Risk of severe pulmonary embolism in cancer patients receiving bevacizumab: Results from a meta-analysis of published and unpublished data

Abstract

To evaluate the association between severe pulmonary embolism events and bevacizumab, we conducted the first meta-analysis evaluating the incidence and risk of pulmonary embolism associated with bevacizumab-based therapy. We searched PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov up to September 2016 for randomized controlled trials comparing bevacizumab with no bevacizumab on cancer patients. Incidence rates, relative risks, and 95% confidence intervals were calculated using fixed- or random-effects models. The primary end point was the association of bevacizumab with pulmonary embolism. Subgroup analyses were performed according to tumor type, dose, and publication status. In total, 23 randomized controlled trials were included. For patients receiving bevacizumab, the overall incidence of severe pulmonary embolism events was 1.76% (95% confidence interval = 1.25%–2.27%). Cancer patients treated with bevacizumab did not increase the risk of pulmonary embolism events (relative risk = 1.00, 95% confidence interval = 0.80–1.25). No significant differences in pulmonary embolism incidence or risk among subgroup analyses were observed. No evidence of publication bias was observed. This study suggested that bevacizumab may not increase the risk of pulmonary embolism in cancer patients.

Keywords

Bevacizumab pulmonary embolism meta-analysis

Introduction

Venous thromboembolic event (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common cause of premature death and morbidity.¹ Patients with cancer have higher risk of VTE than age-matched controls.² It has been reported that several cancer treatments are associated with increased risk of VTE and PE.^3–5 Importantly, patients with cancer who experience VTE and PE have worse prognosis and an increased risk of death.⁶

Several meta-analyses refering to the association between bevacizumab and thromboembolic events have been published. One meta-analysis identified five trials suggesting that treatment with bevacizumab increased risk of arterial thromboembolic event (ATE) but not VTE.⁷ A second meta-analysis including studies in which ATE and VTE were not distinguished reported that treatment with bevacizumab increased risk of both all-grade and high-grade VTE.⁸ A third meta-analysis investigating individual patient data from 10 trials concluded that bevacizumab combined with chemotherapy did not significantly increase the risk of VTE compared with chemotherapy alone.⁹ However, none of the meta-analyses investigated the incidence and risk of PE associated with bevacizumab in patients with cancer.

Compared to other VTE, PE has different pathogenesis and performance and is even more life threatening. As the indications for use of bevacizumab are increasing, we conducted a comprehensive systematic review and combined the published and unpublished data from randomized controlled trials (RCTs) for a meta-analysis to quantify the association between severe PE events and bevacizumab therapy in patients with cancer.

Materials and methods

Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement,¹⁰ we searched PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov from January 1960 to September 2016. Keywords used were “bevacizumab,” “Avastin,” and “cancer,” and the search was limited to RCTs. The PubMed search strategy is contained in S1 Table, and this search strategy was translated as appropriate for the search interfaces used for each database. Additional relevant articles in the reference lists of recent meta-analyses that evaluated bevacizumab in patients with cancer were also searched. In order to avoid duplication, only the most complete, recent, and updated report of each clinical trial was included.

Eligibility criteria

Trials were included if they fulfilled the following criteria—(1) participants: cancer patients, (2) interventions: bevacizumab-containing therapy or bevacizumab alone, (3) comparisons: non-bevacizumab therapy, (4) outcomes: number of patients with PE (grade 3–5 or severe) according to study group were available, and (5) study design: prospective RCTs.

Data extraction

Two reviewers independently collected data from included trials, with discrepancies resolved by consulting a third reviewer. Data collected from studies included trial phase, first author, publishing year, treatment arms, sample size, tumor type, dosage of bevacizumab, median follow-up, and number of patients with PE. Two independent researchers accessed the quality of included studies by using the Jadad scores,¹¹ with discrepancies resolved by consulting a third reviewer. Jadad scores ranged from 0 to 5, where 5 indicates the highest quality. In addition, for studies in which data of PE had not been published, we abstracted the relevant numbers from ClinicalTrials.gov databases of serious adverse events.

