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The Oncologist, Vol. 13, No. 2, 120-125, February 2008; doi:10.1634/theoncologist.2007-0174
© 2008 AlphaMed Press

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Hepatobiliary

Early Antiangiogenic Activity of Bevacizumab Evaluated by Computed Tomography Perfusion Scan in Patients with Advanced Hepatocellular Carcinoma

Andrew X. Zhu, Nagaraj S. Holalkere, Alona Muzikansky, Kerry Horgan, Dushyant V. Sahani

Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA

Key Words. Hepatocellular carcinoma • Bevacizumab • Angiogenesis • CT perfusion scan

Correspondence: Andrew X. Zhu, M.D., Ph.D., Massachusetts General Hospital Cancer Center, 55 Fruit Street, LH/POB 232, Boston, Massachusetts 02114, USA. Telephone: 617-724-0786; Fax: 617-724-3166; e-mail: azhu{at}partners.org

Received September 24, 2007; accepted for publication January 1, 2008.

Disclosure: A.X.Z. has acted as a consultant to Genentech. No other potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.


   ABSTRACT
Top
 Footnotes
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 Acknowledgments
 References
 
Background. Hepatocellular carcinoma (HCC) is a highly vascularized tumor with a poor prognosis. In a phase II study that combined bevacizumab with gemcitabine and oxaliplatin in advanced HCC, we examined computed tomography perfusion (CTp) scan parameters as surrogate markers of angiogenesis after bevacizumab administration.

Methods. HCC patients received bevacizumab alone i.v. at 10 mg/kg on day 1 during cycle 1. CTp scanning was performed at baseline and days 10–12 to assess changes in tissue blood flow (BF), blood volume (BV), mean transit time (MTT), and permeability surface area product (PS).

Results. Compared with baseline, a significant decrease in the estimated tumor perfusion parameters including BF, BV, and PS and an increase in MTT were seen on days 10–12 following bevacizumab administration alone. Patients with progressive disease had lower baseline MTT values and a higher percent increase following bevacizumab administration than those with stable disease or partial responses.

Conclusions. Bevacizumab induced a significant decrease in tumor BF, BV, and PS and an increase in MTT by CTp scan in HCC. Baseline and percent change in MTT following bevacizumab administration correlated with clinical outcome, whereas BF, BV, and PS did not.


   INTRODUCTION
Top
 Footnotes
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 Acknowledgments
 References
 
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer-related death worldwide [1]. In the U.S., 19,160 new cancers of the liver and intrahepatic bile duct were expected in 2007, with an estimated 16,780 deaths [2]. The incidence rate for HCC in the U.S. rose steadily through 1998 and doubled during the period 1975–1995 [3, 4]. Patients with unresectable or metastatic HCC have a poor prognosis, and systemic therapy with cytotoxic agents provides marginal benefit [5].

HCC is a highly vascularized tumor. Elevated levels of vascular endothelial growth factor (VEGF) and high microvessel density (MVD) have been found in HCC [6–8], and greater expression of VEGF has been associated with shorter survival in HCC patients [9–11]. Therefore, inhibition of angiogenesis represents a potential therapeutic target in HCC. In the recent Annual Meeting of the American Society of Clinical Oncology, results of a phase III, randomized, placebo-controlled trial were presented in which sorafenib, an orally active multikinase inhibitor with effects on tumor-cell proliferation and tumor angiogenesis, demonstrated superior survival in advanced HCC [12]. Clinical studies are ongoing in advanced HCC with several other antiangiogenic agents.

VEGF is a key mediator of angiogenesis [13]. Preclinical studies have shown that inhibition of VEGF produces a number of effects on the tumor vasculature, including vessel regression [14], vessel normalization [15, 16], and inhibition of neovascularization [17, 18]. Bevacizumab, a humanized monoclonal antibody to VEGF, improves outcomes when used in combination with standard chemotherapy in colorectal cancer and several other solid tumor types [19, 20]. In addition to its direct antiangiogenic effects, bevacizumab may improve the delivery of chemotherapy by altering tumor vasculature and decreasing the elevated interstitial pressure within tumors [15, 21]. In an attempt to develop an active systemic regimen, we performed a phase II study combining bevacizumab with gemcitabine and oxaliplatin (GEMOX) in patients with unresectable or metastatic HCC [22]. This regimen showed moderate antitumor activity with a response rate of 20% and a median progression-free survival time of 5.3 months.

