Bevacizumab-related Hypertension Research Articles

Clinical risk factors of bevacizumab-related hypertension in patients with metastatic colorectal cancer: a retrospective study.

Bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, is widely used as a first-line treatment for metastatic colorectal cancer (mCRC), with hypertension being a common adverse effect. However, there is limited data on the predisposing factors contributing to bevacizumab-induced blood pressure (BP) elevation. This study aims to identify clinical risk factors associated with bevacizumab-related hypertension in patients with mCRC. This retrospective study included 178 patients treated between January and June 2020. Demographic data and medical histories were extracted from hospital electronic medical records. Among the 178 patients, 54 (30.3%) developed bevacizumab-related hypertension, with a median onset time of 48days. Univariate and multivariate analyses identified pre-existing hypertension [odds ratio (OR), 3.30; 95% confidence interval (CI), 1.56-6.99] and age ≥60years (OR, 2.04; 95% CI, 1.00-4.17) as independent risk factors for bevacizumab-related hypertension. The area under the receiver operating characteristic (ROC) curve was 0.66 (95% CI, 0.57-0.75, P < 0.001). The median overall survival (OS) for the cohort was 30.53months (95% CI, 22.23-38.84). No significant differences in OS were observed between patients with and without bevacizumab-related hypertension (31.13 vs. 27.87months, P = 0.86). Pre-existing hypertension and age ≥60years are significant clinical risk factors for bevacizumab-related hypertension in mCRC patients. Bevacizumab-related hypertension did not affect overall survival. Clinicians should closely monitor BP within the first 2months of bevacizumab treatment in high-risk patients.

Distinct Characteristics and Changes in Liver Function of Patients with Hepatocellular Carcinoma Treated with Atezolizumab Plus Bevacizumab for More Than 1 Year.

Since 2020, atezolizumab plus bevacizumab (Ate/Bev) has been the standard first-line therapy for unresectable hepatocellular carcinoma (HCC), but long-term treatment studies are limited. This study evaluated the clinical characteristics and effects of Ate/Bev for over 1 year. This study included patients with unresectable HCC treated with first-line Ate/Bev between May 2020 and April 2022. Those receiving Ate/Bev for 1 year or more were classified as the long-term treatment group. Of 246 patients, 69 (28.0%) were in the long-term treatment group, which comprised more proportions of intrahepatic tumor burden < 25%, Eastern Cooperative Oncology Group 0, and a lower proportion of portal vein tumor thrombosis than the short-term treatment group. The long-term treatment group had a higher incidence of atezolizumab-related thyroid dysfunction (31.9% vs. 10.7%, p < 0.001; median time to onset [mTTO], 2.8 months), dermatologic toxicity (29.0% vs. 14.7%, p=0.017; mTTO, 3.3 months), bevacizumab-related hypertension (44.9% vs. 22.0%, p=0.001; mTTO, 4.2 months), and proteinuria (69.6% vs. 38.4%, p < 0.001; mTTO, 6.8 months), compared to the short-term treatment group. Regarding liver function in the long-term treatment group, patients initially classified as Child-Pugh class A decreased from 87.0% to 75.4%, and albumin-bilirubin grade 1 decreased from 68.1% to 50.7% after 1 year of treatment. The Ate/Bev long-term treatment group had a lower intrahepatic tumor burden, less portal vein tumor thrombosis, and better performance status and liver function at baseline. Atezolizumab-related immunological adverse events emerged relatively early in treatment compared to the bevacizumab-related. Additionally, some patients demonstrated liver function deterioration during long-term Ate/Bev treatment.

Clinical characteristics of patients with advanced hepatocellular carcinoma who received long-term treatment with atezolizumab and bevacizumab for more than one year.

