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Keywords:

  • hypertension;
  • meta-analysis;
  • vandetanib

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Competing Interests
  8. Funding
  9. References

Aim

To perform a systematic review and meta-analysis of published clinical trials to determine incidence rate and overall risk of hypertension with vandetanib in cancer patients.

Methods

A comprehensive literature search for studies published up to March 2012 was performed. Summary incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials.

Results

A total of 11 trials with 3154 patients were included for the meta-analysis. The summary incidences of all-grade and high-grade hypertension in patients with cancer were 24.2% [95% confidence interval (CI), 18.1–30.2%] and 6.4% (95% CI, 3.3–9.5%), respectively. Subgroup analysis demonstrated that the pooled incidences of all-grade and high-grade hypertension were 21.8% [95% CI, 15–30.5%] and 7.6% (95% CI, 2.8–18.8%), respectively, among non-small-cell lung cancer (NSCLC) patients, and 32.1% (95% CI: 27.3–37.3%) and 8.8% (5.9%–12.9%), respectively, among MTC patients, and 15.4 (95% CI: 3.2–33.7%) and 3.4% (95% CI: 1%–11.1%) respectively, among non-MTC/NSCLC tumors patients. Furthermore, vandetanib was associated with a significant increased risk of all-grade hypertension (RR 5.1, 95% CI: 3.76–6.92, P = 0.000) and high-grade hypertension (RR 8.06, 95% CI: 3.41–19.04, P = 0.000) in comparison with controls.

Conclusions

There is a significant risk of developing hypertension in cancer patients receiving vandetanib. Appropriate monitoring and treatment is strongly recommended to prevent cardiovascular complications.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Competing Interests
  8. Funding
  9. References

Given the heterogeneity of solid tumours and potential crosstalk between key signalling pathways, multitargeted agents represent the next generation of targeted therapies in solid tumours [1], though targeted inhibition of a single signalling pathway, such as the vascular endothelial growth factor receptor (VEGFR) or epidermal growth factor receptor (EGFR) pathway, has been clinically validated in solid tumours, with a number of currently approved drugs such as bevacizumab [2-6], erlotinib [7, 8] and gefitinib [9-11]. Vandetanib is a novel, orally available anticancer agent that inhibits vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR)-dependent signalling [12] as well as rearranged during transfection (RET) tyrosine kinase, which is an important growth driver in certain types of thyroid cancer [13, 14]. Clinical benefits from the administration of vandetanib in unresectable or metastatic medullary thyroid cancer (MTC) and non-small-cell lung cancer (NSCLC) have been observed in clinical trials [15-19]. In April 2011, vandetanib was approved for the treatment of patients with unresectable or metastatic MTC based on a phase III randomized controlled trial demonstrating a 54% reduction in the risk of disease progression [19, 20]. As for previously treated advanced NSCLC patients, our previous systematic review also demonstrated that vandetanib significantly improved progression-free survival [hazard ratio (HR) 0.91, 95% CI 0.83, 1.00, P = 0.039] and overall response rate [risk ration (RR) 1.49, 95% CI 1.04, 2.14, P = 0.03] compared with standard second line treatment, including docetaxel, pemetrexed and erlotinib [21]. Moreover, the efficacy of vandetanib in other malignancies such as metastatic breast cancer, hepatocellular carcinoma, hormone-refractory prostate cancer and metastatic urothelial cancer has been investigated, though the clinical benefit from vandetanib is minimal [22-25].

Although vandetanib is well tolerated in many patients, significant toxicities are associated with its use. Fatigue, diarrhoea, acne, rash, headache, nausea, decreased appetite, abdominal pain and QTc prolongation are the most common adverse events experienced by patients [26, 27]. Additionally, hypertension is a common side effect observed in clinical trials. In the pivotal placebo-controlled phase III trial for advanced MTC [19], 73 of 231 patients treated with vandetanib developed hypertension as compared with five of 99 patients in the control group. As for advanced NSCLC patients, treatment with vandetanib has also been associated with increased occurrence of hypertension, with its incidence ranging from 16–39% [17, 18, 28-31]. However, because of the limited number of patients in each clinical trial, the overall incidence and risk of hypertension with vandetanib is unclear. In addition, monitoring and management of hypertension is very important because poorly controlled hypertension may lead to serious cardiovascular events, dose reduction and life-threatening consequences. Therefore, we conduct this meta-analysis to investigate fully the incidence and relative risk of hypertension among patients administered vandetanib.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Competing Interests
  8. Funding
  9. References

Search strategy

We searched Pubmed (data from 1966 to March 2012), Embase (data from 1980 to March 2012) and the Cochrane Library electronic databases. Keywords included in the search were ‘vandetanib’, ‘ZD6474’, ‘cancer’, ‘randomized’ and ‘hypertension’. The search was restricted to clinical trials and articles published in English. Abstracts presented at the annual meetings of the American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology (ESMO) (from 2001 to March 2012) were also searched manually using the same keywords. Additionally, we searched the clinical trial registration website (http://www.ClinicalTrials.gov) to obtain information on the registered randomized controlled trials (RCTs). We also reviewed the reference lists of the original and review articles to identify relevant studies.