Data analysis

The overall incidences of PE in the two groups were our primary outcome. The PE incidences were presented as risk ratio (RR) with 95% confidence intervals (CI) and combined using random-effects model. For studies that reported zero events, we applied the classic half-integer correction to calculate the RR and variance.¹² Heterogeneity is quantified using I-square and Cochran’s Q test statistics. We considered I² value larger than 50% as the significant heterogeneity, and a random-effects model was used; otherwise (I² < 25%), we used the fixed-effects model.¹³ We used the Begg’s and Egger’s tests to assess the presence of publication bias regarding our primary outcomes.¹⁴ A statistical test with a p < 0.05 indicated statistical significance. All statistical analyses were performed by using Stata software (Version 12.0).

We performed three subgroup analyses, stratified by tumor type, bevacizumab dosages (2.5 mg/kg/week vs 5 mg/kg/week), and publication status of PE data (data published in original article vs collected from ClinicalTrials.gov). All subgroup analyses followed the same analysis procedure.

Results

Literature collection

A total of 1933 articles were found in our initial search; 1807 of which were excluded by screening the titles and abstracts. Further 103 articles were excluded after reviewing full text. Overall, 23 RCTs ^15–37 were included in the final analysis. The trial flow summary is reported in Figure 1.

Figure 1.

Study flow diagram.

Study characteristics

Studies enrolled 16,458 participants who were randomized to bevacizumab group or control group. Seven studies were conducted in breast cancer patients, six in colorectal cancer patients, two in ovarian cancer patients, one each in pancreatic cancer, gastric cancer, non–small cell lung cancer (NSCLC), extensive-stage small-cell lung cancer (ESCLC), melanoma, angiosarcoma, glioblastoma, and lymphoma (Table 1). In addition, eight studies received bevacizumab at 2.5 mg/kg/week, and 15 trials received bevacizumab at 5 mg/kg/week. PE was defined by the common terminology criteria for adverse events (CTCAE) criteria in all the included trials. Data of PE events were collected from ClinicalTrials.gov in 14 trials.^{18–21,25–30,33–35,37} All trials were RCTs, and 11 trials were double blinded. The level of evidence for each trial was graded from scores 2 to 5 according to the Jadad score (S1 Table).

Table 1.

Characteristics of studies included in the primary analysis.

Study	NCT code	Tumor type	Concurrent treatment	Number in intervention/control^a	Bevacizumab dose (mg/kg per week)	Median follow-up (months)
Coudert et al.¹⁵	NCT01142778	Breast	Trastuzumab, docetaxel	47/25	5	NR
Miller et al.¹⁶	NR	Breast	Capecitabine	229/215	5	14.8
Von Minckwitz et al.¹⁷	NCT01250379	Breast	Paclitaxel, docetaxel, capecitabine, gemcitabine, doxorubicin, epirubicin	245/238	5	15.9
Brufsky et al.¹⁸	NCT00262067	Breast	Taxane, gemcitabine, capecitabine, vinorelbine	458/221	5	15
Cameron et al.¹⁹	NCT00976911	Breast	Anthracycline, taxane	1288/1271	5	32
Gianni et al.²⁰	NCT00484939	Breast	Docetaxel, trastuzumab	215/206	5	26
Robert et al.²¹	NCT00486759	Breast	Docetaxel, capecitabine, anthracycline	817/403	5	15.6
Bennouna et al.²²	NCT00700102	Colorectal	Fluorouracil, capecitabine, oxaliplatin, irinotecan	401/409	2.5	11.1
Hurwitz et al.²³	NR	Colorectal	Irinotecan, leucovorin, fluorouracil	393/397	2.5	18
Kabbinavar et al.²⁴	NR	Colorectal	Fluorouracil, leucovorin	100/104	2.5	14.8
Cunningham et al.²⁵	NCT00391092	Colorectal	Capecitabine	134/136	2.5	24.8
de Gramont et al.²⁶	NCT00112918	Colorectal	Fluorouracil, leucovorin, oxaliplatin	1145/1126	2.5	48
Saltz et al.²⁷	NCT00434252	Colorectal	Oxaliplatin, fluorouracil, folinic, capecitabine, oxaliplatin	694/675	2.5	27.6
Aghajanian et al.²⁸	NCT00528567	Ovarian	Gemcitabine, carboplatin	242/242	5	24
Pujade-Lauraine et al.²⁹	NCT00434642	Ovarian	Doxorubicin, paclitaxel, topotecan	179/181	5	NR
Herbst et al.³⁰	NCT00943826	NSCLC	Erlotinib	313/13	5	19
Spigel et al.³¹	NR	ESCLC	Cisplatin, carboplatin, etoposide	51/47	5	7.8
Ohtsu et al.³²	NCT00548548	Gastric	Fluoropyrimidine, cisplatin	386/381	2.5	11.4
Chinot et al.³³	NCT00130728	Glioblastoma	Radiotherapy, temozolomide	461/450	5	12.3
Seymour et al.³⁴	NCT00069095	Lymphoma	R-CHOP	395/386	5	23.6
Kim et al.³⁵	NCT00281697	Melanoma	Paclitaxel	143/69	5	13
Ray-Coquard et al.³⁶	NCT01303497	Angiosarcoma	Paclitaxel	25/23	5	21
Van Cutsem et al.³⁷	NCT01214720	Pancreatic	Gemcitabine, erlotinib	296/287	2.5	6.7

