Efficacy and safety of bevacizumab in elderly patients with metastatic colorectal cancer: results from the Czech population-based registry

Adult mCRC patients treated with first-line bevacizumab-containing therapy in the Czech Republic were included in the present analysis. In the Czech Republic, the administration of targeted therapy is concentrated to comprehensive cancer centres and these drugs are reimbursed only when administered in one of these centres. The data set was obtained from the Czech population-based, retrospective, observational CORECT registry [16] which contains de-identified data of the Czech mCRC patients treated with targeted therapies including bevacizumab, cetuximab, and panitumumab. The protocol was approved by the independent ethics committee at each participating centre (Ethics Committee (EC) of the Ceske Budejovice Hospital, EC of the Chomutov Hospital, EC of the General University Hospital in Prague, EC of the Jihlava Hospital, EC of the Liberec Regional Hospital, EC of the Masaryk Hospital in Usti nad Labem, EC of the Masaryk Memorial Cancer Institute in Brno, EC of the Na Bulovce Hospital in Prague, EC of the Na Homolce Hospital in Prague, EC of the Novy Jicin Hospital, EC of the Pardubice Regional Hospital, EC of the St. Anne’s University Hospital (UH) in Brno, EC of the Thomayer Hospital in Prague, EC of the Tomas Bata Regional Hospital in Zlin, EC of the UH Brno, EC of the UH Hradec Kralove, EC of the UH in Motol, Prague, EC of the UH Olomouc, EC of the UH Ostrava, EC of the UH Pilsen) and complied with the International Ethical Guidelines for Biomedical Research Involving Human Subjects, Good Clinical Practice guidelines, the Declaration of Helsinki, and local laws. Based on the recent validation using the data of all health care payers in the Czech Republic, the CORECT database includes data of approximately 96% of all mCRC patients treated with targeted therapies in the country. The data are entered into the CORECT database by the clinicians and updated at least twice yearly. The final data cut-off date was 30 September 2012.

Both OS and PFS were considered the primary efficacy measures in the present study. Objective response was assessed using the RECIST criteria. Both OS and PFS were calculated from the start of bevacizumab-containing therapy. Only patients who started bevacizumab and chemotherapy at least six months prior to the data cut-off were included in the present analysis. Such design ensured sufficient follow-up for statistically relevant analyses of the time-to-event endpoints.

Adverse events were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 criteria. The severity of adverse events was classified by the attending medical oncologist as ‘mild to moderate’ corresponding to grade 1 to 2 toxicity or ‘severe’ corresponding to grade 3 to 4 toxicity. Only toxicities considered to be related to the administration of bevacizumab therapy were entered into the database.

In accordance with the World Health Organization, elderly mCRC patients were defined as persons aged ≥65 years. In some studies, however, the cut-off to define elderly population was set at age of 75 years. Therefore, in the present study outcomes were analysed based on the patients’age at the start of bevacizumab therapy in following subgroups: (1) <65 years, (2) 65 to 75 years, and (3) ≥75 years.

Standard descriptive statistics were used to characterise the data. Differences in categorical parameters as well as in the incidence of adverse effects among age categories were assessed using the Pearson chi-square test. Comparisons of continuous variables were based on the Kruskal–Wallis test. The survival was estimated using the Kaplan–Meier method. Log-rank test was used to compare OS and PFS for different subgroups. Multivariable Cox proportional hazards model was used to assess the effect of age on survival in the presence of other potential predictive and prognostic factors. Standard level of significance α = 0.05 was used.

In most patients across all age subgroups (n = 2,439, 76.5%), bevacizumab was administered in combination with oxaliplatin-based chemotherapy backbone regimens including infusional 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) and capecitabine/oxaliplatin (XELOX) (Table 1). However, while the percentage of mCRC patients receiving FOLFOX was approximately identical in all age groups, a trend toward decreased use of XELOX in patients aged ≥75 years was observed. In addition, chemotherapy regimens containing irinotecan were less frequently used in patients aged ≥75 years. On the other hand, fluoropyrimidine monotherapy was more likely to be used as chemotherapy backbone in patients aged ≥75 years, and 17.8% and 14.0% of these patients received a 5-fluororuracil/leucovorin (5-FU/LV) regimen or capecitabine, respectively.

Median PFS was 11.4 months (95% confidence interval [CI] 10.9-11.9 months) for patients aged <65 years, 11.3 months (95% CI 10.5-12.0 months) for patients aged 65 to 75 years, and 11.8 months (95% CI 9.6-14.0 months) for patients ≥75 years (Figure 1). The PFS differences between age categories were not statistically significant (p = 0.94). Median OS was 26.9 months (95% CI 25.3-28.5 months) for patients aged <65 years, 27.5 months (95% CI 25.0-29.9 months) for patients aged 65 to 75 years, and 25.1 months (95% CI 11.3-38.9 months) for patients aged ≥75 years (Figure 2). No statistically significant differences in OS were observed between the age groups (p = 0.73). PFS and OS estimates according to age categories and chemotherapy backbone regimens are presented in Table 2.

In order to adjust for the effect of other potential predictive and prognostic factors that may be associated with age, multivariable Cox model for both PFS and OS was designed (Table 3). Similarly to the univariate analysis, the patient age was not significantly associated with PFS in the multivariable model. When patients <65 years were used as the reference, the hazard ratio (HR) was estimated to be 0.99 (p = 0.88) and 1.01 (p = 0.96) in patients aged 65 to 75 years and patients aged ≥75 years, respectively (Table 3). Variables significantly associated with PFS in the final model included the presence of two and more metastatic sites, synchronous mCRC, and rectal primary.

Similarly, in the multivariable Cox model for OS (Table 3), the patient age was not significantly associated with OS (patients aged 65 to 75 years: HR = 0.98, p = 0.73; patients aged ≥75 years: HR = 1.18, p = 0.24). On the other hand, the number of metastatic sites, the presence of metastatic disease at the diagnosis of CRC, and the site of primary tumour were observed to be the strongest independent predictors of OS. Patients with three and more metastatic sites at the start of bevacizumab therapy were found to have almost two times higher risk of death compared to patients with only one metastatic site, and in patients with two metastatic sites the risk of death was increased by more than 40%. Patients with synchronous metastases had the risk of death increased by 25% compared to patients with metachronous mCRC.

The multivariable Cox models for PFS and OS were also calculated on the subset of patients with available information on performance status (n = 1,821). Similarly to the entire cohort, the patient age was not observed to have significant effect on either PFS or OS (data not shown), whereas the number of metastatic sites and the presence of metastatic disease at diagnosis were confirmed as the strongest prognostic factors with respect to both PFS and OS.

Only bevacizumab-associated toxicity events were reported to the registry. Safety data are summarised in Table 4. As expected, the most common bevacizumab-related adverse events were hypertension and thromboembolic events. Hypertension was reported in 71 patients (3.3%), 34 patients (3.6%), and 10 patients (7.8%) in <65 years, 65 to 75 years, and ≥75 years age group, respectively. Thromboembolic event was reported in 65 (3.1%), 36 (3.9%), and 4 (3.1%) patients aged <65 years, 65 to 75 years, and ≥75 years, respectively. The incidence of both proteinuria and bleeding did not exceed 2.0% in any age group. Gastrointestinal perforation was recorded in 8 patients (5 aged <65 years, 3 aged 65 to 75 years). Severe (i.e. grade ≥ 3) adverse events were rarely observed except for hypertension and thromboembolic events, which were, however, reported in less than 4.0% of patients across all age groups.