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Cancer Biomarkers 14 (2014) 259–265 DOI 10.3233/CBM-140404 IOS Press

Adverse cardiovascular events predict survival benefit in non-small lung cancer patients treated with bevacizumab N. Koyamaa,b,∗ a

Division of Pulmonary Medicine, Clinical Department of Internal Medicine, Jichi Medical University Saitama Medical Center, Saitama, Japan b Department of Respiratory Medicine, Saitama Medical University International Medical Center, Saitama, Japan

Abstract. BACKGROUND: Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF) that provides a survival benefit to patients with non-small cell lung cancer (NSCLC). However, the treatment is sometimes accompanied by lifethreatening bleeding events, and studies have not yet identified factors that can predict outcomes for NSCLC patients receiving bevacizumab. METHODS: To identify prognostic factors for patients with NSCLC who are undergoing bevacizumab therapy, this study retrospectively investigated 34 consecutive patients with NSCLC treated with bevacizumab-containing chemotherapy. RESULTS: Adverse cardiovascular events, including hypertension and bleeding events, during bevacizumab therapy were observed in 18 patients (53%). Kaplan-Meier survival analyses and log-rank tests revealed that median overall survival was significantly better in patients who experienced adverse cardiovascular events than those who did not (442 versus 304 days; P = 0.012). In the multivariate Cox proportional hazard model, the onset of adverse cardiovascular events was independently associated with a better overall survival. CONCLUSIONS: The onset of adverse cardiovascular events during bevacizumab therapy may be a favorable prognostic factor for patients with NSCLC. The results of this retrospective study warrant further large-scale prospective trials. Keywords: Adverse cardiovascular event, bevacizumab, non-small cell lung cancer, survival benefit, vascular endothelial growth factor

1. Introduction Lung cancer is the leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80–90% of lung cancer cases, and more than three-quarters of NSCLC that is diagnosed at an advanced stage is associated with high mortality. The standard therapeutic strategy for advanced NSCLC is ∗ Corresponding author: Nobuyuki Koyama, Division of Pulmonary Medicine, Clinical Department of Internal Medicine, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama-shi, Saitama 330-8503, Japan. Tel.: +81 48 647 2111; Fax: +81 48 5188; E-mail: [email protected].

systemic treatment with anti-tumor drugs; platinumdoublet chemotherapy or its combination with bevacizumab is accepted as first-line therapy [1]. Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), a factor that promotes tumor progression and angiogenesis. Recent phase III trials have demonstrated that platinum-double chemotherapy plus bevacizumab and subsequent maintenance treatment with bevacizumab provided a significant survival benefit to patients with non-squamous cell types of NSCLC [13,15,17]. However, a preceding phase II trial reported that bevacizumab therapy is sometimes associated with lifethreatening bleeding events [10]. Bevacizumab can

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also induce adverse cardiovascular events, including hypertension and vascular thrombosis [3]. In light of these potential adverse events, it is important to predict which patients would benefit from continued bevacizumab therapy and which would not. Some studies of patients with NSCLC have described factors that may predict the response to bevacizumab, including serum VEGF, intracellular adhesion molecule (ICAM), and thrombospondin-1 (TSP1) levels [5,7], none of which have been widely used in clinical practice. Dahlenberg et al. reported that the onset of hypertension as a bevacizumab-specific adverse event was associated with improved outcome of NSCLC during the Eastern Cooperative Oncology Group (ECOG) 4599 study [8]. Furthermore, patients who experienced bevacizumab-induced hypertension were found to have a favorable prognosis in a study of colorectal cancer [4]. These reports suggest that the onset of a bevacizumab-specific adverse event may serve as a favorable prognostic factor, whereas a recent report showed that bevacizumab-induced hypertension was not associated with favorable prognoses [9]. In this context, the hypothesis that a bevacizumab-specific adverse event may serve as a favorable prognostic factor remains controversial. Given the current situation that bevacizumab is most often used in combination with various chemotherapeutic regimens, a comprehensive survey of bevacizumab therapy in clinical practice may be required to identify a clinically useful prognostic factor. In the present study, the onset of vascular adverse events was identified as a factor that predicts the prognosis of NSCLC patients treated with bevacizumab. The findings of this study may improve the efficacy and safety of bevacizumab therapy, thereby contributing to the survival benefit of its treatment.