NCT: National Clinical Trial; NR: not reported; NSCLC: non–small cell lung cancer; ESCLC: extensive-stage small-cell lung cancer; R-CHOP: rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.

Number of patients for safety analysis.

Incidence and risk ratio of PE

High-grade (or defined as serious) PE occurred in 154 of 8666 participants randomized to the bevacizumab group and 141 of 7792 participants randomized to the control group. The incidence of PE in bevacizumab group was 1.76% (95% CI = 1.25%–2.27%) and 1.74% (95% CI = 1.28%–2.20%) in patients receiving non-bevacizumab regimens (Table 2). Analysis of 23 trials showed that bevacizumab was not associated with increased risk of PE, the pooled RR was 1.00 (95% CI = 0.80–1.25, p = 0.98) with non-significant heterogeneity (I² = 0%; Figure 2).

Table 2.

Relative risk of PE by subgroup.

Subgroup	Studiesn	Bevacizumab arm			Control arm			Risk ratio (95% CI)	p value	I² (%)
Subgroup	Studiesn	Number of events	Number of patients	Incidence (%)	Number of events	Number of patients	Incidence (%)	Risk ratio (95% CI)	p value	I² (%)
Overall	23	154	8666	1.76	141	7792	1.74	1.00 (0.80–1.25)	0.98	0
Dose
2.5 mg/kg/w	8	88	3550	2.62	81	3514	2.41	1.08 (0.80–1.45)	0.62	30.2
5 mg/kg/w	15	66	5116	1.22	60	4278	1.36	0.90 (0.64–1.27)	0.54	0
Published status
Yes	9	49	1877	2.37	57	1839	2.66	0.85 (0.59–1.23)	0.39	0
No	14	105	6789	1.47	141	7792	1.35	1.09 (0.82–1.45)	0.54	2.8
Tumor type
Colorectal	6	67	2867	2.52	51	2847	1.78	1.31 (0.96–1.88)	0.14	23.8
Breast	7	28	3299	0.79	26	2579	0.90	0.74 (0.44–1.27)	0.27	0
NSCLC	1	11	313	3.51	8	313	2.56	1.38 (0.56–3.37)	0.49	NA
ESCLC	1	0	51	0.96	2	47	5.21	0.19 (0.01–3.75)	0.27	NA
Ovarian	2	4	426	0.92	8	414	1.71	3.01 (0.84–10.82)	0.24	0
Pancreatic	1	9	297	3.03	12	286	4.20	0.72 (0.31–1.69)	0.45	NA
Gastric	1	12	386	3.11	18	381	4.72	0.49 (0.15–1.62)	0.25	NA
Angiosarcoma	1	1	25	5.77	0	23	2.08	2.77 (0.12–64.76)	0.53	NA
Glioblastoma	1	13	464	2.80	12	447	2.68	1.04 (0.48–2.26)	0.91	NA
Lymphoma	1	4	395	1.01	4	386	1.04	0.98 (0.25–3.88)	0.97	NA
Melanoma	1	5	143	3.82	0	69	0.71	5.35 (0.30–95.35)	0.25	NA

