Modified IP Regimen for Ovarian Cancer Leads to 90% Completion Rate

LaToya J. Perry, MD

A modified intraperitoneal (IP) regimen for advanced ovarian cancer demonstrated feasibility, tolerability, and evidence of effectiveness, results of a small pilot study suggest.¹ All but two of 20 patients completed the planned six cycles of therapy, and 14 of 17 evaluable patients completed all 12 cycles of maintenance therapy.

The modified regimen consisted of IP paclitaxel, reduced-dose IP cisplatin, and upfront bevacizumab (Avastin), followed by bevacizumab maintenance therapy. Disease recurred in six patients during a 40-month median follow-up, and 40-month overall survival (OS) was 94%.

“The regimen appears to be tolerable with 90% of patients completing six cycles of primary therapy,” said LaToya J. Perry, MD, a resident at the University of Oklahoma in Oklahoma City, who presented the study at the 2012 SGO Annual Meeting.

“We observed acceleration of neurotoxic symptoms, which peaked at cycle 9 and then plateaued at scores similar to cycle 6, the end of primary therapy. The question of whether bevacizumab maintenance therapy might be potentiating neuropathy, despite discontinuation of paclitaxel and cisplatin, requires further study,” she said.

Since 2006, the recommended systemic therapy for first-line treatment of advanced ovarian cancer has been 135 mg/m2 of intravenous (IV) paclitaxel over 24 hours, 100 mg/m2 of IP cisplatin, and 60 mg/m2 of IP paclitaxel on day 8. Evaluated in the Gynecologic Oncology Group (GOG) 172 trial,² the regimen led to a 50% improvement in the median progression-free survival (PFS) compared with the standard intravenous regimen and a median OS of 66 months.

However, toxicity posed a major obstacle to widespread acceptance and use of the GOG 172 regimen, as only 42% of the patients randomized to IP therapy completed all six cycles of treatment. Additionally, IP catheter complications occurred in a third of patients.

Efforts to improve tolerability without sacrificing the effectiveness of IP therapy have led to clinical evaluation of several modified IP regimens in recent years, Perry noted. Modifications have included higher doses of IV paclitaxel and substitution of carboplatin for cisplatin, with or without the day 8 IV paclitaxel; reduced-dose IP cisplatin; and the addition of bevacizumab to reduced-dose IV paclitaxel and IP cisplatin plus IP paclitaxel.

The regimens have achieved incremental improvements in tolerability. A small phase I GOG study demonstrated a 90% completion rate for planned cycles of therapy, the highest completion rate reported to date.3 The regimen consisted of IV paclitaxel, reduced-dose IP cisplatin, and IP paclitaxel on day 8.

Building on the groundwork of previous trials, Perry and colleagues conducted a phase II study to evaluate yet another IP regimen: 135 mg/m2 of IV paclitaxel, 75 mg/m2 of IP cisplatin, and 15 mg/kg of IV bevacizumab beginning with cycle 2. Patients who completed all six cycles of therapy received a maximum of 12 cycles of IV bevacizumab maintenance therapy.

The trial had two primary objectives: describe toxicities, dose delays, and premature discontinuation associated with the regimen; and assess the PFS and OS in optimally debulked patients treated with the regimen.

Investigators enrolled patients with stage II-III ovarian or primary peritoneal cancer with ≤1 cm residual disease. The primary outcome was the feasibility of administering six cycles of IP therapy, and an 80% completion rate was considered clinically relevant.

Of 22 patients enrolled, two discontinued after two cycles of therapy, one because of an IP port complication and one because of abnormal liver function tests. Of the remaining 20 patients, 18 completed six cycles of primary therapy. One patient discontinued because of IP port complications during cycle 4, and another patient withdrew because of grade 3 neuropathy during cycle 5. A third patient developed enterovesicovaginal fistula after completing six cycles of therapy.

Of the 17 patients who initiated maintenance therapy with bevacizumab, all but three completed the planned 12 cycles. One patient each discontinued because of weakness/hydronephrosis/ hypertension (cycle 8), fatigue (cycle 9), and personal hardship (cycle 11).

Investigators previously reported tolerability data for the primary therapy at the 2009 ASCO Annual Meeting (J Clin Oncol. 2009;27:15s[suppl; abstr 5540]). During maintenance therapy, eight patients had a total of 11 treatment delays because of grade 3-4 toxicity (one patient each with neutropenia, renal toxicity, metabolic abnormalities, infection, and high blood pressure, and three with weight loss/fatigue).

Assessment of neurotoxicity showed steady increases during the first six cycles of therapy and continued increases during the first three cycles of maintenance therapy (P = .009 vs cycle 6). Thereafter, neurotoxicity stabilized or decreased, such that the study population’s neurotoxicity score at the end of maintenance therapy was the same as at the end of primary therapy.

The patients had a 40-month PFS of 68%, and all but two patients remained alive after 40 months of follow-up.

References

1. Perry L, Lanneau G, Curiel J, et al. Phase II study of intravenous bevacizumab (bev) and paclitaxel (pac), and intraperitoneal (ip) cisplatin (c), followed by bevacizumab (bev) maintenance, for advanced ovarian cancer: A report on progression-free survival (PFS) and toxicity. Presented at the 43rd Annual Meeting of the Society of Gynecologic Oncology; March 24-27, 2012; Austin, TX. Gynecol Oncol. 2012;125(suppl):S1- S188. Abstract 54.

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

3. Dizon DS, Sill MW, Gould N, et al. Phase I feasibility study of intraperitoneal cisplatin and intravenous paclitaxel followed by intraperitoneal paclitaxel in untreated ovarian, fallopian tube, and primary peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2011;123(2):182-186.