2. Patients and methods 2.1. Patients The medical records of 34 consecutive patients with non-squamous types of NSCLCs treated with bevacizumab-containing chemotherapy at Saitama Medical University were reviewed after approval of the institutional review board. Epidermal growth factor (EGFR) mutation status was assessed by the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method [12].

2.2. Treatment schedule All patients underwent treatment with bevacizumab (15 mg/kg) combined with either carboplatin at area under the curve (AUC) of 6 mg/mL/min (per Calvert formula) and paclitaxel (200 mg/m2 ) or carboplatin at AUC of 5 mg/mL/min (per Calvert formula) and pemetrexed (500 mg/m2 ). Each treatment regimen was given every 21 days. Maintenance monotherapy with bevacizumab (15 mg/kg on day 1 of a 21-day cycle until disease progression) was subsequently introduced for patients who completed more than four cycles of combined chemotherapy when it was deemed feasible and consistent with patients’ wishes. 2.3. Assessment of therapeutic effect and adverse events Maximal effect on tumor size was classified as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD), according to the Response Evaluation Criteria in Solid Tumors (RECIST) Committee. Additionally, CR+PR was defined as objective response (OR) and CR+PR+SD was defined as disease control (DC). The parameters evaluated were the OR rate (ORR), the DC rate (DCR), the time from the initiation of bevacizumab-containing chemotherapy to the confirmation of disease progression (progression-free survival; PFS) and the time from the initiation of bevacizumab-containing chemotherapy to the death of the patient (overall survival; OS). Adverse events were evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. 2.4. Statistical analysis PFS and OS were calculated using the Kaplan-Meier method, and the log-rank test was used for a comparison of groups. Using multivariate Cox proportional hazards models, potential confounding factors were adjusted. A P value < 0.05 was considered to represent statistical significance.

3. Results 3.1. Patient characteristics Patient characteristics in the present study are shown in Table 1. All patients had adenocarcinoma, and 97% of patients (33/34) had stage IV disease. EGFR mutations were detected in 26% (9/34) of patients.

N. Koyama / Adverse cardiovascular events predict survival benefit in bevacizumab-treated non-small cell lung cancer patients Table 1 Patients’ characteristics (n = 34) Age (Median [range]) < 70  70 Sex Male Female Smoking status Never smoker Light smoker (pack-year  20) Heavy smoker (pack-year > 20) Histological type Adenocarcinoma Clinical stage IIIB IV EGFR gene mutation (−) (+) ECOG Performance Status 0 1 2

Table 3 Therapeutic effects of bevacizumab-containing chemotherapy n (%) 63 [33–76] 26 (76) 8 (24) 21 (62) 13 (38) 13 (38) 4 (12) 17 (50) 34 (100)

Therapeutic response Complete response (CR) Partial response (PR) Stable disease (SD) Progressive disease (PD)

n (%) 4 (12) 14 (41) 15 (44) 1 (3)

Objective response rate (ORR) Disease control rate (DCR)

53% 97%

Progression-free survival (PFS) Overall survival (OS)

188 days 342 days

95% CI (175–201) 95% CI (301–383)

CI, confidence interval. Table 4 Adverse events during bevacizumab-containing chemotherapy

1 (3) 33 (97) 25 (74) 9 (26) 20 (59) 13 (38) 1 (3)

EGFR, epidermal growth factor receptor; ECOG, eastern cooperative oncology group. Table 2 Treatment schedules of bevacizumab Treatment regimen Carboplatin/Paclitaxel Carboplatin/Pemetrexed Treatment line First Second Third Fifth Treatment cycles (Median [range]) < 4 cycles  4 cycles Maintenance treatment with bevacizumab (Median [range]) < 4 cycles  4 cycles

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16 (47) 18 (53) 22 (65) 8 (23) 3 (9) 1 (3) 4 [2–6] 10 (29) 24 (71) 3 [1–13] 7 6

