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Journal of Clinical Oncology, Vol 23, No 9 (March 20), 2005: pp. 1951-1961 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.08.119 Paclitaxel Decreases the Interstitial Fluid Pressure and Improves Oxygenation in Breast Cancers in Patients Treated With Neoadjuvant Chemotherapy: Clinical ImplicationsFrom the Department of Radiation Oncology, Department of Medicine, Division of Hematology-Oncology, and Department of Radiology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA Address reprint requests to Alphonse Taghian, MD, PhD, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; e-mail: ataghian{at}partners.org
PURPOSE: It has been hypothesized that tumors with high interstitial fluid pressure (IFP) and/or hypoxia respond poorly to chemotherapy (CT) because of poor drug delivery. Preclinical studies have shown that paclitaxel reduces the IFP and improves the oxygenation (pO2) of tumors. Our aim is to evaluate the IFP and pO2 before and after neoadjuvant CT using sequential paclitaxel and doxorubicin in patients with breast cancer tumors of  3 cm. PATIENTS AND METHODS: Patients were randomly assigned, according to an institutional review board–approved phase II protocol, to receive neoadjuvant sequential CT consisting of either four cycles of dose-dense doxorubicin at 60 mg/m2 every 2 weeks followed by nine cycles of weekly paclitaxel at 80 mg/m2 (group 1) or vice versa, with paclitaxel administered before doxorubicin (group 2). Patients were re-evaluated clinically and radiologically. The IFP (wick-in-needle technique) and pO2 (Eppendorf) were measured in tumors at baseline and after completing the administration of the first and second drug. RESULTS: IFP and pO2 were measured in 54 patients at baseline and after the first CT. Twenty-nine and 25 patients were randomly assigned to groups 1 and 2, respectively. Paclitaxel, when administered first, decreased the mean IFP by 36% (P = .02) and improved the tumor pO2 by almost 100% (P = .003). In contrast, doxorubicin did not have a significant effect on either parameter. This difference was independent of the tumor size or response measured by ultrasound. CONCLUSION: Paclitaxel significantly decreased the IFP and increased the pO2, whereas doxorubicin did not cause any significant changes. Tumor physiology could potentially be used to optimize the sequence of neoadjuvant CT in breast cancer.
Neoadjuvant chemotherapy (CT) followed by surgery and radiation is now a common approach for treating large primary breast cancers1 and is increasingly being used for operable palpable breast cancers as well.2 Because the use of neoadjuvant CT affords an ideal opportunity to observe the response of a tumor in vivo, it is possible to distinguish responders from nonresponders. In fact, patients who have a complete pathologic response after neoadjuvant CT have a significantly better outcome.3 Why some tumors fail to respond remains a challenge. It is important to find out whether the cancer cells are intrinsically resistant to the drugs or whether penetration of the drugs into the tumors is suboptimal. Only by studying physiologic and molecular parameters together will we be able to distinguish these mechanisms. To date, efforts to determine the physiologic parameters restricting the delivery of therapeutic agents to tumor tissue in breast cancer patients have been modest. The delivery of the drugs to the cancer cells within the tumor is one of the most important parameters in the success of CT.4 Both a heterogeneous, poor blood supply and elevated interstitial fluid pressure (IFP) in tumors can be significant parameters affecting the access of therapeutic agents to neoplastic cells.5 Interstitial hypertension reduces the driving force for the filtration of fluid and large molecules (eg, antibodies) in tumors and also leads to radially outward convection, which opposes inward diffusion.5 Furthermore, when a high IFP is coupled with the high vascular permeability of the tumor vessels, the pressure gradient along vessels becomes less steep. This could reduce the tumor blood flow and induce perfusion heterogeneities, thus influencing the delivery of oxygen and the diffusion of small chemotherapeutic agents.6,7 There is an increased interest in studying the mechanisms that control the elevated IFP in solid tumors and investigating strategies that improve tumor perfusion; if these mechanisms were understood, it might lead to the ability to modify the IFP and thus improve the efficacy of therapy. The induction of apoptosis in experimental tumors with paclitaxel and docetaxel has been shown to reduce the microvascular pressure (MVP) and the IFP.8 It also increased the diameter of tumor vessels without a change in tumor vascular density, thus suggesting that taxanes increase