%). All-grade abdominal pain overall occurred in 34.7% and 51.7% of patients on IV and IP chemotherapy, respectively; grade 3 or higher AEs occurred in 0.0% and 1.4% of patients, respectively.

The data bring up interesting comparisons between iPocc and the phase 3 GOG-0252 trial, results of which were also presented during the 2022 SGO Annual Meeting on Womens’ Cancer. In GOG-0252, IV chemotherapy plus bevacizumab did not demonstrate any differences in PFS and OS vs IP chemotherapy plus bevacizumab in patients with advanced ovarian cancer with no macroscopic disease, regardless of treatment group or patient subgroup.⁶

Fujiwara explained that in iPocc, there was no use of bevacizumab, which may be contradicted when carboplatin is used for IP chemotherapy. “However, the inclusion of larger residual tumors in the iPocc trial may be another reason for the difference between these 2 trials,” he added.

Next steps, according to Fujiwara, should include biomarker selection of patients for IP chemotherapy, which is being explored in the ongoing TRiPocc study, which is an integrated molecular analysis of Asian women with ovarian cancer from the iPocc study.

“Future trials are necessary to elucidate the true role of IP carboplatin-based chemotherapy. It may be a strong weapon for [low-to-middle income countries] where maintenance bevacizumab or PARP inhibitors are not available or affordable,” Fujiwara concluded.

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, iPoccTrial). Presented at: 2022 SGO Annual Meeting on Womens’ Cancer; March 18-21, 2022; Phoenix, AZ. Abstract 241.

2. 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(26):1950-1955. doi:10.1056/NEJM199612263352603

3. Markman M, Bundy BN, Alberts DS. 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(4):1001-1007. doi:10.1200/JCO.2001.19.4.1001

4. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Eng J Med.2006;354(1):34-43. doi:10.1056/NEJMoa052985

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. 2005;99(3):591-596. doi:10.1016/j.ygyno.2005.06.055

6. Walker JL. Long-term survival of GOG 252 randomized trial of intravenous versus intraperitoneal chemotherapy plus bevacizumab in advanced ovarian carcinoma: an NRG Oncology/GOG Study. Presented at: 2022 SGO Annual Meeting on Womens’ Cancer; March 18-21, 2022; Phoenix, AZ. Abstract 094.