Efficacy and Safety of Bevacizumab in Combination with Chemotherapy for Colorectal Cancer – A Real World Study in China


 Background

Large scale randomized trials have demonstrated that bevacizumab in addition to chemotherapy as first-line or second-line treatment has significant survival benefits. We aim to explore the clinical impact of bevacizumab in combination with chemotherapy in first-line or second-line in patients with colorectal cancer (CRC).
Methods

The medical records of patients with CRC who received bevacizumab at first or second-line of treatment were collected retrospectively. The primary outcome of the study was to evaluate the efficacy of bevacizumab in combination with chemotherapy by survival endpoints i.e. overall survival (OS) and progression-free survival (PFS) and the secondary outcome was to evaluate its safety by incidence of adverse events (AE).
Results

Fifty-one patients with CRC had met the selection criteria for treatment with bevacizumab to either cetuximab or FOLFOX or both. The median age was 54 years. During follow-up, ten patients had exhibited progression after treatment while 5 patients died. The median OS and PFS of the overall population were not reached. The Cox proportional regression analysis revealed no significant prognostic factors of OS and PFS for treatment with bevacizumab in various demographic subgroups. The 1-year PFS rates of all 51 patients was 76%. The 1-year and 3-year OS rates for all 51 patients were 95% and 88%, respectively. Toxicities were usually mild in nature, with nausea, vomiting, hand and foot syndrome, neutropenia, asthenia and palpitation being the commonly reported adverse events.
Conclusion

In this real-world setting, the efficacy and safety of bevacizumab in combination with chemotherapy is limited and further research is warranted as to whether bevacizumab with chemotherapy is an optimal treatment as first-line or second-line therapy in Chinese CRC patients.


Results
Fifty-one patients with CRC had met the selection criteria for treatment with bevacizumab to either cetuximab or FOLFOX or both. The median age was 54 years. During follow-up, ten patients had exhibited progression after treatment while 5 patients died. The median OS and PFS of the overall population were not reached. The Cox proportional regression analysis revealed no signi cant prognostic factors of OS and PFS for treatment with bevacizumab in various demographic subgroups. The 1-year PFS rates of all 51 patients was 76%. The 1-year and 3-year OS rates for all 51 patients were 95% and 88%, respectively.
Toxicities were usually mild in nature, with nausea, vomiting, hand and foot syndrome, neutropenia, asthenia and palpitation being the commonly reported adverse events.

Conclusion
In this real-world setting, the e cacy and safety of bevacizumab in combination with chemotherapy is limited and further research is warranted as to whether bevacizumab with chemotherapy is an optimal treatment as rst-line or second-line therapy in Chinese CRC patients.