Study selection

Two investigators (QWX and SZ) independently assessed the eligibility of the articles and abstracts identified by the search and discrepancies were resolved by consensus. Since the daily dose of vandetanib approved by the FDA is 300 mg day−1 [19], we assessed the risk of hypertension with vandetanib at this dose to ensure clinical significance. Because of the dosage variations and limited sample sizes in phase I trials, we excluded these trials from the analysis. Only phase II and III clinical trials in which only vandetanib was administered at the defined dose were included. The relevant clinical trials were manually selected carefully based on the following criteria: (i) prospective clinical trails in patients with cancer, (ii) participants assigned to treatment with only vandetanib at a dosage of 300 mg day−1 and (iii) events or event rate and sample size available for hypertension. If multiple publications of the same trial were retrieved or if there was a case mix between publications, only the most recent publication (and the most informative) was included.

Data extraction and quality assessment

Two independent investigators (LF and HAN) reviewed the publications and extracted the data. The following information was extracted from each included article: year of publication, treatment arm, first author's name, number of enrolled patients, number of patients in the treatment and control groups (when available) and adverse outcomes of interest (hypertension). Available information was extracted and recorded onto a data collection form and entered into an electronic database. The quantitative 5-point Jadad scale was used to assess the quality of included trials based on the reporting of the studies' methods and results [33]. A trial with a score of 3 or above was regarded as high quality.

Clinical endpoints

Hypertension was extracted from the safety profile in each trial. These clinical end points were recorded according to versions II or III of the Common Terminology Criteria for Adverse Events (CTCAE) of National Cancer Institute (http://ctep.cancer.gov/reporting/ctc_archive.html) [34]. Both versions describe the grading of hypertension as: grade I, asymptomatic, transient (<24 h) increase of blood pressure by >20 mmHg (diastolic) or to >150/100 mmHg if previously within normal limit (WNL), intervention not indicated, grade II, recurrent or persistent (>24 h) or symptomatic increase by >20 mmHg (diastolic) or to >150/100 mmHg if previously WNL, monotherapy may be indicated, grade III, requiring more than one drug or more intensive therapy than previously and grade IV, hypertensive crisis. We included all incidences of hypertension of grade 1 or above in our analysis.

Data analysis

The analysis was undertaken on an intention-to-treat basis. Patients were analyzed according to treatment allocated, irrespective of whether they received that treatment. The data of the number of patients with all grades and high grades (grade 3 and grade 4) of hypertension and the number of patients receiving vandetanib were extracted from the adverse events outcomes. For each study, we derived the proportion and 95% confidence interval (CI) of patients with hypertension. For studies with a control group in the same trial, we also calculated and compared the relative risk (RR) of hypertension. For one study that reported zero events in the control arm, we applied the classic half-integer correction to calculate the RR and variance [35]. Between study heterogeneity was estimated using the χ2-based Q statistic [36]. Heterogeneity was considered statistically significant when Pheterogeneity < 0.05 or I2 > 50%. If heterogeneity existed, data were analyzed using a random effects model. In the absence of heterogeneity, a fixed effects model was used. To calculate the pooled incidence, an inverse variance statistical method was used. A statistical test with a P value less than 0.05 was considered significant. The presence of publication bias was evaluated by using the Begg and Egger tests [37, 38]. All statistical analyses were performed by using Stata version 12.0 software (Stata Corporation, College Station, Texas, USA) and Comprehensive Meta Analysis program version 2 software (Biostat, Englewood, NJ).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Competing Interests
  8. Funding
  9. References

Search results

A total of 333 potentially relevant studies were retrieved electronically, 323 of which were excluded for the reasons shown in Figure 1. Ten trials of these citations were subsequently included in the review [15, 16, 18, 19, 25, 29, 31, 39-41]. One additional conference abstract was located as a result of hand searching [42]. Finally, a total of 11 trials with 3154 patients were available for the meta-analysis. Eight trials were RCTs with a control arm [15, 18, 19, 25, 29, 31, 40, 42] and three were single arm trials [16, 39, 41]. Characteristics of these eligible trials are given in Table 1. For calculation of the RRs, eight trials were pooled and 1843 patients were assigned to the drug group (vandetanib 300 mg day−1) and 1311 patients were assigned to the control or placebo groups. The quality of each included study was roughly assessed according to the Jadad scale and six trials had Jadad scores of 5, one trial had a Jadad score of 4, two trials had Jadad scores of 3 and two trials had Jadad scores of 2 (Table 1).

figure

Figure 1. Flow chart of trial selection process

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Table 1. Baseline characteristics of the 11 included trials
StudyPhaseUnderlying malignancyTreatment armsNumber of patientsMedian age (years)Female (%)Median PFS (months)Median treatment (months)Number of high grade hypertension eventsJadad score
  1. HCC, hepatocellular carcinoma; MBC, metastatic breast cancer; MTC, medullary thyroid cancer; NA, not available; NR, not reported; NSCLC, non-small cell lung cancer; PC, paclitaxel+carboplatin; SCLC, small cell lung cancer.

