The effect of neoadjuvant chemotherapy by sequential paclitaxel and doxorubicin on the interstitial fluid pressure and pO2 in patients with palpable breast cancer

Tumors with high interstitial fluid pressure (IFP) are thought to respond poorly to chemotherapy (CT) due to poor drug delivery. In addition, a decrease in IFP is hypothesized to improve drug delivery and therefore result in a better response to CT. Pre-clinical studies suggested that Paclitaxel specifically reduces the IFP, with the consequence of improved pO2 and tumor response to subsequent CT. Evaluate the IFP and pO2, using ultrasound guidance, before and after neoadjuvant CT using paclitaxel (P) or doxorubicin (D) in patients with breast cancer of >3cm. Patients were randomized, according to IRB approved protocol, to receive neoadjuvant sequential CT: 4 cycles of dose-dense D (60mg/m2 / 2 weeks) followed by 9 cycles of P (80 mg/m 2 / week) (D->P arm) or the reverse sequence (P->D arm). Patients were reevaluated clinically and radiologically and IFP (wick-in-needle technique) and pO2 (Eppendorff) were measured in tumors and in normal tissue at baseline, after completion of the first and the second drug. Forty-two patients have enrolled in the protocol, with 30 of them having completed CT. Fifteen patients were randomized to each arm. The mean IFP at baseline was 7.3 mmHg (range 0.6-17), while in normal tissue 1 mmHg (range -1 to 1.3) (p < 0.05). The median tumor pO2 measurements varied between 1.6 and 49.4 mmHg with overall mean of 22 mmHg. The median pO2 in normal tissue was 45 mmHg (range 26-55) (p=0.0002. In the P->D arm, the mean IFP at baseline and after P were 7.3 mmHg and 4.6 mmHg, respectively (p=0.01). The mean pO2 in this group before and after P was 13.2 and 27.0 mmHg, respectively (p=0.01). In the D->P arm, the mean IFP at baseline and after D were 6.6 mmHg and 5.2 mmHg, respectively (p=NS). The mean pO2 at baseline and after D was 19.6 and 13.7 mmHg, respectively (p=0.38). These preliminary data showed that Paclitaxel significantly decreased the IFP and increased the pO2, whereas doxorubicin did not change the IFP and had a tendency to decrease the pO2. These data suggest that tumors with high initial IFP would be better treated with paclitaxel first in order to reduce the IFP and improve the pO2