the blood flow, blood volume, and vascular surface area for exchange of small therapeutic agents in tumors.8 If this hypothesis were valid in human tumors, one could speculate that tumors with high IFP might benefit from exposure to a taxane first to decrease IFP and improve blood flow and oxygenation (pO2) before treatment with other CT drugs to maximize tumor response. It has also been recognized for many years that the pO2 status of tumors is an important factor affecting the cytotoxicity of radiation. The level of cellular pO2 is also an important factor in the action of many antineoplastic agents, several of which have been classified in vitro and in vivo by their selective cytotoxicity towards oxygenated and hypoxic tumor cells in animal models.9-11 Whether intrinsic properties of tumor cells or metabolic factors micromilieu (including tissue pO2) are the dominant factors in the treatment outcome of radiation or CT is still a subject of controversy.12 In an animal model, Milas et al13 also found an increase in the tumor pO2 with taxanes, which was observed with direct measurements using the Eppendorf histograph.13 If this were true in human tumors, one could speculate that tumors with low pO2 measurements might benefit from exposure to a taxane first to improve pO2 before treatment with other CT drugs. Given the findings of Milas et al13 and Griffon-Etienne et al,8 we hypothesized that paclitaxel, compared with doxorubicin, decreases the IFP and increases the tumor pO2. This should potentially improve drug delivery and, hence, tumor response to neoadjuvant CT. In this prospective, phase II, randomized study, we evaluated the effect of paclitaxel and doxorubicin on the tumor IFP and pO2 in patients with palpable breast cancer treated by neoadjuvant CT.
Patients Patients with primary invasive breast cancer, as diagnosed by fine-needle aspirate or core biopsy were enrolled onto this study. To be eligible, patients had to have a palpable breast mass of 3 cm in size clinically, to be otherwise in good health, and to have no evidence of distant metastasis. This study was approved by the internal review board of the Massachusetts General Hospital and Dana-Farber/Partners Cancer Care. Written consent was obtained from each patient. After enrollment in the trial, breast tumor size was estimated by clinical examination and ultrasound (US). The pO2 and IFP were measured under US guidance in conjunction with a breast radiologist.
Overview of Treatment Plan
IFP Measurements
Interstitial pO2 Measurements
All pO2 measurements were performed under local anesthesia using sterile techniques, before the protocol-required core biopsy and with the patient in a supine position. Local anesthesia (3 to 4 mL of 1% lidocaine without epinephrine) was injected in the subcutaneous tissue at the site of the entrance of the trocar and in the peritumor area. To avoid any disturbance of the tumor microenvironment, there was no lidocaine injected inside the tumor before the pO2 measurements, making it unlikely that local anesthesia would have altered the pO2 measurements. After local anesthesia, a trocar (outer diameter, 0.8 mm) equipped with a hypodermic needle was advanced to an initial depth of approximately 2 mm into the tissue of interest where the oxygen-sensitive probe was then placed. All electrode tracks were performed leaving the trocar at one puncture site and guiding the oxygen probe from this site in different directions (usually three tracks: starting at 0 and conducted at approximately –45 or +45 degrees direction). The electrode automatically moved through the tissue in preset steps of 1 mm, immediately followed by a backward step of 0.3 mm to minimize compression effects caused by the forward motion of the electrode. The length of the track depended on the tumor size (varied between 1 and 5 cm). Each pO2 track had a US documentation of its location within or outside the tumor. Depending on the tumor size, a different number of tracks was used, and 50 to 200 pO2 readings were obtained. PO2 histograms (ie, pO2 frequency distributions) were obtained with a class width of 2.5 mmHg. We also assessed other parameters for tumor hypoxia, including the percentage of pO2 values
Statistical Analysis
