Effects of bevacizumab and hyperthermia in a rodent model of hyperthermic intraperitoneal chemotherapy (HIPEC)

Figures & data

Figure 1. Schematic presentation of permeation process in IPEC. The drug (big circles) will move from the perfusate to the tumour, passing cell membranes (dotted line), due to the concentration difference (bold arrow). High pressure in the tumour decreases the rate of penetration, due to the lower pressure gradient between perfusate and tumour, as compared to normal tissue.

Figure 2. Schedule of treatments in the IFP experiment.

Table I.  Results of IFP measurements. IFP at start: IFP at the moment the perfusate was administered in the abdominal cave (time = 0 min). IFP difference: IFP at time = 60 min minus IFP at time = 0 min. (1) Normothermic, without bevacizumab; (2) Hyperthermic, without bevacizumab; (3) Normothermic, 1 dose of bevacizumab; (4) Hyperthermic, 1 dose of bevacizumab; (5) Normothermic, 7 doses of bevacizumab; (6) Hyperthermic, 7 doses of bevacizumab.

	Mean	Standard deviation	95% CI	p
IFP at start				0.003
1	22.9	19.8	2.1 to 43.6
2	28.1	23.4	−0.969 to 57.2
3	−10.5	20.0	−31.5 to 10.5
4	4.8	6.9	−3.8 to 13.4
5	−1.5	2.8	−5.0 to 2.0
6	−3.0	10.9	−14.4 to 8.5
IFP difference				0.269
1	17.1	18.8	−2.6 to 36.8
2	15.6	24.3	−23.1 to 54.4
3	0.2	2.4	−2.3 to 2.8
4	−3.8	14.9	−22.4 to 14.7
5	0.6	2.9	−3.0 to 4.2
6	1.4	6.9	−5.9 to 8.6

Figure 3. Results of LA-ICP-MS. Upper left: normothermic without bevacizumab (63.75%); upper right: hyperthermic without bevacizumab (93.53%); under left: normothermic with bevacizumab (43.18%); under right: hyperthermic with bevacizumab (45.18%). Blue line: tumour border. Coloured parts: platinum concentration from 0.1 µg/g (purple) upwards.

Table II.  Effects of temperature on bio-availability. AUC ratio = AUC blood/AUC perfusate.

	n	Mean	SD	Mean difference	95%CI
AUC blood (µg × min/g)				−102.8	−161.3 to −44.4
Normothermic	16	223.9	86.8
Hyperthermic	16	326.8	74.5
AUC perfusate (µg × min/g)				21.5	−301.0 to 344.0
Normothermic	16	2354.1	440.2
Hyperthermic	16	2332.6	453.0
AUC ratio				−0.053	−0.080 to −0.025
Normothermic	16	0.094	0.035
Hyperthermic	16	0.14	0.042
% covered with perfusate				−5.1	−18.7 to 8.6
Normothermic	14	71.6	19.5
Hyperthermic	14	76.6	15.5
Maximal penetration depth (mm)				0.1	−0.6 to 0.8
Normothermic	15	2.9	0.9
Hyperthermic	14	2.8	0.9

Table III.  Effects of bevacizumab.

	n	Mean	SD	Mean difference	95%CI
AUC blood (µg × min/g)				6.3	−76.1 to 63.5
Without bevacizumab	16	272.2	103.8
With bevacizumab	16	278.5	89.1
AUC perfusate (µg × min/g)				−438.4	−716.5 to −159.5
Without bevacizumab	16	2124.1	330.8
With bevacizumab	16	2562.6	432.7
AUC ratio				0.014	−0.016 to 0.047
Without bevacizumab	16	0.127	0.050
With bevacizumab	16	0.113	0.043
% Surface covered with perfusate				−4.6	−18.3 to 9.1
Without bevacizumab	14	71.8	15.4
With bevacizumab	14	76.4	19.6
Maximal penetration depth (mm)				0.3	−0.4 to 1.0
Without bevacizumab	15	3.0	1.0
With bevacizumab	14	2.7	0.7

Figure 4. Survival in rats treated with normothermic (1) and hyperthermic (2) IPEC (p < 0.001).

Figure 5. Survival in rats treated with (1) and without (2) bevacizumab (p = 0.259).

Table IV.  Tumour volumes and changes.

Preoperative tumour volume (cm3)	n	Mean	SD	Mean difference −0,0951	95%CI −0,1665 to −0,0238
Without bevacizumab	16	0.1236	0.5384
With bevacizumab	12	0.2188	0.0307
% Change day −1 to 6				62.3	−20.7 to 145.3
Without bevacizumab	9	30.4	103.0
With bevacizumab	8	−32.0	44.5
% Change day 6 to 13				23.9	−95.2 to 145.1
Without bevacizumab	7	76.9	123.2
With bevacizumab	8	53.0	71.3