Miller, 2005 [39]IIMBCVandetanib 300 mg day−12450.51001.6NR02
Arnold et al. 2007 [40]IISCLCVandetanib 300 mg day−15356.949.12.71.825
   Placebo5462.442.62.83.02 
Heymach et al. 2008 [29]IINSCLCVandetanib 300 mg day−17363332.9NR23
   Placebo +PC5259295.8NR0 
Kiura et al. 2008 [41]IINSCLCVandetanib 300 mg day−1186138.93.1NR33
Natale et al. 2009 [15]IINSCLCVandetanib 300 mg day−18363422.8NR135
   Gefitinib 250 mg day−18561392.0NR1 
Wells et al..2010 [16]IIAdvanced MTCVandetanib 300 mg day−130497027.9 weeks18.832
Leboulleux et al. 2010 [42]IIMTCVandetanib 300 mg day−17263NR11.018.9244
   Placebo73NR5.819.54 
Natale et al. 2011 [18]IIINSCLCVandetanib 300 mg day−16236139NR2.3245
   Erlotinib 150 mg day−16176136NR2.22 
ZETA: Wells et al. 2012 [19]IIIAdvanced/metastatic MTCVandetanib 300 mg day−123150.74230.524735
   Placebo10053.44419.3245 
ZEPHYR:Lee et al. 2012 [31]IIIAdvanced NSCLCVandetanib 300 mg day−1617NANANANR1625
   Placebo307NANANANR9 
Hsu et al. 2012 [25]IIAdvanced HCCVandetanib 300 mg day−119545.31.0539days25
   Placebo2356130.9540days1 

Incidence of hypertension

A total of 3154 patients with MTC, NSCLC, and other malignancies from 10 trials were included for this analysis [16, 18, 25, 29, 31, 39-42]. The incidence of hypertension ranged from 4.2 to 39.6%. The lowest incidence was noted in a phase II single arm trial among patients with metastatic breast cancer (MBC) [39] and the highest incidence was observed in patients with SCLC [40]. The meta-analysis revealed the heterogeneity of the included studies (I2 = 84.5%, P = 0.0066), and all the studies were included for final analysis using the random effects model. The calculated summary incidence of all grade hypertension among patients receiving vandetanib from all these trials was 24.2% (95% CI 18.1, 30.2%, Figure 2).

figure

Figure 2. Forest plot for meta-analysis of incidence of all grade hypertension from ten trials of patients with cancer assigned vandetanib. Weights are from random effects analysis

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Incidence of high grade hypertension

High grade (grade 3 or 4) hypertension was associated with significant morbidity and might result in dose reduction or discontinuation of vandetanib. Eight of the 11 trials reported incidence of high grade hypertension data [15, 16, 18, 19, 29, 39-41], and the incidence of high grade hypertension ranged between 2.0 and 16.7%, with the highest incidence seen in the phase II trial by Kiura et al. in Japanese patients with NSCLC [41] and the lowest incidence observed in patients with MBC [39]. The calculated summary incidence of high-hypertension among 3154 patients was 6.4% (95% CI 3.3, 9.5%, Figure 3) using the random-effects model (I2 = 57.6%, P = 0.021).

figure

Figure 3. Forest plot for meta-analysis of incidence of high grade hypertension from eight trials of patients with cancer assigned vandetanib. Weights are from random effects analysis

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Incidence of hypertension in patients with MTC, NSCLC and non-MTC/NSCLC tumours

In order to explore the relationship between vandetanib-associated hypertension and tumour type, we further analyzed the incidence of hypertension in patients with MTC, NSCLC and non-MTC/NSCLC tumours. Our results showed that the summary all grade and high grade incidences of hypertension in patients with non-MTC/NSCLC tumours were 15.4% (95% CI 3.2, 33.7%, sample size: 96, Table 2) and 3.4% (95% CI 1, 11.1%, sample size 77, Table 2), respectively. The incidence of all grade and high grade hypertension in non-MTC/NSCLC tumours was lower than NSCLC and MTC. Among patients with NSCLC, the pooled incidences of all grade and high grade hypertension was 21.8% (95% CI 15, 30.5%, sample size 1414, Table 2) and 7.6% (2.8–18.8%, sample size 797, Table 2), respectively. Interestingly, the incidence rate of all grade and high grade hypertension in MTC was higher than in NSCLC and non-MTC/NSCLC tumours with a pooled all grade incidence of 32.1% (95% CI 27.3, 37.3%, sample size 333, Table 2) and high grade incidence of 8.8% (95% CI5.9, 12.9%, sample size 261, Table 2). There was a significant difference detected between MTC and NSCLC in terms of the incidence of vandetanib-associated all grade hypertension (RR 1.48, 95% CI 1.23, 1.77, P < 0.0001), but not high grade hypertension (RR 1.15, 95% CI 0.73, 1.82, P = 0.55). Furthermore, vandetanib was associated with a significantly increased risk of all grade hypertension in comparison with non-MTC/NSCLC tumours (RR 2.06, 95% CI 1.26, 3.36, P = 0.004), but not high grade hypertension (RR 2.26, 95% CI 0.70, 7.33, P = 0.17).