The identification of surrogate biologic markers to measure the effect of antiangiogenic therapy in HCC remains very challenging. Conventional tissue biopsy coupled with an analysis of MVD is hampered by the heterogeneity of tumors as well as the risks associated with obtaining serial tissue specimens in patients with a prevalence of underlying cirrhosis and coagulopathy. In this study, we explored the use of a noninvasive technique, computed tomography perfusion (CTp) scan, as a potential method to monitor changes in angiogenic parameters after bevacizumab treatment. Here, we report baseline and post-bevacizumab treatment values for CTp parameters and the correlation between these parameters and clinical efficacy in patients with advanced HCC.


   PATIENTS AND METHODS
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 Footnotes
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 Acknowledgments
 References
 
Patients and Treatment Protocol
Thirty-three patients with measurable locally advanced, recurrent, or metastatic HCC were entered onto the phase II trial of bevacizumab in combination with GEMOX. The eligibility, treatment schedule, and dose modification schema have been detailed previously [22]. Briefly, patients were treated with bevacizumab at a dose of 10 mg/kg i.v. on day 1 of cycle 1 (14 days). For the subsequent 28-day cycles, patients were treated with bevacizumab at 10 mg/kg on days 1 and 15, gemcitabine at 1,000 mg/m2 i.v. as a dose rate infusion of 10 mg/m2 per minute on days 2 and 16, and oxaliplatin at 85 mg/m2 as a 2-hour i.v. infusion on days 2 and 16 of every cycle. The dose of bevacizumab was fixed at 10 mg/kg. The protocol for this clinical trial was reviewed and approved by the Institutional Review Board at Dana-Farber/Harvard Cancer Center (Boston, MA). All patients were required to provide written informed consent prior to study participation according to institutional and federal guidelines.

CTp Imaging
We obtained dynamic CTp scans to estimate the following parameters in HCC and the background liver: blood flow (BF), blood volume (BV), mean transit time (MTT), and capillary permeability surface area (PS). These parameters were estimated at baseline and at 10–12 days after treatment with bevacizumab.

A 16-section multidetector row CT scanner (LightSpeed QX/i; GE Medical Systems, Milwaukee, WI) was used for perfusion imaging. A noncontrast CT scan of the liver was obtained to localize the tumor for further investigation by dynamic scanning. A 2-cm region of interest (ROI) was selected and dynamic scanning of this area was performed at a static table position 10 seconds after initiation of i.v. injection of 70 ml of iopamidol (Isovue 300; Bracco Diagnostics, Princeton, NJ), power injected at a rate of 7 ml/second. The following parameters were used: 1-second gantry rotation time, 100–120 kVp, 200–240 mA, 25-second duration of transverse data acquisition (four sections per gantry rotation), and 5-mm reconstructed section thickness. Four slices were obtained through the same region every 12 seconds for 4 minutes. The data acquisition parameters and the anatomic location for scanning, including the total duration, were kept constant for each patient and for each repeat CTp study.

The data were quantified on a commercially available workstation (Advantage Windows 4.0; GE Medical Systems) using body perfusion software (CT Perfusion 3.0; GE Medical Systems) to estimate the tissue perfusion parameters—BF, BV, MTT, and PS. For the derivation of the perfusion maps, the arterial input curve of contrast medium concentration Ca(t) was required. The tumor ROIs (area range, 293–1,300 mm2) within the liver were hand drawn both for each map type and within each map type (BF, BV, MTT, and PS) for all four CT slices. Representative parameter values were then averaged across the four sections.

Statistical Considerations
Statistical analysis of CTp parameters was performed using Student's t-test for comparison of datasets of baseline and post-treatment values. p-values were calculated for each comparison, and a value ≤ .05 was considered to indicate a statistically significant difference.

For correlation with clinical outcome, patients were divided into two groups: those with progressive disease and those with either stable disease (≥4 months) or a partial response. The baseline values and percent changes in CTp parameters after bevacizumab administration in these groups were compared using the Wilcoxon rank sum test.


   RESULTS
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 Footnotes
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 Acknowledgments
 References
 
CTp Parameters in HCC and Background Liver Tissues at Baseline
We first examined the CTp parameters in HCC lesions in comparison with surrounding background liver tissues at baseline. Of all the patients enrolled, 25 patients had primary HCC lesions in the liver. As shown in Table 1, BF, BV, and PS were significantly higher and MTT was significantly lower in HCC lesions than in background liver parenchyma.