Background
Colorectal cancer (CRC) represents the third most common cancer worldwide accounting for 1,849,518 (10.2%) of new cases and second most deadly cancer with 880,792 (9.2%) cases across all the age groups in 2018.(1) The 5-year survival rate of CRC is estimated to be 64.4% based on SEER data from 2009-2015. (2) This disease is more commonly observed in men than in women especially among those with African American descent. (2) The rates of CRC was observed to be higher among some regions such as North America, Australia and Europe in contrast to Asia, Africa and South America where lower rates of patients with CRC were reported. (3) The higher rates of CRC in patients could be attributed to "westernized lifestyle" including physical inactivity, obesity, increased alcohol consumption and long term smoking habits.(4) As per World Health Organization (WHO) in 2014, China alone has reported 253,427 new cases of CRC with the mortality rate being 13.2% in the overall population. (5) The treatment options for CRC depends on the stage of cancer at diagnosis and has a strong in uence on the length of survival. (2) The earlier CRC is diagnosed, the better chances a person has of surviving the next ve years. About 38.8% of CRC patients are diagnosed at localized stage.(2) Chemotherapy (CT) is the rst line of treatment usually preferred when tumor lesions do not reach the metastatic stage or are fully resectable. (6) The 5-uorouracil (FU) based chemotherapies increased the overall survival (OS) to 12 months while addition of oxaliplatin and irinotecan to 5-FU increased the OS to 18 months. (7)(8)(9) However, use of chemotherapies is associated with higher toxicity rates such as neutropenia, stomach poisoning disease, hematopoietic disorders.(10, 11) The current therapy for CRC involves chemotherapy based on 5-FU with oxaliplatin and irinotecan and combined with anti-vascular endothelial growth factor (anti-VEGF) (e.g. bevacizumab, a ibercept, ramucirumab) or anti-epidermal growth factor receptor (EGFR) (e.g. cetuximab, panitumumab) targeted therapy. (12) According to the Asian consensus for CRC, most common regimens used in China for CRC include FOLFIRI, mFOLFOX6, XELOX, FOLFOXIRI, bevacizumab or cetuximab combined with raltitrexed or regorafenib. (13) Bevacizumab is a humanized monoclonal antibody (moAb) that can bind to VEGF and is currently the most frequently used anti-VEGF moAb. (14,15) (24,25) Although an increasing number of studies have explored the treatment of bevacizumab in addition to chemotherapy in rst-line and second-line setting, the e cacy of bevacizumab as a treatment option for patients with CRC is unclear due to contrasting results on the survival bene ts. Therefore, data from a real-world study will help the clinicians to gain insight on the effectiveness of this treatment regimen in daily practice across various age groups and clinico-pathophysiological outcomes in patients with CRC. This study was carried out to assess the e cacy and safety of the use of the bevacizumab therapy when added to FOLFOX or cetuximab in CRC patients in rst-line settings.

Study design
This is a retrospective, observational, longitudinal real-world study in a single centre in China. All consecutive patients with CRC treated with bevacizumab either in rst-line or second-line in combination with FOLFOX or cetuximab or their combination between October 2014 and March 2018 were included for the analysis. None of the fty-one patients displayed KRAS mutation while BRAF mutations were unknown in thirty-two patients. Patients who were not treated with bevacizumab either alone or in combination with CT in rst-or second-line settings and those with missing clinical data were excluded from analysis.
The study was approved by Ethics committee of The Third A liated Hospital of Kunming Medical University, Kunming, China (TKMMU-ONC-45378Z) and the study was performed in accordance with the Declaration of Helsinki.

Study Population
The medical records of patients with CRC who received bevacizumab as rst-line or second-line of treatment in combination with chemotherapy was retrospectively collected. The information collected include gender, age at diagnosis, site of disease, American joint committee on cancer (AJCC) staging, body mass index (BMI), site and location of primary tumor, previous therapy (if any), line of current bevacizumab treatment and Eastern cooperative oncology group performance status (ECOG-PS).
Information related to outcomes of interest included date of disease progression as per RECIST 1.1 criteria, date of death and incidence of adverse events. A total of 51 patients with 1-and 3-year survival data were identi ed and included for the analysis.

Study outcomes and endpoints
The primary outcome of the study was to evaluate e cacy of bevacizumab treatment assessed by survival endpoints (OS and PFS) while the secondary outcome was to evaluate safety of bevacizumab assessed by incidence of adverse events (AE). The OS end point was de ned as the time between the date of start of bevacizumab treatment and the date of death from any cause and patients alive or lost to follow-up were censored at the date of last follow-up visit. PFS was de ned as the time between the date of start of bevacizumab treatment and the date of detection of disease progression or death, whichever occurred rst.

Statistical analysis
Quantitative variables were reported as mean and standard deviation while qualitative variables were provided as frequencies and percentages. Kaplan-Meier (KM) curves were constructed for OS and PFS strati ed based on gender, age, AJCC staging, ECOG performance status, line of bevacizumab treatment, treatment combination, site and location of primary tumor and BMI. KM estimator function was used to predict 1-and 3-year survival for OS in different strati ed groups of patients. The survival curves were compared by log-rank test and cox proportional hazards regression analysis was performed for the different clinicopathological factors. Both, univariate and multi variable Cox proportional hazards regression analysis was performed to evaluate the factors predicting survival outcomes. Two-tailed Pvalues, less than 0.05 was considered to be statistically signi cant. All analysis was performed using R software (Version 3.6.1).