PE: pulmonary embolism; CI: confidence interval; NSCLC: non–small cell lung cancer; NA: not applicable; ESCLC: extensive-stage small-cell lung cancer.

Figure 2.

Relative risk of PE in cancer patients’ treatment with bevacizumab compared with control.

Subgroup analysis by dose regimen

We conducted a subgroup analysis according to dose and schedule, with the high-dose group receiving 5 mg/kg/week and the low-dose group receiving 2.5 mg/kg/week. The RR of PE for patients who received low dose of bevacizumab compared with control was 1.08 (95% CI = 0.80–1.45, P = 0.62). Similarly, no significant difference was found between patients treated with high dose of bevacizumab and controls (RR = 0.90, 95% CI = 0.64–1.27, p = 0.62; Table 2).

Subgroup analysis by publication status of PE data

We explored whether the publication status may influence the risk of PE. For PE data reported in nine published articles, the pooled RR of PE was 0.85 (95% CI = 0.59–1.23, p = 0.39). For PE data collected from ClinicalTrials.gov, the pooled RR of PE was 1.09 (95% CI = 0.82–1.45, p = 0.54). No statistically significant difference between subgroups was detected (Table 2).

Subgroup analysis by tumor type

In addition, we also performed a subgroup analysis to clarify whether different tumor type would alter the RR of PE associated with bevacizumab. We found that the majority of the evidence is provided by studies in colorectal cancer and breast cancer patients. Although effect sizes and incidences of PE were variable, no statistically significant differences between types of tumor were observed (Table 2).

Publication bias

The Begg’s and Egger’s test did not indicate significant publication bias in the meta-analysis for the risk ratio of PE (Begg’s test p = 0.958; Egger’s test p = 0.946).

Discussion

PE has the potential to lead to a number of physiological changes due to obstruction of the pulmonary arteries and may lead to death. Previous meta-analysis investigated the association between bevacizumab and thromboembolic events, but none of these studies evaluated the incidence and risk of PE associated with bevacizumab. Therefore, we performed the first meta-analysis refering to this clinical issue. Based on 23 RCTs, our results demonstrated that bevacizumab was not associated with an increased risk of PE in cancer patients. Results were consistent across subgroups defined by dose, data of publication status, and type of tumor.

The incidence of PE is usually unclassified due to its low incidence. Instead, the incidence of PE is considered to be included into the categories, such as thromboembolic events or thrombosis events. After reviewing all published articles, only nine trials fulfilled the inclusion criteria and reported PE data were included. Therefore, we also searched ClinicalTrials.gov, and additional 14 trials were included. It should be mentioned that PE was reported as “serious adverse events” or “other adverse events” in the ClinicalTrials.gov and presented as adverse events according to CTCAE criteria in the publications. The definition of serious adverse events may differ from high-grade (grade 3–5) adverse events. Subgroup analysis by publication status of PE suggested that bevacizumab was not associated with an increased risk of PE in cancer patients.

In subgroup analysis by tumor type, there was a trend of increased risk of PE in colorectal cancer patients. These may be because that in patients with colorectal cancer, the effect on survival is the greatest and therefore more additional cycles of chemotherapy was used in these patients. The increased risk of VTE might be associated with the bevacizumab-combination therapy and not with treatment with bevacizumab by itself. Most patients among selected articles received concurrent treatment including different medicines; it has been reported that both 5-fluorouracil and platinum increased risk of VTE in cancer patients.^4,38 Previous study support the hypothesis that these drugs damage the vascular network and endothelium, induce platelet activation, and upregulate prothrombotic factors,³⁹ which may result in thrombus formation.

