Emerging treatment options for management of malignant ascites in patients with ovarian cancer

Figures & data

Figure 1 Schematic of mode of action for VEGF signaling and bevacizumab. (A) Free unbound VEGF interacting with the receptor. (B) The monoclonal antibody, bevacizumab, binds to VEGF-A, preventing ligand-receptor interaction and downstream signaling.

Abbreviation: VEGF, vascular endothelial growth factor.

Table 1 Studies reporting use of bevacizumab for treatment of ascites associated with ovarian cancer

Study	n	Drug dose	Route of administration	Best response	Toxicity
El Shami (ASCO 2007)^Citation61	9	5 mg/kg monthly	IP	All subjects with resolution of ascites over 2-month observation period	Grade 1 nausea; grade 1 abdominal pain; small bowel obstruction*
Numnum et al^Citation42	4	15 mg/kg every 3 weeks	IV	No paracentesis required during 6-month study period for all subjects	Grade 1 HTN; grade 2 proteinuria and HTN
Hamilton et al^Citation43	1	5 mg/kg × 2 treatments	IP	Resolution of ascites for 18 days (until death)	None reported
Kesterson et al^Citation44	1	15 mg/kg every 3 weeks	IV	Ascites relief for 6 months	No bevacizumab-related toxicities

Note:

* Resolved with conservative management.

Abbreviations: ASCO, American Society of Clinical Oncology; n, number of subjects; IP, intraperitoneally; IV, intravenously; HTN, hypertension.

Figure 2 Schematic of VEGF-trap mode of action. VEGF-trap is a fusion protein that prevents VEGF-receptor binding. (A) VEGF-trap, or aflibercept, incorporates the second binding domain of the VEGFR-1 receptor and the third domain of the VEGFR-2 receptor. (B) This chimeric protein has a high VEGF binding affinity, preventing VEGF-receptor interaction and downstream signaling.

Abbreviation: VEGF, vascular endothelial growth factor.

Figure 3 Schematic of mode of action of catumaxomab. (A) Catumaxomab is a trifunctional monoclonal antibody with two different antigen-binding sites and a functional Fc domain. (B) The two specific antigen-binding sites bind to epithelial tumor cells via the epithelial cell-adhesion molecule (EpCAM) and to T cells via CD3, while activating Fcγ receptor I-positive, IIa-positive, and III-positive accessory cells (dendritic cells, macrophages and natural killer cells) via its functional Fc domain.

Figure 4 Kaplan–Meier plot of time to repeat paracentesis in patients treated with VEGF-trap (aflibercept) for the management of malignant ascites. Median time to repeat paracentesis was 76.0 days (95% confidence interval 64.0–178.0), which was 4.5 times longer than the baseline interval (16.8 days) in the aflibercept group.

Copyright © 2012. Elsevier. Adapted with permission from Colombo N, Mangili G, Mammoliti S, et al. A Phase II study of aflibercept in patients with advanced epithelial ovarian cancer and symptomatic malignant ascites. Gynecol Oncol. 2012;125(1):42–47.⁵³

Abbreviation: VEGF, vascular endothelial growth factor.

Table 2 Summary of efficacy endpoints

	Total number of patients (n = 16)
Primary endpoints
Repeat paracentesis response,
Number of responders, %	62.5
95% exact CI	35.4–84.8
Secondary endpoints
Time to repeat paracentesis, days
Mean (SD) [95% CI]	67.7 (59.9) [35.8–99.6]
Median (range)	50.5 (12–180)
Median [95% CI]a	76.0 [64.0–178.0]
60-day frequency of paracentesis, n (%)
Mean (SD) [95% CI]	1.5 (1.6) [0.63–2.36]
Median (range)	1.4 (0–5)
Progression-free survival, days
Median [95% CI]a	59.5 [41.0–83.0]
Overall survival, days
Median [95% CI]a	92.0 [58.0-NC]

Note:

a Based on Kaplan–Meier estimates.

Copyright © 2012. Elsevier. Adapted with permission from Colombo N, Mangili G, Mammoliti S, et al. A Phase II study of aflibercept in patients with advanced epithelial ovarian cancer and symptomatic malignant ascites. Gynecol Oncol. 2012; 125(1):42–47.⁵³

Abbreviations: CI, confidence intervals; NC, not calculable; SD, standard deviation.

Figure 5 Kaplan–Meier estimates of puncture-free survival and time to next paracentesis in both the catumaxomab and control populations. (A) Puncture-free survival in the pooled population. (B) Time to next paracentesis in the pooled population.

Copyright © 2010. John Wiley and Sons. Adapted with permission from Heiss MM, Murawa P, Koralewski P, et al. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized Phase II/III trial. Int J Cancer. 2010;127(9):2209–2221.⁵⁷

Table 3 Summary of adverse events related to catumaxomab occurring in ≥5% of subjects

	Number of patients (%)
	All grades	Grade ≥ 31
Pyrexia	95 (60.5)	9 (5.7)
Abdominal pain	67 (42.7)	15 (9.6)
Nausea	52 (33.1)	5 (3.2)
Vomiting	43 (27.4)	4 (2.5)
Lymphopenia	22 (14.0)	11 (7.0)
C-reactive protein increased	23 (14.6)	7 (4.5)
Chills	21 (13.4)	2 (1.3)
Gamma-glutamyltranferase increased	18 (11.5)	9 (5.7)
Fatigue	17 (10.8)	5 (3.2)
Diarrhea	16 (10.2)	3 (1.9)
Leukocytosis	16 (10.2)	2 (1.3)
Tachycardia	15 (9.6)	1 (0.6)
Anorexia	14 (8.9)	5 (3.2)
Blood alkaline phosphatase increased	14 (8.9)	4 (2.5)
Anemia	14 (8.9)	2 (1.3)
Hypotension	13 (8.3)	3 (1.9)
Aspartate aminotransferase increased	12 (7.6)	4 (2.5)
Alanine aminotransferase increased	10 (6.4)	3 (1.9)
lleus	10 (6.4)	5 (3.2)
Pain	8 (5.1)	0

Notes:

1 Symptomatic National Cancer Institute Common Toxicity Criteria (NCI-CTC, version 2.0, April 30, 1999) Grade 4 events were observed as isolated cases.

Copyright © 2010. John Wiley and Sons. Adapted with permission from Heiss MM, Murawa P, Koralewski P, et al. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized Phase II/III trial. Int J Cancer. 2010;127(9):2209–2221.⁵⁷

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