Patient Population At the time of the analysis, 59 patients were enrolled onto the study (30 patients in group 1 and 29 patients in group 2) who completed at least the first course of CT. Two patients refused to continue after the first CT. The baseline clinical characteristics of the remaining 57 patients are listed in Table 1; no significant differences were found between study groups. Some measurements at baseline or after first CT failed for technical reasons that were extraneous to the disease or patient status. We report the results for patients for whom the measurements were performed at baseline and after the first CT; 54 patients had both IFP measurements, and 46 patients had both pO2 measurements. There were no significant differences between both groups with respect to baseline IFP or pO2 (Table 2). Of those 54 and 46 patients, three measurements of IFP and pO2 (baseline, after first CT drug, and after second CT drug) were performed in 41 and 32 patients, respectively (Table 3). Thirteen patients did not have the IFP measured for the third time after the second CT drug (four patients had surgery performed after completing the first CT drug per original protocol, three had complete response by US and tumor could not be found, two refused the third measurement, one was taken off the protocol, and three are still receiving the second CT drug). Fourteen patients did not have the pO2 measurement after the second CT drug (three patients had surgery performed after completing the first CT drug per original protocol, three had complete response by US and tumor could not be found, two refused the third measurement, one was taken off the protocol, the pO2 measurements failed in two patients because of technical problems, and three are still receiving the second CT drug). The clinical tumor size varied between 3 and 10 cm, with a mean of 5 cm (standard deviation, 1.7 cm) and a median of 4 cm.
Effect of Doxorubicin and Paclitaxel on the IFP In all patients, except the first patient, the tumor IFP was measured in three to four tracks. For each patient, the IFP was also measured in the normal tissue of the same breast, at a distance from the tumor site. The mean and median normal tissue IFP values were 1.05 and 0.5 mmHg, respectively. For the whole population, there was a highly significant difference between the baseline IFP in normal tissue and tumor (1.05 and 6.5 mmHg, respectively; P < .0001). Paclitaxel used as first drug in group 2 patients significantly decreased the overall mean IFP from 7.0 mmHg (95% CI, 5.2 to 8.9 mmHg) to 4.4 mmHg (95% CI, 2.6 to 6.3 mmHg; P = .02; Table 2 and Fig 1A). There was a decrease in IFP in 17 of 25 patients (Fig 2, upper panels). In contrast, in patients treated with doxorubicin first, the mean IFP before and after doxorubicin was not significantly different (Table 2 and Fig 1A).
For the 41 patients with IFP measurements at the three different time points (Table 3), doxorubicin plus paclitaxel significantly decreased the tumor IFP by 25% (absolute decrease of 1.6 mmHg, 95% confidence limits [CL], –3.9, 0.7 mmHg; P = .02). When this overall decrease in IFP was broken down by group, the IFP of group 1, who were treated with doxorubicin first, changed by 8% (absolute change, +0.4 mmHg; 95% CL, –4.4, 3.5 mmHg; P = .41); however, patients of group 2, who received paclitaxel first, had a significant decrease in IFP by 39% (absolute decrease of 2.9 mmHg; 95% CL, –5.4, –0.4; P = .01). Therefore, patients treated with paclitaxel first had a significant decrease in IFP measured after completion of all CT, whereas patients who started with doxorubicin did not (Fig 3A and 3B). The effect of paclitaxel in reducing the IFP was significant, whether used as a first drug (in group 2) or as a second drug (in group 1). This was in contrast to the effect of doxorubicin (Table 3 and Fig 3A and 3B).
Effect of Doxorubicin and Paclitaxel on pO2 pO2 was measured in 46 patients at baseline and after the first CT drug. The average number of tracks was 4.9 (range, two to 11 tracks). The mean and median numbers of pO2 readings per tumor were 123 and 128, respectively. The correlation between the median pO2 and the HF2.5, HF5, and HF10 was highly significant (P  .000001), with Spearman coefficients of –0.85, –0.92, and –0.90, respectively. Therefore, we used the median pO2 to represent the pO2 status for each tumor, although data on the HF2.5 is also presented (Tables 2 and 3). The median pO2 in tumors varied from 0.8 to 62.6 mmHg. In normal tissue, the mean of the median pO2 measurements was 49 mmHg compared with 14.3 mmHg in tumors (P < .00001). Figure 4 shows the effect of paclitaxel or doxorubicin administered as a first drug on the median pO2 of individual patients. In 19 of 24 patients, paclitaxel increased the median pO2, whereas in five of 24 patients, the median pO2 did not change or decreased (Fig 4, upper panel). In contrast, the effect of doxorubicin was more variable; the median pO2 increased in 10 of 22 patients and did not change or decreased in 12 of 22 patients (Fig 4, lower panel). After paclitaxel, the overall median pO2 significantly increased (P = .001) from a mean of 14.1 mmHg (95% CI, 7.7 to 14.1) to 27.6 mmHg (95% CI, 21.3 to 27.6), and the HF2.5 decreased from 33.9% to 7.6% (P = .001; Table 2). After doxorubicin, the overall change in the mean pO2 and the HF2.5 was not significant (Fig 1B and Table 2).
