In this randomized Phase II clinical trial we found that bevacizumab with or without docetaxel had no significant activity as second-line therapy for patients with metastatic pancreatic adenocarcinoma. Only 3/16 patients in the docetaxel plus bevacizumab arm and 2/16 in the bevacizumab alone treatment arm were free of progression at 4 months and thus accrual to the trial was halted per the early stopping rule. Exploratory coagulation studies suggest that baseline and on-treatment D-dimer and thrombin-antithrombin complex levels are associated with increased toxicity and decreased survival.
Our findings demonstrating a lack of clinical benefit of bevacizumab in pancreatic cancer are disappointing, given recent benefit in other diseases including colorectal, lung, and breast cancer [17
]. However, they are consistent with the results of Kindler et al. who reported the results of a large phase III trial of gemcitabine with or without bevacizumab utilizing the same dose (10 mg/kg) that we chose for this trial [23
]. The authors reported no improvement in overall survival with the addition of bevacizumab to gemcitabine in the front-line setting. Why bevacizumab therapy improves outcome in other malignancies but not in pancreatic cancer is unclear. One proposed mechanism of bevacizumab therapy is a normalization of peritumoral blood vessels which allows improved chemotherapy delivery to the tumor [24
]. Chemotherapy regimens result in much higher objective antitumor activity in colorectal, breast, and lung cancer compared to pancreatic cancer. In colorectal cancer, bevacizumab monotherapy does not have clear clinical activity but improves efficacy of active chemotherapy agents [16
]. Thus, one limitation of bevacizumab-based therapy in pancreatic cancer may be a lack of an effective chemotherapy partner. Additionally, VEGF depletion in pancreatic adenocarcinoma through bevacizumab may be insufficient to interfere with tumor angiogenesis and VEGFR signaling due to redundancy in VEGF family ligands and receptors [25
]. Since our trial was developed, the combination of 5-FU and oxaliplatin has been reported to improve PFS and OS compared to 5-FU alone in the second-line treatment of advanced pancreatic cancer [27
]. Whether bevacizumab may potentiate this chemotherapy combination in a similar manner to colorectal cancer requires future study.
We utilized the toxicity index (TI) to characterize toxicity for this trial. This methodology has been described previously and represents an effort to give a more global assessment of the toxicity that each patient is experiencing by accommodating their differential impact [22
]. In a disease such as pancreatic cancer where patients frequently experience multiple toxicities and disease-related morbidities, the TI may be of higher value in providing a complete impression of toxicity. As expected, the TI was higher for the combination compared to the single agent bevacizumab treatment arm. In terms of bevacizumab-related toxicities, we observed 5 episodes of DVT/PE and one bowel perforation. While our bowel perforation rate is higher than that reported by Kindler et al. [23
] and in colorectal cancer trials [29
], this likely reflects our smaller sample size. Our DVT/PE rate was typical for advanced pancreatic cancer patients and for cancer patients in general receiving bevacizumab [30
Deep venous thrombosis is common in pancreatic cancer and has been associated with decreased response to chemotherapy and shorter PFS and OS [31
]. Some evidence suggests that anticoagulation can improve survival in selected subgroups of patients with advanced malignancy [32
]. We thus hypothesized that plasma coagulation factors would similarly be associated with worse outcome and increased toxicity. The relationship was strongest for D-dimer, with elevated levels both at baseline and on treatment associated with inferior survival and increased toxicity. Our findings with D-dimer parallel several reports on the prognostic significance of D-dimer on OS in lung cancer [33
], ovarian cancer [36
] and breast cancer [37
]. While the sample size of the current trial is modest. Thrombin/antithrombin complexes are also a marker of coagulation activation and significantly elevated in the blood of cancer patients compared to healthy controls [38
]. The relationship of elevated TAT levels to increased toxicity and decreased survival was more modest in our study and confined to specific time points.
The development of a plasma biomarker of bevacizumab effect would be of high clinical value. We hypothesized at the conception of this trial that plasma CEC and VEGF levels might predict for clinical outcome from bevacizumab therapy. Nucleated cells containing endothelial-specific antigens (circulating endothelial cells, or CEC) have been identified and characterized in the blood of patients with a number of pathologic conditions, including malignancy [40
]. However, we found no clear relationship of either marker to clinical outcome in this cohort of pancreatic cancer patients receiving bevacizumab. Kindler et al. also found no relationship of circulating VEGF levels to clinical benefit from bevacizumab in pancreatic cancer [28
]. While CEC remain an attractive potential marker of anti-angiogenic therapy, their use remains investigational.
In conclusion, we observed no evidence of clinical activity of bevacizumab alone or with docetaxel in pancreatic cancer patients previously treated with gemcitabine. However, baseline and on-treatment D-dimer and thrombin-antithrombin complex levels are associated with increased toxicity and decreased survival.