CTC grade 1 2 3 4 Non-hematological adverse events (Grade  2) Allergy Fatigue Nausea Stomatitis Appetite loss Dysgeusia Hepatotoxicity Hyponatremia Proteinuria Neuropathy Myalgia Alopecia Hematological adverse events (Grade  1) Neutropenia Anemia Thrombocytopenia Cardiovascular adverse events (Grade  1) Hypertension Nasal bleeding Gingival bleeding Intraventiricular thrombosis Ventricular arrhythmia Gastrointestinal tract bleeding

1 2 0 16 2 0 11 3 0 7 1 0 14 1 0 11 1 0 12 1 0 0 2 0 6 2 0 10 3 0 2 1 0 10 3 0

0 0 0 0 0 0 0 0 0 0 0 0

1 4 6

5 5 1

8 10 4 0 3 2

7 8 1 0 2 2

1 0 0 0 0 0

2 0 0 1 0 0

0 0 0 0 0 0

CTC, Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

3.2. Chemotherapy regimen

3.3. Response to bevacizumab

Chemotherapy regimens employed in the present study are summarized in Table 2. A similar number of patients received bevacizumab combined with carboplatin and paclitaxel vs. bevacizumab combined with carboplatin and pemetrexed. Approximately 71% of patients (24/34) completed more than four cycles of either chemotherapy, more than half of whom (13/24) proceeded to maintenance monotherapy with bevacizumab. The patients who proceeded to maintenance monotherapy accounted for approximately 38% of all patients (13/34), which is higher than that in the recent retrospective study [6].

The ORR and the DCR were 53% and 97%, respectively. The median PFS and median OS were 188 and 342 days, respectively (Table 3). ORR and DCR in this study were higher than those in previous reports, whereas no prolongation was observed in PFS or OS when compared with previous reports [13,15–17]. 3.4. Adverse events Adverse events during bevacizumab-containing chemotherapies were evaluated according to the CTCAE v4.0 (Table 4). A total of 18 patients cumulatively had

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Fig. 1. Kaplan-Meier survival curves with log-rank tests for progression-free survival for NSCLC patients who underwent bevacizumab therapy according to the onset of cardiovascular adverse events. While there are no significant differences between both patient groups, patients who experienced cardiovascular adverse events had a tendency toward a better progression-free survival.

Fig. 2. Kaplan-Meier survival curves with log-rank tests for overall survival for NSCLC patients who underwent bevacizumab therapy according to the onset of cardiovascular adverse events. Patients who experienced cardiovascular adverse events provide a significant survival benefit.

24 adverse cardiovascular events including hypertension, nasal bleeding, gingival bleeding, intraventricular thrombosis, ventricular arrhythmia, and gastrointestinal bleeding in response to bevacizumab therapy. All patients except for two patients with hypertension (grade 3) and one patient with intraventricular thrombosis (grade 3) had grade 1/2 non-hematological adverse events, which is a lower incidence of grade 1/2 non-hematological adverse events than was seen in previous reports [13,15,17]. All cases of grade 3 hypertension were well controlled by antihypertensive drugs, and grade 3 intraventricular thrombosis resolved

after temporary cessation of bevacizumab therapy. Median time to the onset of cardiovascular events was 44.5 days (range, 1–274 days), and patients had received a median of two cycles of chemotherapy at the time of onset of cardiovascular events. All other cardiovascular events were well tolerated. 3.5. Parameters correlating with survival time Kaplan-Meier survival analysis and log-rank test showed a significant difference in PFS for the parameters of treatment courses (more than four ver-

N. Koyama / Adverse cardiovascular events predict survival benefit in bevacizumab-treated non-small cell lung cancer patients

263

Fig. 3. The multivariate Cox proportional hazard model for potential confounding factors in overall survival for NSCLC patients who underwent bevacizumab therapy. In addition to the effect of objective response, the onset of cardiovascular adverse events was independently associated with a better overall survival, respectively. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; CBDCA, carboplatin; PTX, paclitaxel; PEM, pemetrexed; EGFR, epidermal growth factor receptor.

sus less than three courses), DCR, and experience of bevacizumab maintenance treatment. A tendency toward better PFS was observed in patients who experienced cardiovascular events during bevacizumab therapy (Fig. 1). Further, patients with cardiovascular events during bevacizumab therapy significantly had a better OS than those that did not experience cardiovascular events (Fig. 2). There was also a significant difference in OS for DCR and PS. The association of survival time with the severity of cardiovascular events could not be assessed because most events were classified into grade 1. The multivariate Cox proportional hazards model for potential confounding factors revealed that the onset of adverse cardiovascular events was an independent factor associated with prolonged OS (Fig. 3).