532 Background: Atezolizumab plus bevacizumab (Ate/Bev) has become the standard of care since 2020 as a first-line systemic therapy for unresectable hepatocellular carcinoma (HCC). However, studies on patients receiving long-term treatment with Ate/Bev are still lacking. In this study, we evaluated the clinical characteristics and impacts on patients receiving Ate/Bev treatment for more than one year. Methods: We prospectively enrolled 246 patients with unresectable HCC who received Ate/Bev treatment at three tertiary cancer centers in Korea between May 2020 and April 2022. Comparative analyses were performed between patients treated with Ate/Bev for more than one year and those treated for less than one year. Additionally, treatment-related adverse events (AEs), and changes in liver function were evaluated. Results: Of the 246 patients, 69 (28.0%) were treated with Ate/Bev for more than one year. The long-term treatment group showed better Eastern Cooperative Oncology Group performance status, liver function, and lower residual hepatic tumor burden at baseline, compared to the group treated for less than one year. Furthermore, the long-term treatment group had a higher incidence of atezolizumab-related thyroid dysfunction (30.4% vs. 10.7%, p ‹ 0.001), dermatologic toxicity (30.4% vs. 14.1%, p = 0.006), and bevacizumab-related hypertension (43.5% vs. 22.6%, p = 0.002) and proteinuria (68.1% vs. 39.0%, p ‹ 0.001), compared to the less than one-year treatment group. The median time to onset of thyroid dysfunction and dermatologic toxicity after Ate/Bev treatment was 2.8 months and 3.3 months, respectively, while the median time to onset of hypertension and proteinuria was 4.2 months and 6.8 months, respectively. In the long-term treatment group, 30 patients (43.5%) showed an increase in Child-Pugh score, 20 (29.0%) had an increase in Child-Pugh grade during Ate/Bev treatment. Conclusions: The Ate/Bev long-term treatment group had better performance status, liver function, and a lower residual hepatic tumor burden at baseline. Atezolizumab-related immunologic adverse events occurred mostly early in the course of treatment, whereas bevacizumab-related adverse events occurred relatively later. In addition, a fraction of patients experienced deterioration of liver function during long-term Ate/Bev treatment.

The Effect of Bevacizumab-Related Hypertension on the Prognosis of Patients with Colorectal Cancer and Non-Small Cell Lung Cancer

The Effect of Bevacizumab-Related Hypertension on the Prognosis of Patients with Colorectal Cancer and Non-Small Cell Lung Cancer

Association between bevacizumab-related hypertension and response to treatment in patients with metastatic colorectal cancer

BackgroundBevacizumab has become standard of care as first-line treatment of metastatic colorectal cancer (mCRC), after proving increased response rates and improvement in survival outcomes. Hypertension (HTN) is a common complication of the treatment with bevacizumab and, owing to its close relation with antiangiogenic mechanism, may represent a clinical biomarker to predict the efficacy of the treatment. The aim of this study was to retrospectively evaluate if HTN grades 2 to 3 were correlated with response to treatment with bevacizumab in first line, as well as with improved progression-free survival (PFS) and overall survival (OS), in a series of patients with mCRC.MethodsRetrospective evaluation of clinical records of patients with histologically proven mCRC, treated with bevacizumab as first-line treatment, between January 2008 and December 2013.Results79 patients were evaluated. 51.9% of patients developed HTN G2-G3 during chemotherapy-bevacizumab treatment. In the group of patients who developed bevacizumab-related HTN, 73.2% showed response to treatment (complete response (CR)+ partial response (PR)) and 97.6% achieved disease control (CR, PR or stable disease) compared to 18.4% of patients with response and 63.2% with disease control in the group that did not (OR 12.08; 95% CI 4.13 to 35.29; p<0.001 responders vs non-responders; OR 20.8; 95% CI 2.56 to 168.91; p 0.005 controlled vs non controlled disease). The median OS was 28 months (22.7–33.3). Significant statistical difference was obtained in PFS between the two groups (p<0.001). In the group that developed bevacizumab-related HTN, the median OS was 33 months (25.7–40.3), and in the group that did not, it was 21 months (16.5–25.5) with no significant statistical difference between the two groups (p 0.114).ConclusionsIn this subset of patients, HTN G2-3 was predictive of response to treatment with bevacizumab and of PFS but not of OS.