In 32 patients, pO2 was measured at baseline and at two time points after doxorubicin or paclitaxel in group 1 (doxorubicin followed by paclitaxel) and group 2 (paclitaxel followed by doxorubicin). In group 1, doxorubicin did not significantly change the tumor pO2; however, paclitaxel used as a second drug significantly increased the pO2 compared with doxorubicin (P = .01) or baseline (P = .05; Fig 5 and Table 3). In group 2, paclitaxel increased the pO2 by 250% (from a mean of 10.9 mmHg to 27.3 mmHg; P = .009), and after doxorubicin (used as a second drug), the pO2 dropped by almost 50% (from 27.3 mmHg to 13.9 mmHg; P = .03; Fig 5 and Table 3).
US Tumor Volume and Response to CT To evaluate whether the changes in IFP and pO2 observed after doxorubicin or paclitaxel were a result of differential changes in tumor volume, the US tumor volume was calculated from the three dimensions based on the previously mentioned formula.18 The mean percent decrease in US tumor volume after the first CT drug was 29.2% after doxorubicin and 35.8% after paclitaxel. This difference was not significant (P = .29). The mean percent decrease in US tumor volume from postfirst to postsecond CT drug was 42.7% after paclitaxel and 52.8% after doxorubicin (P = .79). The mean percent decrease in US tumor volume from baseline to postsecond CT drug was 79.5% for group 1 and 70.6% for group 2. This difference was also not significant (P = .99).
Correlation Between Changes in IFP and Changes in pO2
Neoadjuvant CT has been shown in randomized trials to be equivalent to adjuvant CT in terms of clinical benefit.2,19 A number of trials have shown excellent response rates to regimens that combine an anthracycline with a taxane.20 We used single-agent therapy in the neoadjuvant setting in a dose-dense regimen21 to correlate the response to each individual drug with biologic parameters. This report details the initial data showing the effect of paclitaxel and doxorubicin on IFP and pO2 in breast cancer patients treated with neoadjuvant CT. Paclitaxel significantly reduced the IFP whether it was used as first (group 2) or second drug (group 1; Figs 1A, 3A, and 3B). In contrast, after doxorubicin treatment, the overall change in IFP was not significant. This significant reduction in IFP induced by paclitaxel, in contrast to doxorubicin, was not caused by differential changes in tumor volume; both drugs had similar effects on the tumor volume. Dexamethasone is commonly given as a prophylactic before paclitaxel administration, to minimize any hypersensitivity reaction to cremophor. It could be argued that dexamethasone treatment is the cause of the decrease in IFP after paclitaxel. However, in the study of Kristjansen et al, in experimental tumors,21A the administration of dexamethasone between day 1 and 4 significantly reduced the IFP on day 4 and the pressure was not different from baseline on day 7. In our patients, dexamethasone was generally administered before infusion of the paclitaxel during the first 3 to 5 weekly cycles with a dose decrease each cycle if there was no evidence of allergic reaction. Our data showed that the IFP was measured more than 1 week (mean ± standard deviation, 15 ± 6.0 days) after the last paclitaxel cycle. Furthermore, dexamethasone is also used prior to each doxorubicin cycle to reduce nausea. Therefore, it is very unlikely that the decrease in IFP would be due to dexamethasone. IFP in normal tissues and tumors is regulated by vascular permeability, lymphatic drainage, and the MVP, which is dependent on the arteriovenous pressure difference of the microcirculation and the architecture of the vascular network.22 In tumors, the high vascular permeability and absence of a functional lymphatic drainage increases the accumulation of plasma proteins in the interstitium, thus increasing the oncotic pressure and IFP.23 Other mechanisms, like the compression of blood vessels by tumor cell proliferation in a confined space, can reduce the diameter of blood vessels and, thus, increase the vascular resistance plus both the MVP and IFP.8,24 Paclitaxel-induced apoptosis increases the diameter of tumor vessels and reduces both the MVP and IFP.8 The downregulation of tumor vascular endothelial growth factor (VEGF) expression by paclitaxel25,26 