Table 2. Incidence and relative risk of hypertension with vandetanib
GroupsIncidence (95% CI)Relative risk (95% CI)
  1. MTC, medullary thyroid cancer; NA, not available; NSCLC, non-small cell lung cancer.

All grade
Overall24.2% (18.1, 30.2)5.10 (3.76, 6.92)
MTC32.1% (27.3, 37.3)4.99 (2.56, 9.74)
NSCLC21.8% (15.0, 30.5)6.15 (4.14, 9.12)
Non-MTC/NSCLC tumours15.4% (3.2, 33.7)2.01 (1.02, 3.94)
High grade
Overall6.4% (3.3, 9.5)8.06 (3.41, 19.04)
MTC8.8% (5.9, 12.9)NA
NSCLC7.6% (2.8, 18.8)10.22 (3.47, 30.11)
Non- MTC/NSCLC tumours3.4% (1, 11.1)NA

Relative risk of hypertension

RR calculated from a randomized controlled trial could be used to determine specifically the contribution of vandetanib to the development of hypertension in these patients with many confounding factors such as underlying malignancy, renal function, and other therapeutic interventions. As a result, a meta-analysis of RR associated with vandetanib in comparison with controls was performed. The relevant clinical trials were manually selected carefully based on the following criteria: (i) prospective clinical trails in patients with cancer, (ii) participants assigned to treatment with only vandetanib at a dosage of 300 mg day−1, (iii) events or event rate and sample size available for hypertension and (iv) the studies have a control group in the same trial. After the selection process, seven [18, 19, 25, 29, 31, 40, 42] and five RCTs [15, 18, 19, 29, 40] were included for calculating RR of all grade and high grade hypertension, respectively. The pooled RR for all grade hypertension showed that treatment of vandetanib significantly increased the risk of developing all grade hypertension in cancer patients with a RR of 5.1 (95% CI 3.76, 6.92, P = 0.000, Figure 4) using a fixed effects model (I2 30.0%, P = 0.199), and similar results were observed in NSCLC (RR 6.15, 95% CI 4.14, 9.12, P = 0.000, Figure 4), MTC (RR 4.99, 95% CI 3.76, 6.92, P = 0.000, Figure 4) and non-MTC/NSCLC tumours (RR 2.01, 95% CI 1.02, 3.94, P = 0.043, Figure 4) based on subgroup analysis. As for high grade hypertension in patients prescribed vandetanib, the combined RR also demonstrated that vandetanib was associated with a significantly increased risk of high grade hypertension among cancer patients (RR 8.06, 95% CI 3.41, 19.04, P = 0.000, Figure 5) using a fixed effects model(I2 = 25.1%, P = 0.254). Subgroup analysis also confirmed that the risk of high grade hypertension increased in NSCLC patients treated with vandetanib (RR 10.22, 95% CI 3.47, 30.1, P = 0.000, Figure 5). Due to only one MTC trial and one SCLC trial included in the subgroup analysis, we could not perform a combined analysis. Thus, on the whole vandetanib was associated with a significantly increased risk of all grade and high grade hypertension when compared with controls in these cancer patients.

figure

Figure 4. Relative risk of vandetanib-associated all grade hypertension vs. control from seven randomized controlled trials of patients with cancer

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figure

Figure 5. Relative risk of vandetanib-associated high grade hypertension vs. control from five randomized controlled trials of patients with cancer

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Publication bias

Begg's funnel plot and Egger's test were performed to assess the publication bias of the literature. The shapes of the funnel plots did not reveal any evidence of obvious asymmetry (P = 0.881 for all grade RR and P = 0.602 for high grade RR, respectively). Then, Egger's test was used to provide statistical evidence of funnel plot symmetry. The results still did not suggest any evidence of publication bias (P = 0.247 for all grade RR and P = 0.077 for high grade RR, respectively).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Competing Interests
  8. Funding
  9. References

Hypertension associated with angiogenesis inhibitors is a common adverse event noted in clinical trials. In addition to vandetanib, several other angiogenesis inhibitors, such as bevacizumab [43-45], sorafenib [46] and sunitinib [47], have also been associated with the development of hypertension. The association of vandetanib with hypertension may be directly related to its inhibitory effect on the VEGF receptor. Possible mechanisms include impaired angiogenesis leading to a decrease in the density of microvessels, endothelial dysfunction associated with a decrease in nitric oxide production and an increase in oxidative stress and changes in neurohormonal factors or the renin-angiotension-aldosterone system [47, 48]. A small study by Veronese et al. showed that the role of neurohormonal factors in sorafenib-induced hypertension may be limited [49]. However, as yet there is a lack of data on the possible mechanism of developing vandetanib-associated hypertension. Studies focusing on this issue are required.