Association between bevacizumab-related hypertension and response to treatment in metastatic colorectal cancer patients.

e14636 Background: Almost 20-25% of colorectal cancer (CRC) patients present metastases at the time of diagnosis. Multiple signaling pathways have been implied on the stimulation of tumoral angiogenesis, being the VEGF (vascular endothelial growth factor) pathway among the most important ones. Bevacizumab has become standard of care as first line treatment of metastatic CRC (mCRC), after proving increased response rates and improvement in survival outcomes. Hypertension (HTN) is a common complication of the treatment with bevacizumab and due to its close relation with anti-angiogenic mechanism, may represent a clinical biomarker to predict the efficacy of the treatment. The aim of this study was to retrospectively evaluate if HTN grades 2 to 4 were correlated with response to treatment with bevacizumab in first line, as well as with improved progression free survival (PFS) and overall survival (OS), in a series of mCRC patients. Methods: Retrospective evaluation of clinical records of patients with histol...

Analysis of Early Hypertension and Clinical Outcome With Bevacizumab: Results From Seven Phase III Studies

Hypertension is associated with antivascular endothelial growth factor treatment, but the clinical implications of hypertension are uncertain. To assess the prognostic and predictive value of bevacizumab-related hypertension, a comprehensive analysis of whether hypertension and efficacy outcomes are associated was conducted on seven company-sponsored placebo-controlled phase III studies of bevacizumab. Patient-specific data were available from 6,486 patients with metastatic colorectal, breast, non-small cell lung, pancreatic, and renal cell cancers. Primary hypertension endpoint was a blood pressure (BP) increase of >20 mmHg systolic or >10 mmHg diastolic within the first 60 days of treatment. Additional endpoints included other predefined thresholds of change in BP and severity of hypertension graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events. To analyze the general prognostic importance of an early BP increase, multivariate Cox regression models were used to assess the correlation between BP changes and progression-free (PFS) and overall survival (OS) outcomes in the control groups. To analyze whether early BP increases could predict for benefit from bevacizumab, similar analyses were conducted in the bevacizumab-treated and control groups. In six of seven studies, early BP increase was neither predictive of clinical benefit from bevacizumab nor prognostic for the course of the disease. For study AVF2107g, early increased BP was associated with longer PFS and OS times in the bevacizumab group but shorter OS time in the control group. Early treatment-related BP increases do not predict clinical benefit from bevacizumab based on PFS or OS outcomes. BP increases do not appear to have general prognostic importance for patients with advanced cancer.

Hypertension as a predictive biomarker in bevacizumab treatment for colorectal cancer patients

Bevacizumab treatment is associated with an increased risk of hypertension (HTN), a potential marker for effectiveness. We aimed to assess whether grades 2-3 HTN during bevacizumab treatment was associated with increased overall survival (OS) or progression-free survival (PFS). One hundred and eighty-one patients with metastatic colorectal cancer (CRC), who were treated in our Department from January 2009-February 2011 were included. Bevacizumab was administered jointly with standard first- or second-line chemotherapy protocols. Blood pressure was measured before each treatment. HTN was graded using common toxicity criteria. There were 181 CRC patients. Grades 2-3 HTN developed in 81 patients (44.75 %) but not in 100 patients (55.25 %); no patient developed grades 4-5 HTN. Median follow-up was 15.2 months. HTN was associated with better OS in HTN-positive versus HTN-negative patients (median not reached vs. 36.8 months, p = 0.029) and better PFS (29.9 vs. 17.2 months, p = 0.024, respectively). Bevacizumab-related HTN may represent a biomarker for clinical benefit in metastatic colorectal cancer patients.

Association between bevacizumab-related hypertension and vascular endothelial growth factor (VEGF) gene polymorphisms in Japanese patients with metastatic colorectal cancer

Bevacizumab, a monoclonal antibody that binds to VEGF, has a well-known toxic effect of hypertension. We studied possible associations between bevacizumab-related hypertension and gene polymorphisms to assure safer cancer therapy. We retrospectively studied 60 Japanese patients with metastatic colorectal cancer who had received bevacizumab-based chemotherapy. Genotypes were determined for five well-known functional single-nucleotide polymorphism of the VEGF gene at positions C-2578A, T-1498C, G-1154A, G-634C, and C936T. Hypertension was graded according to CTCAE v4.0 on the basis of home blood pressure. The VEGF-2578 C/C and -1498 T/T genotypes were associated with significantly less hypertension during the first 2 months of bevacizumab-based chemotherapy (p = 0.004, p = 0.025, respectively). During the treatment period as a whole, the VEGF-2578 C/C and 936 C/C genotypes were associated with less hypertension (p = 0.031, p = 0.043, respectively). Preexisting hypertension was not associated with bevacizumab-related hypertension. This study demonstrated a significant relation between a lower incidence of grade 2 or higher bevacizumab-related hypertension and the VEGF-2578 C/C genotype for the entire treatment period in Japanese patients with metastatic colorectal cancer. This genotype might be useful for ensuring safer treatment of patients who receive bevacizumab-based chemotherapy.

