Abstract
Background: Although the efficacy and safety of combining first-line chemotherapy with bevacizumab in elderly patients with colorectal cancer (CRC) is supported by the results of a phase III trial, real-practice data are limited. Patients and Methods: Our multi-center, community-based observational study included 233 elderly patients with CRC (median age=73 years, range=70-84 years). Baseline comorbidities and geriatric evaluation were also analyzed. Pre-specified end-points of the study were safety, tolerability and outcome results. Results: The incidence of both chemotherapy-induced and specific bevacizumab-related toxicities was low, and not influenced by baseline concurrent morbidities. Median progression free survival (PFS) and median overall survival (OS) were 9.9 months and 23.6 months, respectively. Fifty-six percent of patients received second-line chemotherapy. Conclu sion: The upfront treatment of older patients with CRC with chemotherapy and bevacizumab is safe and efficacious in a real-world setting. No un expected toxi cities were reported. Multi-dimensional geriatric evaluation is under-used in clinical practice.
Colorectal cancer (CRC) incidence and prevalence are rising among senior citizens and epidemiological data suggest that the towering demand for the care of older patients with CRC is likely to increase further (1, 2). Although many elderly cancer patients have concurrent chronic disorders or present with diminished organ functions, impairment of daily vital activities or minor cognitive deficits, a significant proportion of them receive systemic chemotherapy or biological agents (3, 4). Bevacizumab, a humanized vascular endothelial growth factor inhibitor, has proven efficacy when added to systemic chemotherapy in first or subsequent lines of therapy regardless of patient age (5), and one out of three patients receive bevacizumab beyond 65 years of age (6). Nevertheless, specific data regarding its use in the older population are limited and its harm-to-benefit risk is considered challenging (7). A patient's chronologic age does not always reflect their overall health status and older patients are highly heterogeneous because of dissimilar types and grades of concurrent morbidities, thus increasing the difficulty in choosing how to optimally treat the older population. Advanced age is also a common exclusion criterion regarding recruitment into clinical trials, so that elderly patients have been under-represented in CRC studies and the few included, usually comprising fewer than 15% of the whole trial population, are highly selected.
Baseline clinical conditions and comorbidities, and baseline disease characteristics.
Although anti-angiogenic treatment effect does not seem to be influenced by age (8), specific outcome data on the use of bevacizumab in elderly patients derive from retrospective subpopulation analyses of large randomized controlled trials (9), small-sized phase II studies (10-13), non-randomized community-based registries (14-17), or cohort studies (18, 19), and have been summarized elsewhere (20). In all, the available data suggest that medically-fit older patients with CRC may derive the same benefits compared to younger patients, with a similar toxicity profile, except for a significant increase in arterial thrombosis (21). Recently, the randomized phase III AVEX study prospectively enrolled older patients with CRC (median age=76 years, range=70-87 years), showing how the combination of capecitabine and bevacizumab may double the rate of responses (19.3% vs. 10%) and significantly prolong the median progression-free survival [PFS: 9.1 vs. 5.1 months, Hazard Ratio (HR)=0.53] (22). A trend for an advantage in overall survival (OS) was also reported (20.7 vs. 16.8 months, HR=0.79).
Treatments received and disease course.
In this scenario, we decided to carry out real-practice retrospective research to investigate and monitor the use of upfront bevacizumab for older patients among Italian oncologists. The primary aims of our national, community-based, observational study were to survey the safety of the anti-angiogenic treatment use for older patients with CRC in real-world clinical practice, and to report on the efficacy of bevacizumab in those patients.
Patients and Methods
Nine Italian oncological Departments participated in the survey; a large part of the Country was covered since three Departments were located in the north (Udine, Padova, Aviano), three in the center (Pisa, Ancona, Bologna), and three in the south (Potenza, Napoli, Catania) of Italy. The study population included all consecutive patients with CRC aged 70 years or more who received any first-line chemotherapy in the participating oncological Departments between 01/01/2008 and 31/12/2012 to allow a minimum follow-up of 12 months. For each included patient, sociodemographic and clinical information were retrieved from medical charts or electronic medical records with a predefined standardized data collection form. The data were handled in an anonymized format. The information collected included baseline clinical variables such as age, sex, site of primary tumor, number and type of significant comorbidities, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and date of first chemotherapy cycles administered, along with type of combination chemotherapy, safety data regarding generic and specific toxicities, and survival results. Upon delivery, filled forms were reviewed by the study coordinator for the completeness and consistency of the recorded information. Although no formal onsite data monitoring was performed, any omission, error or inconsistent data were checked through telephone contact with the compiling physician and corrected as appropriate. The data were then recorded into an electronic database using an entry form created specifically for this study. For the input of selected variables, a range of allowable values was established. Further quality control of the data included the identification of missing and out-of-range values, tests for logical data relationships, and the generation of output for review. Any inconsistency was investigated by reviewing the recorded data, re-examining the compiled form, or through contact with the Center, and corrected as appropriate. Patients were split into two groups according to the presence of concurrent morbidities. Specifically, the treatment outcomes of patients without significant concurrent morbidities were compared to those of patients with any comorbid condition. The study was conducted according to International Society for Pharmacoepidemiology Guidelines (23), Ethical Guidelines for Epidemiological Studies (24), and International Ethical Guidelines for Biomedical Research Involving Human Subjects (25) and reported according to current guidelines for non-interventional, observational studies (STROBE) (26). Ethical approval was gained from the Scientific Review Board of the coordinating Institution.