To the best of our knowledge, this is the first meta-analysis to investigate the overall risk of hypertension associated with vandetanib in cancer patients and to find the difference in the incidences between NSCLC, MTC and non-MTC/NSCLC tumours. Our meta-analysis results show that a high incidence of hypertension associated with vandetanib is observed in cancer patients. The majority of hypertension associated with vandetanib is grade I or II and the significance of moderate hypertension in cancer patients treated with vandetanib is less clear. Since cancer patients are surviving longer, improving the quality of life by reducing complications is an important issue. It is accepted that hypertension is an independent risk factor for both renal and cardiovascular events [50, 51]. Therefore, it is important that mild to moderate hypertension induced by vandetanib should be recognized and managed appropriately. Severe hypertension is not infrequent with the use of vandetanib, but the significance of severe hypertension is evident because of its cardiovascular complications.

The risk of hypertension may vary substantially with tumour type. Thus we performed a sub-group analysis based on tumour types. Our results showed that the summary all grade and high grade incidences of hypertension in patients with non-MTC/NSCLC tumours was lower than NSCLC and MTC, while the incidence rate of all grade and high grade hypertension in MTC was higher than other kinds of tumours. The variability in the incidence of all grade and high grade hypertension in the different cancer types may be due to variations in treatment duration. The median treatment period for a non-thyroid malignancy ranges from 1.3 to 3.0 months. However, the median duration of thyroid cancer therapy ranges from 18.8 to 24 months. Further exploratory analyses found that vandetanib was associated with a significantly increased risk of all grade hypertension in comparison with NSCLC and non-MTC/NSCLC tumours. Thus, clinicians and patients need to know that there are different risks for different diseases.

The management of vandetanib-associated hypertension is still under debate. According to the manufacturer package insert for vandetanib, all patients receiving vandetanib should be monitored for hypertension and it should be controlled as appropriate. In cases of severe or persistent hypertension despite the initiation of antihypertensive treatment, dose reduction or interruption may be necessary. If patients with high blood pressure cannot be controlled, vandetanib should not be restarted [27]. In most patients, hypertension can be controlled with standard antihypertensive medications. However, the biological effect of these antihypertensive medications on angiogenesis and its implications should be considered, and need to be fully understood. Both enalapril (an angiotensin-converting enzyme [ACE] inhibitor) and candesartan (an angiotensin II receptor antagonist) can specifically inhibit VEGF induced myocardial angiogenesis in the normal heart [52]. In addition, Wu et al.'s study also confirmed that candesartan could significantly suppress VEGF expression and show an antiangiogenesis effect in a xenograft model of bladder cancer [53]. However, Miura et al. found that nifedipine (a calcium channel blocker) could induce VEGF secretion from coronary smooth muscle cells [54]. As a result, the possibility exists that some antihypertensive medications are more effective in treating anti-VEGF-associated hypertension and have less toxic effects when used in conjunction with vandetanib.

One of the strengths of the present meta-analysis is that we quantitatively identified the incidence of hypertension by using data from trials of patients who had undergone vandetanib therapy for different cancers. Clinical benefits from the administration of vandetanib in MTC and other type of tumours have been observed in clinical trials. As a result, it is worthwhile to devote resources toward a detailed evaluation of its adverse effects because it might be widely used in clinical practice. Besides, a detailed analysis of the adverse effects would be warranted if the information on potential harm appears to be essential for guiding the decisions of clinicians, consumers, and policymakers. Many of the RCTs in our study have extremely few patients so that the data are not reliable for detecting meaningful differences in the incidence of adverse events. However, this meta-analysis combines data from a number of trials and thus has greater statistical reliability. Moreover, no evidence of publication bias has been found, but our meta-analysis is still far from perfect. Some limitations need to be carefully considered when interpreting the results. First, our findings are clearly affected by the limitations of the individual clinical trials included in the analysis [46]. (i) These trials may have underestimated the incidence of vandetanib-associated hypertension because of imperfections of the CTCAE version 2 or 3 for recording adverse events [34]. In both these versions, patients are considered hypertensive only if diastolic pressure is increased by more than 20 mm Hg or blood pressure is greater than 150/100 mm Hg. In our study, this grading criteria would have missed many patients with hypertension according to the standard criteria for the diagnosis of hypertension (140/90 mmHg). (ii) The grading criteria do not clearly differentiate between grade 2 and 3 hypertension, and our findings of high grade hypertension could be affected by the overlap between these two grades. (iii) Baseline hypertension of the patients was not described in the trials included in our meta-analysis, which may have led to an overestimation of the incidence of vandetanib induced hypertension. Second, we only assessed the incidence and risk of hypertension with vandetanib (300 mg day−1) in this study. The risk at other doses or in combination with other anticancer drugs is not evaluated. Thirdly, although our findings show that patients with MTC have a higher incidence of all grade and high grade hypertension, this finding may be limited by the small sample size of MTC patients. Finally, it was not an individual patient data analysis, and therefore, it precludes a more comprehensive analysis, such as adjusting for baseline factors and other differences that exist between the trials from which the data are pooled.

In conclusion, despite the limitations of our meta-analysis, we conclude that vandetanib is associated with a significantly increased risk of developing hypertension. Early detection and effective management of hypertension might allow for safer use of this drug. And further studies will be needed to identify the mechanism of vandetanib-associated hypertension.