O3-069 - Association between Bevacizumab-Related Hypertension and VEGF Gene Polymorphisms in Japanese Colorectal Cancer Patients

ABSTRACT Objective Bevacizumab, a monoclonal antibody that binds to VEGF, has a well-known complication of hypertension. We studied the possible association between bevacizumab-related hypertension and gene polymorphisms links to determine the mechanism of this toxic effect and assure safer cancer therapy. Methods We retrospectively studied 60 Japanese patients with metastatic colorectal cancer who had received bevacizumab containing chemotherapy from November 2007 to December 2011 and agreed to this study. Genotypes were determined for five well-known single nucleotide polymorphism (SNPs) of the VEGF gene at positions C-2578A, T-1498C, G-1154A, G-634C and C936T. SNPs were studied with the use of TaqMan SNP Genotyping Assays. Hypertension was graded by home blood pressure according to CTCAE v4.0. Results The VEGF -2578 C/C, -1498 T/T and -634 C/C polymorphisms were significantly associated with grade 2 or more severe bevacizumab-induced hypertension (P = 0.018, P = 0.035, P = 0.040, respectively). Conclusions The association of the three SNPs with bevacizumab-related hypertension was confirmed. All polymorphisms were related to a decreased risk of developing grade 2 or more severe bevacizumab-induced hypertension. These polymorphisms can possibly be used to confirm safer treatment of patients with bevacizumab containing chemotherapy.

O3-069 - Association between Bevacizumab-Related Hypertension and VEGF Gene Polymorphisms in Japanese Colorectal Cancer Patients

O3-069 - Association between Bevacizumab-Related Hypertension and VEGF Gene Polymorphisms in Japanese Colorectal Cancer Patients

The use of high dose d,l-leucovorin in first-line bevacizumab+mFOLFIRI treatment of patients with metastatic colorectal cancer may enhance the antiangiogenic effect of bevacizumab

The role of d,l-leucovorin (d,l-LV) dose on efficacy and toxicity of first-line bevacizumab+mFOLFIRI or mFOLFIRI treatment has never been investigated in patients with metastatic colorectal cancer. This study was an investigator initiated retrospective observational investigation performed on 450 consecutive patients. The mFOLFIRI regimen consisted of irinotecan (180 mg/m(2)), d,l-LV low (200 mg/m(2)) or high (400 mg/m(2)) dose and bolus 5-fluorouracil (5-FU) (400 mg/m(2)), followed by a 46-h infusion of 5-FU (2400 mg/m(2)). The bevacizumab+mFOLFIRI regimen consisted of bevacizumab (5 mg/kg)+mFOLFIRI. The efficacy (objective response [OR], progression-free [PFS] and overall survival [OS]) and toxicity was evaluated and compared. The use of high versus low dose d,l-LV in bevacizumab+mFOLFIRI regimen improved the OR rate (63 and 38 %, respectively; P = 0.00015), median PFS (13 and 9 months, respectively; P = 0.000005) and median OS (26 and 21 months, respectively; P = 0.0058). The efficacy of mFOLFIRI and the toxicity pattern of both bevacizumab+mFOLFIRI and mFOLFIRI regimens were independent of d,l-LV dose. Beside the d,l-LV dose the bevacizumab-related hypertension was an independent marker of longer survival. The use of high d,l-LV dose in bevacizumab+mFOLFIRI regimen would enhance the antiangiogenic effect of bevacizumab and subsequently the efficacy of treatment without increasing the number of adverse events. These findings need to be further confirmed in a randomized controlled prospective trial.