Patient Demographics Details
A total of 51 patients from a single center in China received bevacizumab in addition to FOLFOX or cetuximab or both (cetuximab with FOLFOX). Most of the patients were older in age with thirty-one patients aged >50 years and had a median age of 54 years (range: 24-80 years). The median BMI of the   However, the OS were statistically insigni cant when compared between rst-and second-line bevacizumab groups (P < 0.189). This proves that bevacizumab combined with CT will bring survival bene t irrespective of the line of treatment. (32) In general, the clinical outcomes of bevacizumab in our study is good, as the median OS and PFS was not reached for the overall population. However, the cohort is still being followed up for further observations. Age is a major risk factor for the incidence of CRC. CRC is predominantly a disease in older individuals with 90% of cases diagnosed over 50 years.(33) The percentage of deaths due to CRC is highest among people aged 75-84 years (24.3%).(2) Results from pooled analysis of RCTs showed that treatment with bevacizumab and CT added a meaningful bene t in older patients and was comparable with that observed in younger patients.(34) First-line bevacizumab based CTs were effective in patients > 75 years of age, however shorter PFS and OS was observed when compared to younger patients. (35) In our study, the Cox proportional hazard ratios showed that patients aged ≤ 50 years were more responsive to bevacizumab treatment than patients aged > 50 years. However, the current study does not draw any solid conclusion as only 20 patients out of 51 patients were aged ≤ 50 years. However, these data are important as it provides evidence that treatment in elderly patients with CRC is underrated. Further, improvement in PFS and OS due to bevacizumab treatment were found to be independent of gender disparities in another study.(36) Our analysis revealed that males were more responsive to bevacizumab treatment than females in both univariate and multivariate regression analysis, however, results were not statistically signi cant..
A meta-analysis of seven RCTs reported that female gender and rectal primary site were signi cant predictors for PFS bene t.(37) The univariate and multivariate HRs in our study showed that rectal site of disease was associated with a more favourable response on addition of bevacizumab to rst-line CT than colon site of disease. The impact of primary tumour location on bevacizumab plus adjuvant CT in CRC patients remains controversial. It is an important prognostic factor to predict the clinical response of a patient to bevacizumab treatment. Loupakis et al. reported that clinical outcomes of both two-sided  40) Though our study did not report any HRs with respect to OS and PFS, it was observed that for most of the patients, primary side of tumour was located on left side than the right side.
Bevacizumab is generally well-tolerated however is associated with risk of thromboembolic events. (20,41) The other AEs associated with bevacizumab treatment include higher incident rates of hypertension, proteinuria and bleeding. (22,24) No grade IV toxicities were observed in our study. The toxicities majorly observed included grade II nausea, grade I neutropenia, grade I vomiting, grade I hand and foot syndrome which were mild in nature.
The choice of bevacizumab treatment with chemotherapy is dependent on patient comorbidities, preferences around toxicities and practical considerations such as convenience and cost. For patients with good ECOG PS, initial therapy with bevacizumab and combination regimen with FOLFOX, FOLFIRI and XELOX is preferred, while with poor ECOG PS status, uoropyrimidine plus bevacizumab without second cytotoxic agent is recommended. (16) In China, most patients receive bevacizumab at their own expense due to high cost of the drug. In addition, due to concerns over toxicity with chemotherapy, the durations of bevacizumab and chemotherapy exposure may not be adequate. (32) This is the rst study as per our knowledge to analyse the e cacy and safety of bevacizumab in combination to chemotherapy in a real world setting. However, the limitations of the study should be taken into account before drawing a conclusion. Since this study is based on real-world data in Chinese population, the small sample size of patients may introduce bias. Though our study points out the various demographic factors associated on deciding the clinical regimen for patient with CRC, large scale prospective studies are required to establish the e cacy of bevacizumab in clinical practice with respect to various socio-demographic details of patients.

Conclusion
Our study points out the various demographic factors associated on deciding the clinical regimen for patient with CRC. However, further research is warranted as to whether bevacizumab with chemotherapy is an optimal treatment as rst-line or second-line therapy in Chinese CRC patients.