The bevacizumab plus oxaliplatin-based chemotherapy regimen is more suitable for metastatic colorectal cancer patients with a history of schistosomiasis

Background: People suffer from schistosomiasis, leading to liver fibrosis, splenomegaly and thrombocytopenia. The effects of bevacizumab plus oxaliplatin or irinotecan-based chemotherapy regimens on platelets are different, but have not been determined. We conducted a retrospective analysis in metastatic colorectal cancer (mCRC) patients evaluating the impact of bevacizumab on platelet, in order to find a more suitable plan for mCRC patients with a history of schistosomiasis. Methods: The medical records of all mCRC patients with a history of schistosomiasis who received FOLFOX or FOLFIRI with or without bevacizumab from September 1, 2017 to June 30, 2019 in Kunshan Hospital were reviewed. Platelet counts and spleen sizes were compared from the first cycle until completion of chemotherapy. Results: Evaluable splenic enlargement and thrombocytopenia results were obtained from 73 Bevacizumab-treated patients and 80 non-bevacizumab treated patients. In patients treated with oxaliplatin, the rates of splenic enlargement (19.5% vs. 66.7%, P =0.01) and thrombocytopenia (31.7% vs. 77.2%, P =0.02) were lower in the bevacizumab-treated cohort than that in the nonbevacizumab cohort. When stratified for irinotecan, there were no statistical differences of frequency of splenic enlargement between the two groups, however, the rates of thrombocytopenia were higher in the bevacizumab-treated cohort than that in the nonbevacizumab cohort (59.4% vs. 8.7%, P =0.01 ). Conclusion: The bevacizumab plus oxaliplatin-based chemotherapy regimen is more suitable for mCRC patients with a history of schistosomiasis, especially for lower platelet count patients. vs. vs. nonbevacizumab cohort) (K/uL). This may be due to schistosomiasis and the resulting liver fibrosis and splenomegaly. So our patients are more likely to encounter thrombocytopenia during chemotherapy which may lead to increased risk of bleeding, greater blood transfusion requirement, treatment delay, chemotherapy dose reduction, or even discontinuation of chemotherapy. Figuring out the effect of chemotherapy drugs on platelet counts is more important for them. This study shows that bevacizumab decreases the rate of thrombocytopenia from oxaliplatin-based chemotherapy, but increases that from irinotecan-based chemotherapy. Bevacizumab decreases the rate of splenic enlargement from oxaliplatin-based chemotherapy, but doesn’t change that from irinotecan-based chemotherapy. We got similar results when we stratified patients with splenic enlargement and shrink. Our study adds evidence of protective effect of bevacizumab on oxaliplatin-induced splenomegaly, which is a surrogate for HSI, and resultant reductions in thrombocytopenia in metastatic colorectal cancer patients. The data suggests that we can get a better understanding of changes in platelet counts by monitoring changes in spleen size during oxaliplatin-based chemotherapy. Additional work is needed to identify patients at greatest risk for oxaliplatin-induced HSI and might derive benefit from bevacizumab with regard to its ability of reducing the rate of thrombocytopenia. This study shows that bevacizumab increases the incidence of thrombocytopenia from irinotecan. Additional work is needed to identify patients at greatest risk for increased rate of thrombocytopenia, for whom dose reduction or regimen adjustment should be considered. With a better understanding of impact of drugs on platelet count, we can now select regimen more suitable for patients here, whose baseline platelet counts are lower and are more likely to encounter thrombocytopenia.


Introduction
There were about 12 million schistosomiasis patients in China in 1950s. [1] Although great achievements have been attained in the control of that, there were still 37,601 schistosomiasis patients in China at the end of 2017. [2] Kunshan city lies in the Yangtze river basin, which is the endemic area of schistosomiasis, [1] people here suffered a lot from schistosomiasis and the resulting hepatic fibrosis, splenomegaly and thrombocytopenia. Their basic platelet counts were low, so the impact of chemotherapy on platelet counts was important for them. If the platelets do not meet the requirements of chemotherapy, the patient's treatment will not be carried out, directly affecting the prognosis.
Oxaliplatin or irinotecan in combination with 5-fluorouracil regimens are back bones of systemic treatment for metastatic or recurrent colorectal cancer patients. Their impacts on thrombocytopenia are different. Angiogenesis represents an attractive therapeutic target for patients with cancer. [3] Bevacizumab (Avastin, Genentech, South San Francisco, CA) is a recombinant humanized immunoglobulin monoclonal antibody that binds and inhibits the biological activity of human vascular endothelial growth factor-A (VEGF-A). [4] Bevacizumab enhances the effect of chemotherapy in colorectal cancer and was approved by FDA for the treatment of metastatic colorectal cancer as the first angiogenesis inhibitor. [5] Its main adverse effects are hypertension, proteinuria, thromboembolic events, wound-healing complications, congestive heart failure and gastrointestinal perforation.[6-11] The impact of bevacizumab to chemotherapy upon thrombocytopenia is unknown, it varied among clinical trials. Many studies reported that bevacizumab was associated with increased risk of all-grade thrombocytopenia. [12,13] It increased the incidence of grade 1 or 2 thrombocytopenia from irinotecan based chemotherapy in patients with metastatic colorectal cancer. [5,14] However, it was reported that bevacizumab could reduce the rate of thrombocytopenia from oxaliplatin based chemotherapy, because of its protective impact upon oxaliplatininduced hepatic sinusoidal injury (HSI). [15][16][17] In order to find a more suitable plan for patients with metastatic colorectal cancer with low platelets, we conducted a retrospective analysis evaluating the impact of bevacizumab on platelet in metastatic colorectal cancer (mCRC) patients.