4. Discussion The present study shows that the onset of adverse cardiovascular events is a favorable prognostic factor for NSCLC patients treated with bevacizumab. Previous reports have suggested that the onset of hypertension may be associated with improved survival in patients with advanced NSCLC and those with metastatic colorectal cancer, both of whom were treated with bevacizumab-containing chemotherapies [4,8]. Mean-

while, no other trials in NSCLC have reported this association, although the reason for the inconsistency is unknown [2,14,15]. Unlike these studies, the adverse cardiovascular events included bleeding episodes, arrhythmia, and thrombotic episodes as well as hypertension in the present study. The molecular mechanisms that link bevacizumab to these cardiovascular events remain unclear. Some plausible explanations include hypertension resulting from suppressed production of nitric oxide, arterial thrombosis stemming from endothelial dysfunction and defects in the interior vascular lining, and bleeding events triggered by the decreased renewal capacity of the endothelium [11,18]. Although these adverse events may be phenotypically heterogeneous, their onset is similarly deemed to reflect the high pharmacological activity of bevacizumab for the blockade of VEGF pathway. Accordingly, the different types of adverse cardiovascular events might share clinical significance as prognostic factors for bevacizumab therapy, suggesting that the pursuit of biomarkers for prognosis should focus on the overall adverse cardiovascular events characteristic of bevacizumab. Data from the present study suggest that NSCLC patients in whom bevacizumab therapy can produce a favorable outcome may be at increased risk for the onset of cardiovascular events. Careful attention should be paid to cardiovascular events when treat-

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ing patients with bevacizumab, whereas cessation of all bevacizumab therapies in response to onset of cardiovascular events may abrogate the survival benefit in such patients. In fact, most bevacizumab therapies in the present study could be continued or resumed soon after resolution of the events. Although no fatal cardiovascular events were observed in the present study, this approach may contribute to discrepancies between the present study and previous studies in terms of the prognostic value of adverse cardiovascular events. The results in this study support the notion that cessation or continuation of bevacizumab therapy should be carefully considered. Furthermore, continuing bevacizumab therapy after prompt and appropriate measures for adverse cardiovascular events and carefully monitoring patient progress may determine whether bevacizumab-induced adverse cardiovascular events can be controlled during treatment, thereby resulting in better outcomes. The present study has several potential limitations. First, the incidence of bevacizumab-specific adverse events might be higher in NSCLC patients who had undergone longer-term bevacizumab therapy. However, the median time to onset of adverse events and the number of treatment cycles at the onset of adverse events indicated that adverse cardiovascular events occurred early in the course of therapy. Second, the small sample size in the present study may bias the result, although most of the patients analyzed seemed to be representative of the general population of NSCLC. Furthermore, the susceptibility to development of adverse cardiovascular events may vary among the patients according to lifestyle factors, comorbidities, and genetic backgrounds. Further large-scale prospective trials and confirmatory evidence at the molecular level are needed to address these limitations.

Conflict of interest Nobuyuki Koyama has received honoraria and/or lectures from Astrazeneca K.K., Boehringer Ingelheim Japan, Inc., Chugai Pharmaceutical Co., LtD., Eli Lilly Japan K.K., GlaxoSmithKline K.K., and Kyowa Hakko Kirin Co., LtD., and payment for the development of educational presentations from Pfizer Japan Inc.

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5. Conclusion The onset of adverse cardiovascular events may predict a survival benefit in NSCLC patients treated with bevacizumab. Careful consideration and prompt responses should be given as to whether to continue or terminate bevacizumab at the time of the onset of these events and what must be done to minimize the damage. The results of the present study warrant further largescale prospective trials.

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Adverse cardiovascular events predict survival benefit in non-small lung cancer patients treated with bevacizumab.

Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF) that provides a survival benefit to patients with non-small cel...
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