could also be partly responsible for the reduction in IFP, although it is not clear whether this regulation is intrinsic to the tumor cells or secondary to features of the tumor physiology. Inhibition of VEGF signaling with a blocking antibody reduces the permeability of the tumor vasculature27 and the IFP in experimental tumors28 and in rectal tumors in patients.29 In contrast, doxorubicin can increase VEGF mRNA and vascular permeability in tumors,30 which may explain the increase in IFP in tumors with pretreatment IFPs less than 5 mmHg (Fig 2, lower panel). Thus, the paclitaxel-induced reduction in tumor IFP may be a result of the decompression of blood vessels by increase in apoptosis8 and a decrease in VEGF levels.29 Paclitaxel increased the pO2 significantly when used as either the first or second drug (Fig 3A and 3B). In contrast, when administered first, doxorubicin did not change the overall pO2 (Fig 1B). When doxorubicin was administered after paclitaxel, it significantly reduced the median pO2 and, thus, could not maintain the higher oxygen levels induced by paclitaxel (Fig 5A). Thus, paclitaxel was clearly more effective than doxorubicin at reducing tumor hypoxia and, therefore, maintaining normal pO2 levels in breast tumors. It should be noted that several patients did not have a third measurement because of various reasons, as mentioned in Patients and Methods. Some patients responded clinically completely to CT, and there was no tumor detected under US. Although unlikely, it is possible that biases could be present when analyzing the changes in IFP and pO2 from the second to the third measurements because of the lack of the third measurement for those patients. Tissue oxygen levels are regulated by oxygen consumption, blood flow rate, and hemoglobin saturation in blood vessels. Based on mathematical simulations, changes in the HF of tumors are 10-fold more sensitive to changes in oxygen consumption than alterations in perfusion rate.31 After paclitaxel-induced apoptosis, the improvement in tumor pO2 is most likely a result of the significant cell loss, which leads to a reduction in oxygen consumption.13 In addition, paclitaxel-induced cell loss leads to blood vessel decompression and larger vascular diameters, which may also improve blood flow and oxygen delivery.8 Similar to paclitaxel, doxorubicin induces tumor cell apoptosis32,33; however, it also reduces tumor blood flow,34,35 which may counter-balance or negate the advantage associated with a reduction in oxygen consumption. The lack of correlation between the changes in IFP and the changes in pO2 were striking, and although tumor cell killing and vessel decompression might seem to be important for pO2 as well IFP, there was no correlation in these observed changes. This was also found by Milosevic et al36 in patients with cervical cancer. This observation would imply that exploiting the physiologic changes in a tumor for therapeutic gain should take into account which parameter is altered. Drugs with oxygen concentration–dependent cell killing would be used after the initial drug has normalized the pO2, whereas large molecules, such as antibodies like trastuzumab, could potentially be more susceptible to the level of IFP. A recent study by Milosevic et al36 has shown that the tumor IFP can predict survival in patients with cervix cancer treated by radiation therapy, independently of other clinical prognostic factors and tumor oxygen measurements, suggesting that it is a potential useful parameter of response. A recent update37 showed that the group of patients with oxic and low IFP tumors had a significantly higher disease-free survival than the other groups. Preclinical studies, with a variety of CT agents, have shown that a reduction in tumor IFP can be associated with improved blood flow and pO2 and enhanced accumulation of molecules in tumors.38,39 Indeed, prostaglandin E1 and STI-571 inhibition of platelet-derived growth factor receptors decreased the IFP and enhanced the uptake of the low molecular mass compound 51 chromium-EDTA in tumors in rats.38,40 In these studies, the exact mechanism responsible for the decrease in IFP or the enhanced accumulation of small molecules was not identified. The reduction in tumor IFP with paclitaxel could