P-0214 Hypertension as A Predictive Biomarker in Bevacizumab

ABSTRACT Introduction Bevacizumab is an anti-angiogenic antibody, which inhibits VEGF (vascular endothelial growth factor) and thereby reduces blood flow to the tumor. It is used to treat several different cancers. Due to its effect on blood vessels, it causes hypertension (HTN), and it has been proposed that developing HTN during treatment with bevacizumab may be a predictor of efficacy. The aim of our study was to prospectively assess if grade 2-3 HTN during bevacizumab treatment (HTN-pos) was associated with overall survival (OS) or progression free survival (PFS) in bevacizumab treated cancer patients. Methods 218 patients were included, 184 of them had metastatic colorectal cancer, 23 had metastatic breast cancer and 11 had metastatic non-small cell lung cancer. The patients were treated with a bevacizumab-and-chemotherapy regimen. Median follow up was 15.6 months. Blood pressure was measured before each treatment and HTN was graded according to common toxicity criteria (CTC). Results Median OS from first bevacizumab treatment to death was 43.7 months and median PFS from first treatment to progression was 21.5 months. 44.6% of patients developed grade 2 or 3 HTN during bevacizumab treatment (HTN-pos) and 55.4% of patients did not develop grade 2 or 3 HTN during bevacizumab treatment (HTN-neg). No patients developed grade 4 or 5 HTN. HTN was associated with improved median PFS, of 26.7 months (m) in HTN-pos patients vs. 15.5m for HTN-neg patients (p=0.019) and improved median OS which was not reached in HTN-pos patients vs. 36.8m for HTN-neg patients (p=0.034). Improved OS and PFS were also observed for 184 colorectal cancer patients only: Median PFS was 29.9m for HTN-pos patients vs. 17.2m for HTN-neg patients, p=0.024 and median OS was not reached for HTN-pos patients vs. 36.8m for HTN-neg patients, p=0.029. Conclusion Our data suggest that bevacizumab related HTN may represent a biomarker for clinical benefit in metastatic colorectal, and possibly, breast and lung cancer patients receiving bevacizumab treatment.

Impact of SHMT1 polymorphism on the clinical outcome of patients with metastatic colorectal cancer treated with first-line FOLFIRI+bevacizumab

The impact of thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), and serine hydroxymethyltransferase 1 (SHMT1) gene polymorphisms and that of dihydropyrimidine dehydrogenase (DPD) enzyme activity, serum total homocysteine level, and estimated serum creatinine clearance on first-line 5-fluorouracil, leucovorin, irinotecan, and bevacizumab (FOLFIRI+bevacizumab) regimen efficacy in metastatic colorectal cancer patients was investigated. DNA was extracted from peripheral blood mononuclear cells. Genotyping was performed for TYMS 5'UTR variable number tandem repeat, TYMS 3'UTR ins/del, MTHFR C677T, and SHMT1 C1420T polymorphisms. The DPD activity of peripheral blood mononuclear cells was also determined. The univariate and multivariate analyses demonstrated that the SHMT1 1420T allele was associated with better response (P=0.025) and longer progression-free survival (PFS) (P=0.00004) and overall survival (OS) (P=0.034). Grade ≥2 hypertension was also an independent prognostic factor of longer progression-free survival and OS. Bevacizumab-related hypertension might be a predictive marker of treatment efficacy (P=0.0002 for OS) in the case of wild (CC) SHMT1 1420 genotypes only.

Bevacizumab-Induced Hypertension

Bevacizumab, a recombinant humanized monoclonal antibody targeting the vascular endothelial growth factor (VEGF), has been approved in the US as first- and second-line treatment of colorectal cancer and in the first-line treatment of advanced non-small cell lung cancer. The US FDA has also granted approval for the use of bevacizumab for the treatment of patients with metastatic renal cell carcinoma and glioblastoma, and in Europe, it is also approved in metastatic breast cancer in combination with paclitaxel. Bevacizumab is under investigation in the first-line and adjuvant setting of almost all types of solid tumors. However, anti-VEGF therapy is associated with significant toxicity. The incidence of grade 3-4 hypertension differs among the various malignancies in which bevacizumab is administered, possibly because of drug interactions with co-administered chemotherapy drugs. Hypertension appears to be dose dependent, and it is under investigation as a biomarker for VEGF inhibition efficacy. There are three main theories concerning the underlying pathophysiology: (i) the nitric oxide theory; (ii) the renal impairment theory; and (iii) the pre-eclampsia-like theory. The correct evaluation of the levels of hypertension is of critical importance and home blood pressure monitoring seems to be the most effective technique. A baseline assessment and follow-up monitoring of blood pressure is considered necessary for all patients receiving bevacizumab. There are no evidence-based recommendations regarding which antihypertensives are more appropriate for the management of bevacizumab-related hypertension. It has been suggested that the benefits from antihypertensive treatment are largely independent of the drugs used, as long as they adequately lower blood pressure. Randomized prospective studies are necessary to provide data that will be useful for the development of specific guidelines for the management of bevacizumab-related hypertension. In the meantime, treatment of anti-VEGF-induced hypertension should follow current guidelines for diagnosis and management of hypertension in general.