Progression-free survival as registered in the entire cohort and in patients with or without baseline comorbid conditions.
Progression-free survival results according to the development or worsening of hypertension.
Statistical analysis: Demographics and medical comorbidities before treatment started were all captured and presented. Predefined endpoints of the study were the safety and tolerability of bevacizumab (toxicities were graded according to Common Terminology Criteria for Adverse Events v.4.03 (CTCAE) whenever possible (27), response rate (according to investigators' clinical decision), PFS (calculated as the time interval from the first bevacizumab infusion to disease progression or death, whichever came first), and OS (calculated as the time inter val between the first bevacizumab infusion and death for any cause). PFS and OS were estimated according to the Kaplan-Meier method and survival curves, with 95% Hall-Weller bands, were generated. The log-rank test was used to compare PFS and OS between patients with and without comorbidities, and between patients with and without hyper tension. Cox regression analysis was used to estimate crude and adjusted hazard ratios (HRs), with 95% confidence intervals (95% CIs). Statistical analysis was performed using SAS© statistical package 9.2 (SAS Institute Inc., Cary, NC, USA).
Median overall survival for the whole cohort, and median overall survival according to baseline concurrent morbidities.
Overall treatment tolerability and incidence of treatment-induced toxicities of grade 2 or more.
Results
Data from 223 patients were entered from nine participating study sites. The median patient age at treatment start was 73 years (range=70-84 years), the PS was 0 or 1 for the large majority of them (92%), and 57% of the patients were male. One hundred and fifty-five patients had primary tumor in the colon, while 68 patients had stage IV rectal cancer. Surgical resection of the primary had been previously performed in 136 patients (61%), 85 of which had received adjuvant chemotherapy after primary tumor resection due to the evidence of stage III disease. As expected, the liver was the most involved organ (65%), followed by the lung (39%) and lymph nodes (31%). Table I presents the main characteristics of the enrolled patients.
Comorbidities at study entry were reported in the majority of patients (76%), concurrent diseases were mainly mild-to-moderate in grade and not clinically significant. The number and types of concurrent morbidities at study entry are also reported in Table I.
Incidence of specific bevacizumab-related toxicities.
Baseline comprehensive geriatric evaluation was obtained for only 46 patients. In all those cases, Activities of Daily Living (ADL) and Instrument Daily Living (IDL) independency scores were high. Molecular information on “Kirsten rat sarcoma viral oncogene homolog 2 (KRAS) and “v-raf murine sarcoma viral oncogene homolog B” (BRAF) status was available for 58% (n=130) and 37% (n=87) of the patients, respectively. In all, a mutation in codon 12 or 13 was reported for 54 out of 130 cases, and a V600E BRAF mutation in seven out of 87 tumors. The vast majority of patients were not tested for other RAS tumor mutations.
In approximately 22% of the cases, capecitabine was prescribed as companion chemotherapy; an oxaliplatin-based regimen was opted for nearly 60% of the patients, the others received bevacizumab combined with an irinotecan-based regimen (Table II). All patients had the anti-angiogenic drug initially administered at the dose of 2.5 mg/kg in 60 to 90 min, followed by 30-min infusions if the drug was well tolerated. With referral to treatment duration, the median number of cycles received was nine; after achieving disease stabilization or response, 76 patients continued on 5-fluorouracil and bevacizumab or bevacizumab alone. No unexpected toxicities were noted and the overall safety profile of the treatment is summarized in Table III. Notably, specific bevacizumab-related side-effects were modest overall (Table IV): in 72 patients (34%) hypertension developed or worsened, 16 patients reported a venous thromboembolism (VTE) (7%) and four patients had arterial thrombosis (2%). Two patients reported myocardial infarction during the treatment course (1%), both of them had risk factors for ischemic cardiovascular disease. Proteinuria was reported in 27 patients (12%); no gastrointestinal perforation was registered.