W.X.Q., L.N.T. and S.Z. took part in the literature review, data extraction and analysis and writing of the manuscript. A.N.H. and F.L. took part in the literature search, statistical analyses and wrote the first draft of the original manuscript. W.X.Q., D.L.M. and Y.J.S. took part in conceptualization and writing the manuscript. Y.Y. took part in conceptualization, data analysis and interpretation and provided scientific advice. All authors contributed to the revision of the manuscript. The views expressed in this review are the opinions of the authors. All authors had full access to all the data in the study. Q.W.X. and Y.Y. take responsibility for the integrity of the data and the accuracy of the data analysis.

Competing Interests

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Competing Interests
  8. Funding
  9. References

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare Z.S. had support from the National Natural Science Foundation of China (81172105) and Science and Technology Commission of Shanghai (09140902200)for the submitted work, A.N.H. had support from the National Natural Science Foundation of China (81001191) and Science and Technology Commission of Shanghai (10PJ1408300) for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.

Funding

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Competing Interests
  8. Funding
  9. References

The study was supported by grants from the National Natural Science Foundation of China (81001191 and 81172105) and Science and Technology Commission of Shanghai (10PJ1408300 and 09140902200).

The authors thank Professor S.A. Wells for providing eligible adverse data.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Competing Interests
  8. Funding
  9. References
  • 1
    Pennell NA, Lynch TJ Jr. Combined inhibition of the VEGFR and EGFR signaling pathways in the treatment of NSCLC. Oncologist 2009; 14: 399411.
  • 2
    Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, Sovak MA, Yi J, Nycum LR. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 2012; 30: 20392045.
  • 3
    Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van Laethem JL, Verslype C, Scheithauer W, Shang A, Cosaert J, Moore MJ. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol 2009; 27: 22312237.
  • 4
    Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. 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: 42864293.
  • 5
    Kelly WK, Halabi S, Carducci M, George D, Mahoney JF, Stadler WM, Morris M, Kantoff P, Monk JP, Kaplan E, Vogelzang NJ, Small EJ. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol 2012; 30: 15341540.
  • 6
    Saltz L, Badarinath S, Dakhil S, Bienvenu B, Harker WG, Birchfield G, Tokaz LK, Barrera D, Conkling PR, O'Rourke MA, Richards DA, Reidy D, Solit D, Vakiani E, Capanu M, Scales A, Zhan F, Boehm KA, Asmar L, Cohn A. Phase III trial of cetuximab, bevacizumab, and 5-Fluorouracil/Leucovorin vs. FOLFOX-bevacizumab in colorectal cancer. Clin Colorectal Cancer 2012; 11: 101111.
  • 7
    Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, De Rosa F, Milanowski J, Karnicka-Mlodkowski H, Pesek M, Serwatowski P, Ramlau R, Janaskova T, Vansteenkiste J, Strausz J, Manikhas GM, Von Pawel J. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol 2007; 25: 15451552.
  • 8
    Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, Kris MG, Tran HT, Klein P, Li X, Ramies D, Johnson DH, Miller VA. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005; 23: 58925899.
  • 9
    Gaafar RM, Surmont VF, Scagliotti GV, Van Klaveren RJ, Papamichael D, Welch JJ, Hasan B, Torri V, van Meerbeeck JP. A double-blind, randomised, placebo-controlled phase III intergroup study of gefitinib in patients with advanced NSCLC, non-progressing after first line platinum-based chemotherapy (EORTC 08021/ILCP 01/03). Eur J Cancer 2011; 47: 23312340.
  • 10
    Ku GY, Haaland BA, de Lima Lopes G Jr. Gefitinib vs. chemotherapy as first-line therapy in advanced non-small cell lung cancer: meta-analysis of phase III trials. Lung Cancer 2011; 74: 469473.
  • 11
    Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010; 362: 23802388.
  • 12
    Wedge SR, Ogilvie DJ, Dukes M, Kendrew J, Chester R, Jackson JA, Boffey SJ, Valentine PJ, Curwen JO, Musgrove HL, Graham GA, Hughes GD, Thomas AP, Stokes ES, Curry B, Richmond GH, Wadsworth PF, Bigley AL, Hennequin LF. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 2002; 62: 46454655.
  • 13
    Murakumo Y, Jijiwa M, Asai N, Ichihara M, Takahashi M. RET and neuroendocrine tumors. Pituitary 2006; 9: 179192.
  • 14