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  		Table 1. CTp scan parameters of HCC lesions and liver parenchyma

 
CTp Parameters in HCC at Baseline and Changes Following Bevacizumab Administration
Pre- and post-treatment CTp data were available for 23 of the 33 enrolled patients. There was a significant decrease in the estimated tumor BF, BV, and PS and a significant increase in MTT on days 10–12 after treatment with bevacizumab compared with baseline values (Table 2). An example of blood flow change in an indexed HCC lesion after bevacizumab administration is illustrated in Figure 1.


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  		Table 2. Changes in CTp scan parameters after bevacizumab administration

 


Figure 1
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  		Figure 1. Grey scale and color blood flow maps of hepatocellular carcinoma (arrows) at baseline (A, B) and after bevacizumab administration (C, D) in a patient are shown. Dramatic changes in tumor blood flow were visible on day 12 after bevacizumab administration (D).

 
Correlation of CTp Parameters at Baseline with Clinical Outcome
The clinical outcome of patients in this study has been reported previously [22]. Briefly, all patients have come off the study and 19 patients have died. Of the 30 patients who were evaluable for efficacy, six (20%) had a confirmed partial response and eight (27%) had stable disease. The median progression-free survival time was 5.3 months (95% confidence interval [CI], 3.7–14.7 months) and the updated overall survival time was 10.4 months (95% CI, 8.0–20.8 months).

The correlation between CTp parameters and clinical outcome was examined in 21 patients with available CTp data. For this analysis, patients were separated into two groups: those with progressive disease (n = 10) and those with either stable disease (≥4 months) or a partial response (n = 11). As shown in Table 3, patients with progressive disease had a lower mean MTT at baseline than those with stable disease or a partial response (p = .018). In contrast, the mean values for BF, BV, and PS at baseline did not correlate with clinical outcome.


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  		Table 3. Correlation of baseline CTp parameters with treatment response

 
Correlation of Changes in CTp Parameters Following Bevacizumab Administration with Clinical Outcome
We then examined the percent change in CTp scan parameters at day 10–12 after bevacizumab administration and its relation to clinical outcome. Patients with progressive disease had a greater mean percent change in MTT after bevacizumab administration than those with stable disease or a partial response (p = .032) (Table 4). The other CTp parameters after bevacizumab treatment did not correlate with clinical efficacy according to our analysis.


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  		Table 4. Correlation of changes in CTp parameters after bevacizumab administration with treatment response

 

   DISCUSSION
Top
 Footnotes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
Acknowledgments
 References
 
Increasing evidence has suggested the importance of angiogenesis in hepatocarcinogenesis. In an attempt to develop an active systemic regimen for HCC, we postulated that an agent with proven antiangiogenic activity, such as bevacizumab, might have direct anti-HCC effects and augment the efficacy of GEMOX-based chemotherapy. Our results with longer follow-up demonstrate that GEMOX plus bevacizumab has moderate antitumor activity in patients with advanced HCC.

The development of adequate methodologies for assessing the biologic effects of antiangiogenic agents is necessary to appropriately quantify the short- and long-term efficacy of these approaches. The demonstration that sorafenib has an overall survival benefit in advanced HCC has validated the use of molecularly targeted agents in HCC [12]. With many antiangiogenic agents currently being studied in advanced HCC, it has become more relevant and critical to develop novel assays to assess the biologic surrogate endpoints. However, assessing the effectiveness of these therapies by tissue biopsy or the analysis of MVD is hampered by the heterogeneity of tumors, and the concern of greater risks in obtaining serial tissue specimens in HCC. In this study, we used a noninvasive technique, CTp scan, as a potential method to measure changes in angiogenic parameters after bevacizumab treatment. Because HCC is a highly vascularized tumor, the development of new vessels is associated with increased perfusion, and therefore increased contrast enhancement. The degree of contrast enhancement has been shown to match the intensity of tumor neovascularization in HCC [23]. There is enough evidence to support that this method can be used to estimate the angiogenic activity of a tumor, and thus its biologic aggressiveness, and to evaluate tumor response to novel treatment methods.