Bevacizumab Related Hypertension and Reversible Posterior Leukoencephalopathy Syndrome in Gynecologic Malignancies: A case Control Study

Background: Bevacizumab is increasingly being used in the treatment of gynecologic malignancies, but has significant side-effects including hypertension and reversible posterior leukoencephalopathy (RPLS), which must be recognized by the gynecologic oncologist. Methods: A 26-month institutional retrospective review of bevacizumab in the treatment of gynecologic malignancies. Patients were grouped according to whether they had bevacizumab-related hypertension (defined as at least a grade one hypertensive toxicity) or not. There were no differences in patient demographics between the groups. Risk factors for developing bevacizumab-related hypertension were assessed using t-tests, Wilcoxon rank sum test and Fisher’s exact test. Results: Our group has treated 45 patients with bevacizumab. Fifteen (33%) patients had a pre-existing diagnosis of hypertension, 12 (80%) of whom had at least one elevated blood pressure during treatment. The 30 (67%) patients who did not have a pre-existing diagnosis of hypertension still had a high incidence of bevacizumab-related elevated blood pressure (14, 47%). The majority of patients (26, 58%) had at least one therapy cycle complicated by hypertension. Patients who experienced bevacizumab-related hypertension were significantly more likely than not to have a history of hypertension (odds ratio of 4.6, 95% CI 1.1-19.6). There was a 4.4% incidence of reversible posterior leukoencephalopathy. Patients with age equal to or greater than 75 years, stage IV disease, and creatinine elevations greater than or equal to 1.4 mg/dL were significantly more likely to develop bevacizumab-related hypertension. Other factors such as numbers of prior chemotherapies, cycles of bevacizumab, BMI, cancer site, and histology were not significantly associated with bevacizumab-related hypertension. Conclusions: Hypertension is a problem for patients on bevacizumab whether or not they have a pre-existing diagnosis. However, those with a history of hypertension were significantly more likely to have bevacizumab-related hypertension.

Correlation between bevacizumab-related hypertension and response in mCRC patients.

3581 Background: Patients (pts) with metastatic colorectal cancer (mCRC) receiving all active drugs (irinotecan, oxaliplatin, fluorouracil) achieve the best outcome. Bevacizumab (Bev) increases progression-free (PFS) and overall survival when added to chemotherapy (ChT). Arterial hypertension (aHT) has been reported in all trials involving Bev. We hypothesized that Bev-induced aHT may be a potential predictive marker of response to treatment with ChT + Bev, and retrospectively analyzed the modifications of arterial blood pressure according to response rate and PFS. Methods: Pts with histologically proven, mCRC receiving Bev in combination with Cht as first-line treatment were eligible. Arterial blood pressure was measured before each Bev administration and daily between subsequent cycles. Pts were re-staged every 8 weeks, according to RECIST criteria. Results: 53 pts were considered for the present analysis: 33 M and 20 F; median age was 59 years (range 34-78). Forty pts (75.5%) were affected by metastasis from colon cancer, 13 pts (24.5%) from rectal cancer. Twenty-eight pts had liver metastasis, 7 pts lung metastasis, 7 pts had metastasis at liver and lung. The remaining 11 pts had metastasis at peritoneum, nodes, bone or brain. Fifty pts had undergone surgery on primary tumor (38 colon; 12 rectal), and 18 pts had been treated with adjuvant ChT. First-line ChT regimens were: FOLFIRI (47 pts), XELOX (4 pts), XELIRI (2 pts). Thirteen pts were affected by pharmacologically controlled aHT. Nine pts (17%) developed G2-G3 aHT during the administration of ChT + Bev. After starting adequate anti-hypertensive therapy, they continued Bev until disease progression. All pts were evaluable for response: 15 (28.3%) had complete (3) or partial (12) response. Among pts with induced-aHT, 77.8% achieved a complete or partial response, as compared with 34.1% of pts who did not have aHT (p = 0.01). Median PFS in the whole population was 9.9 months (range 7-12.7). A statistically significant improvement in median PFS was recorded for pts with induced-aHT (18.7 vs 8.5 months; p = 0.02). Conclusions: Our data suggest that Bev-related aHT may represent a predictive factor of response and prolonged PFS in pts with mCRC receiving first-line Bev. No significant financial relationships to disclose.