    Ichihara M, Murakumo Y, Takahashi M. RET and neuroendocrine tumors. Cancer Lett 2004; 204: 197211.
  • 15
    Natale RB, Bodkin D, Govindan R, Sleckman BG, Rizvi NA, Capo A, Germonpre P, Eberhardt WE, Stockman PK, Kennedy SJ, Ranson M. Vandetanib versus gefitinib in patients with advanced non-small-cell lung cancer: results from a two-part, double-blind, randomized phase ii study. J Clin Oncol 2009; 27: 25232529.
  • 16
    Wells SA, Gosnell JE, Gagel RF, Moley J, Pfister D, Sosa JA, Skinner M, Krebs A, Vasselli J, Schlumberger M. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol 2010; 28: 767772.
  • 17
    de Boer RH, Arrieta O, Yang CH, Gottfried M, Chan V, Raats J, de Marinis F, Abratt RP, Wolf J, Blackhall FH, Langmuir P, Milenkova T, Read J, Vansteenkiste JF. Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a randomized, double-blind phase III trial. J Clin Oncol 2011; 29: 10671074.
  • 18
    Natale RB, Thongprasert S, Greco FA, Thomas M, Tsai CM, Sunpaweravong P, Ferry D, Mulatero C, Whorf R, Thompson J, Barlesi F, Langmuir P, Gogov S, Rowbottom JA, Goss GD. Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 2011; 29: 10591066.
  • 19
    Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, Baudin E, Elisei R, Jarzab B, Vasselli JR, Read J, Langmuir P, Ryan AJ, Schlumberger MJ. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 2012; 30: 134141.
  • 20
    Sherman SI. Targeted therapies for thyroid tumors. Mod Pathol 2011; 24: (Suppl 2): S4452.
  • 21
    Qi WX, Tang LN, He AN, Shen Z, Yao Y. The role of vandetanib in the second-line treatment for advanced non-small-cell-lung cancer: a meta-analysis of four randomized controlled trials. Lung 2011; 189: 437443.
  • 22
    Horti J, Widmark A, Stenzl A, Federico MH, Abratt RP, Sanders N, Pover GM, Bodrogi I. A randomized, double-blind, placebo-controlled phase II study of vandetanib plus docetaxel/prednisolone in patients with hormone-refractory prostate cancer. Cancer Biother Radiopharm 2009; 24: 175180.
  • 23
    Boer K, Lang I, Llombart-Cussac A, Andreasson I, Vivanco GL, Sanders N, Pover GM, Murray E. Vandetanib with docetaxel as second-line treatment for advanced breast cancer: a double-blind, placebo-controlled, randomized Phase II study. Invest New Drugs 2012; 30: 681687.
  • 24
    Choueiri TK, Ross RW, Jacobus S, Vaishampayan U, Yu EY, Quinn DI, Hahn NM, Hutson TE, Sonpavde G, Morrissey SC, Buckle GC, Kim WY, Petrylak DP, Ryan CW, Eisenberger MA, Mortazavi A, Bubley GJ, Taplin ME, Rosenberg JE, Kantoff PW. Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J Clin Oncol 2012; 30: 507512.
  • 25
    Hsu C, Yang TS, Huo TI, Hsieh RK, Yu CW, Hwang WS, Hsieh TY, Huang WT, Chao Y, Meng R, Cheng AL. Vandetanib in patients with inoperable hepatocellular carcinoma: a phase II, randomized, double-blind, placebo-controlled study. J Hepatol 2012; 56: 10971103.
  • 26
    Morabito A, Piccirillo MC, Falasconi F, De Feo G, Del Giudice A, Bryce J, Di Maio M, De Maio E, Normanno N, Perrone F. Vandetanib (ZD6474), a dual inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinases: current status and future directions. Oncologist 2009; 14: 378390.
  • 27
    AstraZeneca-vandetanib prescribing information. Available at http://www1.astrazeneca-us.com/pi/vandetanib.pdf (last accessed 8 July 2012).
  • 28
    Heymach JV, Johnson BE, Prager D, Csada E, Roubec J, Pesek M, Spasova I, Belani CP, Bodrogi I, Gadgeel S, Kennedy SJ, Hou J, Herbst RS. Randomized, placebo-controlled phase II study of vandetanib plus docetaxel in previously treated non small-cell lung cancer. J Clin Oncol 2007; 25: 42704277.
  • 29
    Heymach JV, Paz-Ares L, De Braud F, Sebastian M, Stewart DJ, Eberhardt WE, Ranade AA, Cohen G, Trigo JM, Sandler AB, Bonomi PD, Herbst RS, Krebs AD, Vasselli J, Johnson BE. Randomized phase II study of vandetanib alone or with paclitaxel and carboplatin as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol 2008; 26: 54075415.
  • 30
    Herbst RS, Sun Y, Eberhardt WE, Germonpre P, Saijo N, Zhou C, Wang J, Li L, Kabbinavar F, Ichinose Y, Qin S, Zhang L, Biesma B, Heymach JV, Langmuir P, Kennedy SJ, Tada H, Johnson BE. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol 2010; 11: 619626.
  • 31
    Lee JS, Hirsh V, Park K, Qin S, Blajman CR, Perng RP, Chen YM, Emerson L, Langmuir P, Manegold C. Vandetanib Versus placebo in patients with advanced non-small-cell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor: a randomized, double-blind phase III trial (ZEPHYR). J Clin Oncol 2012; 30: 11141121.
  • 32
