The field of oncology has improved dramatically in the past few years with the advances in molecular biology of different cancers and the introduction of targeted therapies. It has been three decades since Folk man described his observations on the dependence of tumours on the sustained angiogenesis in tumour survival, growth and metastases. There has been a great effort in drug development and therapeutics targeting angiogenesis.

VEGF is a homodimeric heparin binding glycoprotein which has seminal role in angiogenic process. The VEGF family includes six glycoproteins referred as VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, placenta growth factors, PIGF-1 (placenta growth factor) and PIGF-2 [1] . VEGF, unlike other angiogenic factors, is selectively mitogenic for endothelial cells and increase vessel permeability.

VEGF exerts its effects by specific binding to the cell membrane receptors, VEGFR-1, VEGFR-2 or VEGFR- 3. These receptors are tyrosine kinases, having extracellular immunoglobulin like domains, a transmembrane domain and an intracellular tyrosine kinase domain [2] [3] . In addition, neuropilin 1 (NRP-1) and NRP-2 are co-receptors for specific isoforms of VEGF family members and increase binding affinity of these ligands to their respective receptors [4] . Following the binding of ligand, the receptor undergoes transautophosphorylation with subsequent activation of a cell type dependent signaling cascade processes promoting endothelial cell growth, movement, and survival.

Angiogenesis, sprouting of new blood vessels from the existing ones is critically involved in the pathogenesis and metastases of colorectal cancer. Antiangionesis therapy is an established treatment modality for majority of cancers including colorectal cancer. Bevacizumab is a recombinant humanized monoclonal antibody which targets VEGF-A and prevents its binding to VEGFR2. It is approved in the first and second line treatment of metastatic colorectal cancer along with combination chemotherapy. Bevacizumab in combination with chemotherapy improves progression free survival (PFS) and overall survival (OS) in first and second line setting (Hurwitz et al., 2004 [5] ; Kabbinavar et al., 2005 [6] ; Saltz et al. 2008 [7] ).

Hypertension is an on-target and a common side effect of the treatment with bevacizumab. In the pivotal study by Hurwitz et al. [5] , all grades of hypertension was observed in 22.4% of patients in the bevacizumab containing arm compared with 8.3% who received chemotherapy alone. Hypertension as a side effect was consistently demonstrated in phase 11/111 clinical trials of bevacizumab. A meta analysis by Loupakis et al. has shown that the relative risk of colorectal cancer patients treated with bevacizumab developing grade 3/4 hypertension is 4.87, p = 0.0001 [8] .

A number of studies have shown that bevacizumab induced arterial hypertension may correlate with the clinical outcome in colorectal cancer patients [9] . Identification of hypertension as a potential biomarker has increased our understanding of the mechanism of action of anti-angiogenic agents, yet how to implement this knowledge remains uncertain [10] .

Several mechanisms are proposed for bevacizumab induced hypertension. It includes rarefaction, decreased number of small arteries and arterioles, increased vascular resistance due to decreased nitric oxide and prostacyclin production etc. [11] [12] .

The literature search for studies with regard to hypertension in patients on bevacizumab in Indian population reveals that it is sparse and a prospective study in this topic is negligible. The true incidence of bevacizumab induced hypertension and its grading remains unclear due to paucity of prospective studies in this regard. In our institution, majority of metastatic colorectal cancer patients receive bevacizumab along with cytotoxic chemotherapy. In Indian, a context prospective study on this topic is negligible; so we find it to be of high importance.

Since the study is prospective, we are able to monitor the blood pressure systematically and closely which is highly essential. Hence, we expect our study to be more reliable with regard to the incidence and grading of hypertension. Further continuation studies in this set of patients aim to study hypertension and severity as a biomarker for bevacizumab efficacy in this group of patients.

This study was approved by the Institutional Human Ethics Committee and informed consent was obtained from the participants in the study. This was a prospective observational study. Those patients receiving bevacizumab and combination chemotherapy from the institution as per the department protocol & procedures were included in this study. Being an observational study no active intervention was done solely for the purpose of the study. The patients were only observed and data collected. The objective of the study was to assess the incidence of hypertension and the pattern of hypertension.

A total of 30 patients satisfying the inclusion and exclusion criteria were enrolled in the study (Table 1).

The median age of patients was 52 yrs. 23% of patients were hypertensive prior to the study and they were on antihypertensives and majority of them were on calcium channel blocker. 70% of the patients received FOLFOX chemotherapy while 30% received CapeOX. The median number of cycles of bevacizumab was 9 cycles.

100% of patients developed hypertension of any grade and 20% received treatment as a part of newly detected hypertension. Majority of the patients had grade 1 hypertension. Other grade of hypertension was grade 2. None of the patients stopped bevacizumab usage due to uncontrolled hypertension. The changes in systolic and diastolic hypertension in the first week of bevacizumab are shown in Figure 1 and Figure 2 respectively. Changes in both systolic and diastolic BP were more pronounced in already known hypertensives compared to normotensives prior to bevacizumab (Figure 3 and Figure 4).

The blood pressure peaked on 6^th day of bevacizumab administration (Figure 3). The incidence of hypertension was more after two cycles of Bevacizumab (Figure 5 and Figure 6). None of patients showed blood pressure drop after 1 hr of bevacizumab administration while 88% showed increased blood pressure 1 hr after bevacizumab administration.

Hypertension is a common on target side effect of Bevacizumab. In this prospective study 100% of the patient developed any grade of hypertension during the treatment period. But only 20% of patients continued to be

hypertensive and required medications while the remaining 80% had transient hypertension only. The incidence of hypertension in various trials varies between 19% to 67%. Our study reveals more incidence of hypertension. This may be due to the fact that majority of other studies were retrospective and not aimed at serial BP monitoring prospectively. In our study the most common grade of hypertension was grade1 while in other studies also it was grade 1. It was observed that hypertension peaks maximum on 6^th day of bevacizumab administration. As 100% of patients developed any grade of hypertension, risk factors like prior history or family history cannot be assessed. In this study, those patients who developed hypertension were treated as per the standard general guideline with angiotensin converting enzyme inhibitor or calcium channel blockers. Blood pressure was monitored closely on discontinuation of bevacizumab and that the doses of antihypertensive drugs were monitored and reduced as appropriate. The objective response rate and hypertension were not assessed in this study as all patients in this study developed hypertension. Assessment of correlation of different grades of hypertension and survival needs longer follow up. Several studies have shown that there is a positive correlation between hypertension and survival. But there are also conflicting results as to whether hypertension is a marker of clinical efficacy to bevacizumab treatment.

Hypertension of any grade may develop in bevacizumab treated patients. The incidence is very high and it may reach even up to 100% if prospectively and meticulously evaluated for longer period of time. Hence, the important message is that there must be strict monitoring and guidelines of treatment of bevacizumab induced hypertension. It will be better if all patients are provided with BP monitoring chart even after discharge from hospital. This may be helpful in preventing long term effects of hypertension as the incidence is high in this set of patients. Further randomized controlled trials of long term follow up addressing the correlation of treatment response & survival with different grades of hypertension may be of definite benefit in settling the conflict regarding the same.

Funding: Nil.

Conflict of interest: None Declared.

Ethical approval: The study was approved by the Institutional Human Ethics Committee of Government Medical College, Thiruvananthapuram, Kerala, India.

Aravindh S.Anand,Mintu MathewAbraham,JayalekshmiVelayudhan, (2016) Hypertensive Profile of Metastatic Colorectal Carcinoma Patients Treated with Bevacizumab—A Prospective Study. Journal of Cancer Therapy,07,114-120. doi: 10.4236/jct.2016.72013