For the whole cohort of patients, the median PFS was 9.9 months (95% CI=8.8-11.8 months), and PFS results were not influenced by the presence of comorbidities (Figure 1A and B, with marked 95% Hall-Weller bands). The PFS rate at 12 months approached 40% and was 13.5% at 24 months. As reported in Figure 2, no improve in median PFS was noted for patients in whom hypertension developed or worsened compared to those in whom it did not (p=0.41); a similar outcome was also reported regardless of the development of proteinuria (data not shown). The median OS was 23.6 months (95%CI=20.6-29.1 months), as shown in Figure 3A. Again, the presence of comorbidities did not affect survival results (Figure 3B). Interestingly, a 3-month shorter median survival was observed in patients with CRC older than 75 years (n=89) compared to that reported for those aged 70 to 75 years (n=134) (median OS of 21.3 months vs. 24.5 months), although the difference was not statistically significant (p>0.05). Survival outcomes were also similar regardless of KRAS mutational status. After first-line failure, additional treatment for advanced disease was reported for 135 patients (61%), including second-line chemotherapy or treatment with Epidermal growth factor receptor (EGFR) inhibitors. None of the patients included in the analysis received bevacizumab beyond disease progression.
Discussion
The use of anti-angiogenic drugs in patients with advanced CRC is supported by strong scientific evidence, and common bevacizumab-related side-effects have been extensively described. However, due to a disputable risk-to-benefit ratio, the widespread use of angiogenic inhibitors is not universally accepted for elderly patients. Recently, the presentation of the AVEX trial defined the combination of capecitabine and bevacizumab as a possible new standard treatment for this population (22), given the superiority of the combination compared to capecitabine alone. In our study, the upfront combination of bevacizumab with chemotherapy was well-tolerated, and specific anti-angio genic-induced toxi city was limited. Notably, a significant proportion of older patients enrolled in our study (85%) received a doublet che mo therapy with the antiangiogenic drug; moreover, 56% and 22% of patients received second- or third-line therapy, respectively.
The treatment produced a median PFS of approximately 10 months and a median OS of almost two years. However, the median OS was slightly reduced in patients older than 75 years compared to those aged 70 to 75 years (21.3 months vs. 24.5 months). This is in accordance with other studies which reported a shortened OS when analyzing older cohorts (28). Older patients in whom hypertension developed or worsened did not experience longer survival compared to other patients (p=0.05). Indeed, whether the development of hyper tension may predict treatment efficacy is uncertain. While retrospective studies intriguingly suggested this hypothesis (29, 30), a large data review of seven randomized phase III trials showed that the correlation between the vascular side-effect and the clinical outcome was uncertain, since the development of bevacizumab-induced hypertension was inconsistently associated with a more favorable outcome (31).
We recognize that the study has several limitations. Firstly, the statistical design of the study, retrospective in nature, and its limited sample size prevent from drawing definitive conclusions. However, it is worth noting that senior patients are usually underwent-represented in well-designed randomized clinical trials and those who are enrolled, having good PS and no or very few comorbidities, may not correspond to the average elderly population. In our study, older patients were consecutively enrolled and, although selected for good general condition, they appeared to be representative of the average older patient. Secondly, all patients were enrolled from experienced oncologists, working in high-volume urban areas. Whether the same results would be achieved from patients enrolled in the countryside is uncertain. Thirdly, all occurring toxicities were considered and analyzed in a binary form (yes vs. no), but not always graded with standardized criteria. Fourthly, the opportunity to continue on maintenance bevacizumab until disease progression with either chemotherapy or not was based on a uncontrolled clinical judgment. This may have impacted on PFS results. However, data on the optimal maintenance therapy are still being discussed and single-agent bevacizumab may be an acceptable option.
Conclusion
Our community-based observational study highlights the need for real-practice clinical data and confirms that treating older patients with first-line chemotherapy combined with bevacizumab is a safe strategy, regardless of their age or disease RAS status. The overall safety profile and the outcomes did not differ from those expected from other trials. Interestingly, the presence of comorbidities did not negatively impact on survival. Multi-dimensional geriatric evaluation, although simple and reliable, is under-used in clini cal practice. Finally, with a lack of strong predictive factors, rather than further reasoning on how to select patients who would benefit the most, we should better speculate whether there are elderly patients with advanced CRC to whom anti -angiogenic treatment should be offered, and, if so, who they are.
Footnotes
-
Conflicts of Interest
All Authors declare they have no conflict of interest in regard to this study. No writing assistance was utilized in the production of this article.
- Received January 6, 2015.
- Revision received January 31, 2015.
- Accepted February 2, 2015.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
References
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.