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The Addition of Bevacizumab to Oxaliplatin-Based Chemotherapy: Impact Upon Hepatic Sinusoidal Injury and Thrombocytopenia

Background
Oxaliplatin-based chemotherapy can cause hepatic sinusoidal injury (HSI), portal hypertension, and splenic sequestration of platelets. Evidence suggests that bevacizumab may protect against HSI.


Methods
Two cohorts of metastatic colorectal cancer (CRC) were analyzed: a nonrandomized exploratory cohort of 184 patients treated at a single institution from 2003 to 2010 and a confirmatory cohort of 200 patients from a multi-institutional randomized trial (NO16966). All patients were treated with frontline fluoropyrimidine and oxaliplatin with or without bevacizumab. Changes in splenic volumes and platelet counts were compared by treatment, two-sided log-rank test.


Results
In the exploratory cohort, the bevacizumab-treated patients (n = 138) compared with the nonbevacizumab-treated patients (n = 46) demonstrated a longer median time to splenic enlargement (≥30%, P = .02) and reduced rate of thrombocytopenia (<150 000/mm3, P = .04). In the confirmatory cohort (106 bevacizumab arm and 94 placebo arm), the median time to a spleen enlargement of 30% or more was 7.6 vs 5.4 (P = .01), and six-month cumulative incidence of thrombocytopenia (platelets < 100 000/mm3) was 19% vs 51% (P < .001) for bevacizumab compared with placebo. The development of an increasing spleen size was associated with the risk of either grade 1 or grade 2 thrombocytopenia (P < .001). The cumulative rate of grade 1 or grade 2 thrombocytopenia was statistically less in the bevacizumab arm, with six-month grade 2 thrombocytopenia rates of 4% vs 23% (P < .001). Patients with a large spleen prior to chemotherapy initiation appeared to be at highest risk of this toxicity.


Conclusion
In metastatic CRC, the addition of bevacizumab to oxaliplatin-based chemotherapy reduces the frequency of splenic enlargement and the rate of thrombocytopenia.