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A Phase II trial of intravenous bevacizumab, paclitaxel and intraperitoneal cisplatin followed by intravenous bevacizumab maintenance for treatment of stage II-III ovarian cancer

Grainger L. Lanneau

Naval Medical Center, San Diego, CA, USA

LaToya J. Perry

Cadence Physician Group, Winfield, IL,USA

Kathleen N. Moore

Stephenson Oklahoma Cancer Center at the University of Oklahoma, Oklahoma City, OK, USA

E-mail : kathleen-moore@ouhsc.edu

Julie Curiel RN

Stephenson Oklahoma Cancer Center at the University of Oklahoma, Oklahoma City, OK, USA

Michael A. Gold

Tulsa Cancer Institute, Tulsa OK, USA

Robert S. Mannel

Stephenson Oklahoma Cancer Center at the University of Oklahoma, Oklahoma City, OK, USA

Joan L. Walker

Stephenson Oklahoma Cancer Center at the University of Oklahoma, Oklahoma City, OK, USA

D Scott McMeekin

Stephenson Oklahoma Cancer Center at the University of Oklahoma, Oklahoma City, OK, USA

DOI: 10.15761/COGRM.1000117

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Abstract

Objective

 Acceptance of intraperitoneal (IP) chemotherapy has not been widespread with anticipated toxicity commonly cited as a limitation of this therapy. We evaluated a modified IP regimen with IV bevacizumab to determine feasibility and assess toxicities.

Methods

 A phase II study was conducted in patients with advanced ovarian cancer following cytoreduction to < 1cm residual disease. The primary aim was to evaluate feasibility as defined as completion of 6 cycles. Patients received IV paclitaxel 135 mg/m2 and IV bevacizumab 15 mg/kg (cycle 2-6) on day 1 followed by cisplatin 75 mg/m2 IP day 2, repeated every 21 days x 6 cycles. Following primary therapy, patients received IV bevacizumab 15 mg/kg maintenance q21 days x 12 cycles. The FACT GOG NTX tool was used to prospectively monitor neuropathy scores over treatment.

Results

20 evaluable patients are presented including 85% with stage III disease, and 75% with no gross residual. 85% received 6 cycles of IP therapy and 77% of these received all 12 cycles of maintenance. Scores for neuropathy worsened through cycle 6, peaked at 9 and improved by 18. Toxicity was acceptable with neutropenia the most common grade 3-4 adverse event, and 8 patients experienced grade 2-3 neuropathy. With a median follow-up of 63 months, the median PFS and OS is 50 and 71 months respectively.

Conclusions

 Adding IV bevacizumab to a modified IP regimen is feasible. As compared to GOG 172, the lower cisplatin dose and omission of day 8 IP paclitaxel may allow a higher completion rate. Despite modifications, neuropathy remains important issue in IP based cisplatin regimens.

Introduction

 Ovarian cancer is the leading cause of death from gynecologic cancer in the United States [1]. The high death rate stems from late presentation and tumor that has spread beyond the ovary and throughout the peritoneal cavity at the time of diagnoses [2]. Three randomized clinical trials have demonstrated the superiority of intraperitoneal (IP) over intravenous (IV) platinum based chemotherapy in patients with optimally debulked advanced stage ovarian cancer [3-5] (Table 1). The most recent is Gynecologic Oncology Group (GOG) protocol 172; a phase III randomized trial comparing IV paclitaxel plus cisplatin versus IV paclitaxel (135 mg/m2 over 24 hours on day 1) plus IP cisplatin (100 mg/m2 on day 2) and IP paclitaxel (60 mg/m2on day 8) in patients with <1 cm residual disease. Both progression-free (PFS) (median, 18.3 vs. 23.8 months) and overall survival (OS) (median, 49.7 vs. 65.6 months) was significantly improved with the IP regimen [5].

Study

PFS (median)

OS (median)

SWOG/GOG-104

Alberts et al. [4]

49 mo (IP) vs. 41 mo (IV), p=0.02

GOG-114/SWOG

Markman et al. [3]

28 mo (IP) vs. 22 (IV), p= 0.01

63 mo (IP) vs. 52 (IV), p= 0.05

GOG-172

Armstrong et al. [5]

24 mo (IP) vs.18 (IV), p= 0.05

65.6 mo (IP) vs. 49.7 (IV), p= 0.03

Table 1. Phase III IP based clinical trials

Variable

N= 20

N (%)

%

Age

Median

59 yrs

Stage

1 IIB

2 IIC

2 IIIA

1 IIIB

14 IIIC

15% Stage II

85% Stage III

Histology

12 High Grade Serous

4 Low Grade Serous

4 Non-serous     

1 Endometrioid

1 Mucinous

1 Clear cell

1 Carcinosarcoma

 60%

20%

15%

Residual Disease

15 No gross

5 Gross, < 1 cm

75%

25%

Widespread acceptance of this IP regimen was not seen because of toxicities associated with the therapy [6]. Only 42% of women on the IP arm of GOG 172 received 6 cycles of therapy, and 49% received 3 or fewer cycles [5]. Patients who were randomized to the IP therapy group in GOG-172 had higher rates of adverse events for neurologic, gastrointestinal, metabolic, infection, febrile, and hematologic toxicities [6].

Parallel with the studies of IP therapies