Given the potentially differing dose intensity of bevacizumab may influence the risk of PE, we conducted a subgroup analysis according to dose and schedule with the high-dose group receiving 5 mg/kg/week vs the low-dose group receiving 2.5 mg/kg/week. Results showed that both high and low dose of bevacizumab were not associated with PE. This was in contrast with the study by Nalluri et al.,⁸ which suggested that the bevacizumab was associated with dose-independent increased risk of VTE. These may be because ATE and VTE were not distinguished in the study by Nalluri et al.,⁸ and it has been confirmed that bevacizumab was associated with ATE.⁷

Our study has several limitations. First, trials included in this study were conducted at various international institutions by different investigators, and patient selection criteria varied between studies. Second, all patients received chemotherapy, which may itself be thrombogenic.^4,38 Thus, whether bevacizumab monotherapy would increase the risk of PE cannot be answered by this meta-analysis. Third, PE and other adverse events are generally reportable only up to 30 days following last treatment date. Therefore, events occurring after 30 days following last treatment would not have been captured, thus creating a bias in the analysis. Finally, an important limitation of this study is the lack of information on cancer burden, smoking history, surgical history, body mass index (BMI), proximity to surgery, and other factors addressed in earlier comments.⁸

In summary, the current analysis suggests that the use of bevacizumab did not increase the risk of PE among patients with cancer. Whether bevacizumab alone is associated with PE would require trials comparing bevacizumab as a single agent to no therapy, which would be infeasible.

Footnotes

Acknowledgements

J.C. and W.Y. designed the article; M.L., Y.Z., and Z.C. wrote the manuscript, searched the library, and reviewed all articles; Y.Q., Z.P., Z.C., and Y.S. extracted data and evaluated the bias. All authors reviewed the manuscript. M.L. and Y.Z. contributed equally to this work.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by the grants from Science and Technology Planning Project of Guangdong Province (No.2016ZC0178) and The Doctoral Scientific Research Foundation of Affiliated Hospital of Guangdong Medical University (No.10301B010012).

References

Heit

JA.

Venous thromboembolism: disease burden, outcomes and risk factors. J Thromb Haemost 2005; 3: 1611–1617.

Blom

Doggen

Osanto

. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005; 293: 715–722.

Aapro

Scherhag

Burger

HU.

Effect of treatment with epoetin-β on survival, tumor progression and thromboembolic events in patients with cancer: an updated meta-analysis of 12 randomized controlled studies including 2301 patients. Br J Cancer 2008; 99: 14–22.

Seng

Liu

Chiu

. Risk of venous thromboembolism in patients with cancer treated with cisplatin: a systematic review and meta-analysis. J Clin Oncol 2012; 30: 4416–4426.

Miroddi

Sterrantino

Simmonds

. Systematic review and meta-analysis of the risk of severe and life-threatening thromboembolism in cancer patients receiving anti-EGFR monoclonal antibodies (cetuximab or panitumumab). Int J Cancer 2016; 139: 2370–2380.

Sørensen

Mellemkjaer

Olsen

. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000; 343: 1846–1850.

Scappaticci

Skillings

Holden

. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 2007; 99: 1232–1239.

Nalluri

Chu

Keresztes

. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA 2008; 300: 2277–2285.

Hurwitz

Saltz

Van Cutsem

. Venous thromboembolic events with chemotherapy plus bevacizumab: a pooled analysis of patients in randomized phase II and III studies. J Clin Oncol 2010; 29: 1757–1764.

10.

Moher

Liberati

Tetzlaff

. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. BMJ 2009; 339: b2535.

11.

Jadad

Moore

Carroll

. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17: 1–12.

12.

Choueiri

Schutz

. Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. J Clin Oncol 2010; 28: 2280–2285.

13.