Data Collection
The baseline data collected consisted of patient demographics, body mass index (BMI) and disease characteristics. From the first cycle until completion of chemotherapy, data were collected on platelet counts, numbers of cycles delivered and spleen sizes. Contrast-enhanced CT studies were performed with a multidetector row-64 CT scanner (Light-Speed, GE Healthcare) using a collimation of 5 mm.

Statistical Analysis
Comparisons between groups were carried out with the Fisher exact test and Wilcoxon rank-sum test. Time-to-event distributions were estimated by the Kaplan-Meier curves, and variable comparison between treatment groups was made using the Log-rank test. The Cox proportional hazards regression model was utilized to characterize associations between patient characteristics and the incidences of splenomegaly and thrombocytopenia. All statistical analyses were performed via Stata 14.0 (StataCorp, College Station, TX). All the statistical tests were two-sided, and P < 0.05 was considered statistically significant.

1.
The baseline characteristics significantly between the two groups as well.

2.
Bevacizumab had impact on the rate of thrombocytopenia from chemotherapy In bevacizumab-treated cohort, the six-month cumulative incidence rates of splenic enlargement of 10% or greater and thrombocytopenia were similar between the oxaliplatin group and irinotecan group. In nonbevacizumab-treated cohort, the incidence rates of splenic enlargement were similar between the two groups while the rates of thrombocytopenia were lower in the irinotecan group (Table2).

Bevacizumab decreased the rate of thrombocytopenia from oxaliplatin
Of the 98 patients treated with oxaliplatin and fluoropyrimidine, 41 received bevacizumab. Of the 55 patients treated with irinotecan and fluoropyrimidine, 32 received bevacizumab. There were no statistical differences between the groups (Table3). The results of analyses were presented in Table4, Figure1A and Figure 1B.
In patients treated with oxaliplatin, the six-month cumulative incidence rates of splenic enlargement of 10% or greater were lower in the bevacizumab-treated cohort than in the nonbevacizumab cohort (19.5% vs. 66.7%, P=0.01) (Fig 2A 2C   2D). There was no splenic enlargement more than 20% in the bevacizumab-treated cohort. The median time to splenic enlargement of 10% or greater in patients treated with oxaliplatin was longer in the bevacizumab cohort, but the difference was not significant (120d (4.0m) vs. 103d (3.4m), P= 0.85). The six-month cumulative incidence rates of thrombocytopenia were lower in the bevacizumab- we found that the six-month cumulative incidence rates of splenic enlargement and thrombocytopenia were lower in the bevacizumab-treated cohort than in the nonbevacizumab cohort. In patients without liver metastasis, we drew similar conclusions. In patients with liver metastasis, the rates were lower in the bevacizumab-treated cohort, while the differences were not significant (26.1% vs. 60.6%, P = 0.14; 43.5% vs. 75.8%, P = 0.27). It may be because of the interference of liver metastasis on the protective effect of bevacizumab on oxaliplatin-induced splenomegaly or the small number of patients involved in this study.
Irinotecan, a synthetic analog of camptothecin, is a topoisomerase I inhibitor. Its dominant hematologic side effect is neutropenia, while thrombocytopenia, when it occurs, is usually mild. It was reported bevacizumab increased the incidence of thrombocytopenia from irinotecan based chemotherapy (5% vs. 0%) in patients with metastatic colorectal cancer, [5,14] however, some other studies showed that the addition of bevacizumab to irinotecan-based chemotherapy did not alter the incidence of thrombocytopenia. [28][29][30] Our study shows that in patients treated with irinotecan, the six-month cumulative incidence rates of thrombocytopenia are much higher in the bevacizumab-treated cohort than in the nonbevacizumab cohort (59.4% vs. 8.7%, P = 0.01). In patients with or without liver metastasis, the rates were both higher in the bevacizumab-treated cohort, while the differences were not    Figure 1 23 A. Cumulative incidences of splenomegaly defined as 10% or greater increase in spleen volum A. Cumulative incidences of splenomegaly defined as 10% or greater increase in spleen volum