    Zang J, Wu S, Tang L, Xu X, Bai J, Ding C, Chang Y, Yue L, Kang E, He J. Incidence and risk of QTc interval prolongation among cancer patients treated with vandetanib: a systematic review and meta-analysis. PLoS ONE 2012; 7: e30353.
  • 33
    Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, Tugwell P, Klassen TP. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet 1998; 352: 609613.
  • 34
    NCI, Cancer Therapy Evaluation Program. CTC v 2.0 and common terminology criteria for adverse events criteria V3.0 (CTCAE). 2006. Available at http://ctep.cancer.gov/reporting/ctc.html (last accessed 8 July 2012).
  • 35
    Choueiri TK, Schutz FA, Je Y, Rosenberg JE, Bellmunt J. Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. J Clin Oncol 2010; 28: 22802285.
  • 36
    Zintzaras E, Ioannidis JP. Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol 2005; 28: 123137.
  • 37
    Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985; 27: 335371.
  • 38
    Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50: 10881101.
  • 39
    Miller KD. A multicenter phase II trial of ZD6474, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor, in patients with previously treated metastatic breast cancer. Clin Cancer Res 2005; 11: 33693376.
  • 40
    Arnold AM, Seymour L, Smylie M, Ding K, Ung Y, Findlay B, Lee CW, Djurfeldt M, Whitehead M, Ellis P, Goss G, Chan A, Meharchand J, Alam Y, Gregg R, Butts C, Langmuir P, Shepherd F. Phase II study of vandetanib or placebo in small-cell lung cancer patients after complete or partial response to induction chemotherapy with or without radiation therapy: National Cancer Institute of Canada Clinical Trials Group Study BR.20. J Clin Oncol 2007; 25: 42784284.
  • 41
    Kiura K, Nakagawa K, Shinkai T, Eguchi K, Ohe Y, Yamamoto N, Tsuboi M, Yokota S, Seto T, Jiang H, Nishio K, Saijo N, Fukuoka M. A randomized, double-blind, phase IIa dose-finding study of vandetanib (ZD6474) in Japanese patients with non-small cell lung cancer. J Thorac Oncol 2008; 3: 386393.
  • 42
    Leboulleux SBL, Krause TM, De La Fouchardiere C, Tennvall J, Awada A, Go' mez JM, Tisseron Carrasco A, Licour M, Schlumberger MJ. Vandetanib in locally advanced or metastatic differentiated thyroid cancer (papillary or follicular; DTC): a randomized, double-blind phase II trial. Ann Oncol 2010; 21: viii315. abstr:1008.
  • 43
    Geiger-Gritsch S, Stollenwerk B, Miksad R, Guba B, Wild C, Siebert U. Safety of bevacizumab in patients with advanced cancer: a meta-analysis of randomized controlled trials. Oncologist 2010; 15: 11791191.
  • 44
    An MM, Zou Z, Shen H, Liu P, Chen ML, Cao YB, Jiang YY. Incidence and risk of significantly raised blood pressure in cancer patients treated with bevacizumab: an updated meta-analysis. Eur J Clin Pharmacol 2010; 66: 813821.
  • 45
    Ranpura V, Pulipati B, Chu D, Zhu X, Wu S. Increased risk of high-grade hypertension with bevacizumab in cancer patients: a meta-analysis. Am J Hypertens 2010; 23: 460468.
  • 46
    Wu S, Chen JJ, Kudelka A, Lu J, Zhu X. Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis. Lancet Oncol 2008; 9: 117123.
  • 47
    Zhu X, Stergiopoulos K, Wu S. Risk of hypertension and renal dysfunction with an angiogenesis inhibitor sunitinib: systematic review and meta-analysis. Acta Oncol 2009; 48: 917.
  • 48
    Sica DA. Angiogenesis inhibitors and hypertension: an emerging issue. J Clin Oncol 2006; 24: 13291331.
  • 49
    Veronese ML, Mosenkis A, Flaherty KT, Gallagher M, Stevenson JP, Townsend RR, O'Dwyer PJ. Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol 2006; 24: 13631369.
  • 50
    Kaplan NM, Opie LH. Controversies in hypertension. Lancet 2006; 367: 168176.
  • 51
    Peterson JC, Adler S, Burkart JM, Greene T, Hebert LA, Hunsicker LG, King AJ, Klahr S, Massry SG, Seifter JL. Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med 1995; 123: 754762.
  • 52
    Siddiqui AJ, Mansson-Broberg A, Gustafsson T, Grinnemo KH, Dellgren G, Hao X, Fischer H, Sylven C. Antagonism of the renin-angiotensin system can counteract cardiac angiogenic vascular endothelial growth factor gene therapy and myocardial angiogenesis in the normal heart. Am J Hypertens 2005; 18: 13471352.
  • 53
    Wu J, Wang Q, Guo J, Hu Z, Yin Z, Xu J, Wu X. Characterization of angiotensin II antagonism displayed by Ib, a novel nonpeptide angiotensin AT(1) receptor antagonist. Eur J Pharmacol 2008; 589: 220224.
  • 54
    Miura S, Fujino M, Matsuo Y, Tanigawa H, Saku K. Nifedipine-induced vascular endothelial growth factor secretion from coronary smooth muscle cells promotes endothelial tube formation via the kinase insert domain-containing receptor/fetal liver kinase-1/NO pathway. Hypertens Res 2005; 28: 147153.