Higgins

JPT

Green

. Cochrane handbook for systematic reviews of interventions. Chichester and Hoboken, NJ: Wiley-Blackwell, 2008.

14.

Choueiri

Mayer

. Congestive heart failure risk in patients with breast cancer treated with bevacizumab. J Clin Oncol 2011; 29: 632–638.

15.

Coudert

Pierga

Mouret-Reynier

. Use of [(18)F]-FDG PET to predict response to neoadjuvant trastuzumab and docetaxel in patients with HER2-positive breast cancer, and addition of bevacizumab to neoadjuvant trastuzumab and docetaxel in [(18)F]-FDG PET-predicted non-responders (AVATAXHER): an open-label, randomised phase 2 trial. Lancet Oncol 2014; 15: 1493–1502.

16.

Miller

Chap

Holmes

. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005; 23: 792–799.

17.

Von Minckwitz

Puglisi

Cortes

. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol 2014; 15: 1269–1278.

18.

Brufsky

Hurvitz

Perez

. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 2011; 29: 4286–4293.

19.

Cameron

Brown

Dent

. Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol 2013; 14: 933–942.

20.

Gianni

Romieu

Lichinitser

. AVEREL: a randomized phase III Trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol 2013; 31: 1719–1725.

21.

Robert

Diéras

Glaspy

. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol 2011; 29: 1252–1260.

22.

Bennouna

Sastre

Arnold

. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomized phase 3 trial. Lancet Oncol 2013; 14: 29–37.

23.

Hurwitz

Fehrenbacher

Novotny

. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350: 2335–2342.

24.

Kabbinavar

Hurwitz

Fehrenbacher

. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 2005; 23: 3697–3705.

25.

Cunningham

Lang

Marcuello

. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol 2013; 14: 1077–1085.

26.

de Gramont

Van Cutsem

Schmoll

. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol 2012; 13: 1225–1233.

27.

Saltz

Clarke

Díaz-Rubio

. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008; 26: 2013–2019.

28.

Aghajanian

Goff

Nycum

. Final overall survival and safety analysis of OCEANS, a phase 3 trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent ovarian cancer. Gynecol Oncol 2015; 139: 10–16.

29.

Pujade-Lauraine

Hilpert

Weber

. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol 2014; 32: 1302–1308.

30.

Herbst

Ansari

Bustin

. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet 2011; 377: 1846–1854.

31.

Spigel

Townley

Waterhouse

. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer: results from the SALUTE trial. J Clin Oncol 2011; 29: 2215–2222.

32.

Ohtsu

Shah

Van Cutsem

. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol 2011; 29: 3968–3976.

33.

Chinot

Wick

Mason

. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 2014; 370: 709–722.

34.

Seymour

Pfreundschuh

Trnĕný

. R-CHOP with or without bevacizumab in patients with previously untreated diffuse large B-cell lymphoma: final MAIN study outcomes. Haematologica 2014; 99: 1343–1349.

35.

Kim

Sosman

Fruehauf

. BEAM: a randomized phase II study evaluating the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced melanoma. J Clin Oncol 2012; 30: 34–41.

36.

Ray-Coquard

Domont

Tresch-Bruneel

. Paclitaxel given once per week with or without bevacizumab in patients with advanced angiosarcoma: a randomized phase II trial. J Clin Oncol 2015; 33: 2797–2802.

37.

Van Cutsem

Vervenne

Bennouna

. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol 2009; 27: 2231–2237.

38.

Yoshikawa

Yanagi

Noda

. Venous thromboembolism in colorectal cancer patients with central venous catheters for 5-FU infusion-based pharmacokinetic modulating chemotherapy. Oncol Rep 2005; 13: 627–632.

39.

Fotopoulou

duBois

Karavas

. Incidence of venous thromboembolism in patients with ovarian cancer undergoing platinum/paclitaxelcontaining first-line chemotherapy: an exploratory analysis by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group. J Clin Oncol 2008; 26: 2683–2689.