also be associated with an enhanced penetration of small molecules or drugs into tumors. The hypothesis raised by our study is that tumors with a decrease in IFP and an increase in pO2, obtained after the initial drug, would ultimately have a better overall response because of the improved penetration of the second drug and the improved cytotoxicity of oxygen-dependent drugs (ie, doxorubicin and cyclophosphamide). It is possible that hypoxic tumors and/or tumors with high IFP could be selected to start with paclitaxel CT to improve the physiologic status, and then other drugs could be administered to maximize the overall response. The individualization of preoperative CT sequencing in the treatment of patients with breast cancer based on tumor physiology could potentially improve the tumor response to CT and ultimately improve survival. Our data shows that paclitaxel decreases the IFP and increases the pO2 significantly in patients with palpable breast tumors. In contrast, the overall effect of doxorubicin on the IFP and the pO2 was not significant. Doxorubicin significantly decreased the pO2 in tumors exposed to paclitaxel. These changes were independent of the tumor response to both drugs as evaluated by US. This study was not powered to demonstrate a significant difference in clinical outcome based on the sequencing of drugs, but it could be a hypothesis-generating study to evaluate the various sequencing of CT drugs in the neoadjuvant CT setting to maximize the tumor response and ultimately improve survival. In the future, tailored treatment protocols could be designed for individuals, based on pretreatment characteristics or changes in the physiologic profile of their tumors during therapy, to improve the tumor response to treatment. These data suggest that tumors with high initial IFP and/or low initial pO2 would be better treated with paclitaxel first to reduce the IFP and increase the pO2 and, thus, improve the drug delivery of subsequent CT in particular large molecules such as trastuzumab. Knowledge of the tumor pressure and pO2 throughout the course of therapy might allow the selection and scheduling of anticancer treatments selectively cytotoxic to oxygenated cells as well as hypoxic cell cytotoxins. If the hypothesis that tumors with high IFP have a better clinical outcome when agents such as paclitaxel are used first can be substantiated by this study, then the concept of physiologic monitoring of a tumor during therapy could become a useful adjunct in a world where greater individualization of therapy is becoming more widely accepted as a means to improve cancer treatment.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Research Funding: Alphonse G. Taghian, Bristol-Myers Squibb. For a detailed description of this category, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
We thank all our patients who participated in this study; Daniel Kopans, MD, Elizabeth Rafferty, MD, and Dianne Georgian-Smith, MD, for their contribution; Barbara L. Smith, MD, Jerry Younger, MD, Paula Ryan, MD, Michele Gadd, MD, Kevin Hughes, MD, David Smith, MD, Lidia Schapira, MD, Beverly Moy, MD, Rakesh K. Jain, MD, Daniel Haber, MD, Lyndsay Harris, MD, Eric Winer, MD, and Bruce Chabner, MD, for their helpful discussion in the design of the protocol and their valuable contribution; Sara Bauminger, Sharon Fadika, and Karleen Habin, the research staff, for their valuable help; and Marie Doherty for her significant effort in this study.
Supported by a grant from Massachusetts Department of Public Health, an Investigator Initiated grant from Bristol-Myers-Squibb, the Massachusetts General Hospital Cancer Center, the Susan and Michael Schechter Research Fund, Jane Mailloux Research Fund, and the National Cancer Institute (NCI)/Avon supplement to NCI Specialized Programs of Research Excellence (SPORE) award, P50 CA89393, entitled "Dana-Farber SPORE in Breast Cancer." Presented in part at the International Conference of Radiation Research, Brisbane, Australia, August 17-21, 2003, and at the 23rd Annual Meeting of the European Society of Therapeutic Radiology and Oncology, Amsterdam, Netherlands, October 24-28, 2004. Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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INTRODUCTION