Bevacizumab-related hypertension: Search for underlying mechanisms

e14520 Background: Hypertension is a commonly observed side effect of inhibitors of VEGF/VEGFR-2 signaling such as bevacizumab. The mechanisms leading to this increase in blood pressure during anti-angiogenic therapy have not been elucidated. Recent studies suggest that functional rarefaction (a decrease in perfused microvessels) or anatomic rarefaction (a reduction in capillary density) may play an important role. The purpose of this study was to search for possible mechanisms that cause hypertension in patients treated with anti-angiogenic therapy and to confirm our hypothesis that systemic inhibition of VEGF inhibits vascular function and causes rarefaction. Methods: Patients treated with bevacizumab for any type of cancer were eligible. Measurements of blood pressure, flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NMD), aortic pulse wave velocity (PWV), and capillary density and diameter with sidestream dark field (SDF) imaging of the mucosal microcirculation of the lip were performed at baseline, after 6 weeks of treatment, and 3 months after discontinuation of bevacizumab treatment. Results: Fourteen patients were included in this study. During bevacizumab treatment the mean systolic and diastolic blood pressure values increased, +3.4 mmHg (p=0.406), and +5.6 mmHg (p=0.023) resp. Mean FMD showed a statistically significant decrease of -3.1% (p=0.006). Mean NMD was unchanged. After 6 weeks treatment mean PWV increased significantly +0.7 m/s (p=0.0.027). A significant reduction in capillary density was seen from 18.0 capillary loops per image at baseline to 12.7 after 6 weeks (p=0.000007). Also a significant reduction in capillary diameter was seen, from 6.9 to 5.6 μm (p=0.002). Results after discontinuation of bevacizumab treatment were not yet available. Conclusions: Rarefaction (reduction in capillary density) and endothelial dysfunction observed in this study provide a plausible mechanism for the increase in blood pressure which results from treatment with bevacizumab. No significant financial relationships to disclose.

From Theoretical Synergy to Clinical Supra-Additive Toxicity

From Theoretical Synergy to Clinical Supra-Additive Toxicity

Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab

Arterial hypertension occurring during antiangiogenic therapy has been correlated with the biological inhibition of the vascular endothelial growth factor-related pathway and may represent a possible clinical marker for treatment efficacy. The aim of our study was to retrospectively assess if grades 2-3 hypertension were associated with response to bevacizumab, progression-free survival (PFS) and survival in metastatic colorectal cancer patients treated with first-line bevacizumab. Patients with histologically proven, metastatic colorectal cancer receiving bevacizumab as first-line therapy in combination with irinotecan and 5-fluorouracil were eligible for our analysis. Thirty-nine metastatic colorectal cancer patients were eligible. Eight patients (20%) developed grades 2-3 hypertension. A partial remission was observed in six of eight cases with bevacizumab-related hypertension (75%) and in 10 of 31 (32%) patients with no hypertension (P = 0.04). Median PFS was 14.5 months for patients showing bevacizumab-related hypertension, while it was 3.1 months in those without hypertension (P = 0.04). Median overall survival was not reached in patients with hypertension while it was 15.1 months in the remaining cases (P = 0.11). Our data indicate that bevacizumab-induced hypertension may represent an interesting prognostic factor for clinical outcome in advanced colorectal cancer patients receiving first-line bevacizumab.