Several researchers have investigated the role of CTp in various oncologic and nononcologic applications. Few studies, however, have established an association between CTp-derived tumor BF and tumor grade and survival [24–26]. Of particular note, Sahani and colleagues demonstrated that a decrease in rectal cancer vascularity after radiation was associated with a better response to therapy at surgery, whereas persistence of excessive vascularity was associated with only a modest therapeutic response [27]. Another recent study by Willet and colleagues showed a correlation between CTp parameters and MVD, validating the use of this technique to quantify tumor angiogenesis in rectal cancer [21]. In their study, a significant decrease in tumor BF and BV and an increase in MTT of rectal cancer were observed within 10–12 days of bevacizumab treatment [21]. Similarly, we observed substantial decreases in CTp-derived BF, BV, and PS and an increase in MTT within HCC tissues after bevacizumab administration. We believe that these findings on CTp are representative of bevacizumab-induced antiangiogenic responses in HCC. Interestingly, we also observed a correlation between the mean MTT at baseline and the mean percent change in MTT after bevacizumab administration with treatment response. Because we only studied a limited number of HCC lesions with dynamic CTp in any given patient, it is conceivable that the appearance and behavior of different HCC nodules may differ in the same patient.

A CT-based method is advantageous because CT is the most widely used radiographic approach for assessing malignancies. The deconvolution-based CTp algorithm used in our study is a fast and robust imaging technique for evaluating tumor biology and angiogenesis. CTp parameters, which include BF, BV, PS, and MTT, are considered to serve as surrogate measures for tumor biology. For example, MTT is a measure of tumor interstitial pressure and vessel leakiness. A short MTT is considered to reflect high intratumoral perfusion pressure, which in turn represents a relatively high tumor perfusion and capillary leakiness. We consistently observed a significantly shorter MTT in HCC lesions than in the surrounding liver parenchyma. Other investigators have made similar observations in the head and neck, where the MTT was found to be significantly lower in malignant tumors than in the benign tissues in that region [28]. Despite the more dramatic changes in MTT following bevacizumab treatment in patients with progressive disease, the clinical outcome remains poorer than for those who had higher baseline MTT values in patients with stable disease or a partial response. This could be attributed to the fact that the majority of cases in our cohort had advanced disease and other poor prognostic indicators. Whether MTT at baseline or change in MTT after treatment can serve as a useful surrogate marker in antiangiogenic therapy requires future studies with larger patient populations and in various disease-stage settings.

Tumor perfusion can also be estimated using contrast-enhanced magnetic resonance imaging (MRI) because the pharmacokinetic behavior of gadolinium-based agents is similar to that of iodinated contrast agents. A dynamic acquisition of T1- or T2-weighted images through the tumor after a bolus injection of gadolinium-based contrast material has been used in various studies. Although MRI offers the advantage of superior contrast resolution without the risk of exposure to ionizing radiation, the absolute quantification of tumor perfusion is difficult because signal intensity and the gadolinium concentration are not linearly related [29, 30]. Using microbubble contrast agents and ultrasound (US) imaging is another novel emerging method for measuring blood volume and flow [31]. The blood flow calculated by fitting the enhancement curve to an exponential model was found to correlate well with absolute measures of blood flow in phantom studies, and in animal experiments of myocardial blood flow using radiolabeled microspheres. However, limited depth penetration, high operator dependence, and the lack of validated commercially available software remains an impediment for widespread use of US for angiogenic imaging.

In conclusion, we have demonstrated that bevacizumab induced significant decreases in BF, BV, and PS and an increase in MTT within HCC tissue as measured by CTp scanning. Baseline and percent change in MTT following bevacizumab administration correlated with clinical outcome, whereas BF, BV, and PS did not.


   ACKNOWLEDGMENTS
Top
 Footnotes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Acknowledgments
References
 
We are indebted to the patients who participated in this study, their families, and the referring physicians. We thank the many physicians and nurses who cared for these patients at our institutions. We thank Drs. Jeffrey Clark and Dan Duda for critically reviewing the manuscript. This work was supported by Sanofi-Synthelabo, a member of the Sanofi-Aventis group, and Genentech, Inc.


   FOOTNOTES
 
Conception/design: Andrew X. Zhu, Dushyant V. Sahani

Financial support: Andrew X. Zhu

Administrative support: Andrew X. Zhu

Provision of study materials or patients: Andrew X. Zhu, Nagaraj S. Holalkere, Dushyant V. Sahani

Collection/assembly of data: Andrew X. Zhu, Nagaraj S. Holalkere, Kerry Horgan, Dushyant V. Sahani

Data analysis and interpretation: Andrew X. Zhu, Nagaraj S. Holalkere, Alona Muzikansky, Dushyant V. Sahani

Manuscript writing: Andrew X. Zhu, Dushyant V. Sahani

Final approval of manuscript: Andrew X. Zhu, Nagaraj S. Holalkere, Alona Muzikansky, Kerry Horgan, Dushyant V. Sahani


   REFERENCES
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 Footnotes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Acknowledgments
 References
 

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